Special Issues – Page 2

Investigator and Health Systems Insights on Real-World Evidence Associated With a First-Generation BTK Inhibitor in Patients With CLL/SLL

May 3, 2022May 3, 2022 RR

Written by: AJMC® Editorial Staff

Content Sponsored by: BeiGene

Adults experience chronic lymphocytic leukemia (CLL) at a greater rate than they do any other type of leukemia.¹ In 2014, ibrutinib became the first Bruton tyrosine kinase (BTK) inhibitor approved by the FDA for the treatment of CLL.^2,3 In a 3-year safety study of patients with CLL/small lymphocytic lymphoma (SLL) taking a daily dose of this first-generation medication, ibrutinib was shown to have both a high response rate that increased in quality and frequency over time and modest toxicity.⁴

However, treatment with ibrutinib has been shown to be associated with adverse events (AEs) that can lead to discontinuation and/or down-dosing.^5,6 In particular, atrial fibrillation (AF) is a known AE associated with BTK inhibitor treatment that has been reported in clinical trials.^7,8

To determine the economic burden of down-dosing and therapy discontinuation due to AEs after initiation of ibrutinib therapy in patients with CLL/SLL, a team from Milliman, Inc, analyzed 2015 to 2019 data from a proprietary Medicare Advantage claims database that contains annual enrollment information and all Parts A, B, and D claims for approximately 2.5 million annual members.⁹ Investigators identified patients who developed AF within the first 12 months of starting treatment with ibrutinib. The results of this claims-based analysis were presented during a Science & Innovation Theater presented during the Academy of Managed Care Pharmacy Nexus 2021, held from October 18 to 21, 2021, in Denver, Colorado.⁹

In the group identified for analysis, investigators examined rates of and average time to discontinuation, down-dosing, and AEs as well as total health care costs accumulated during the 12 months following ibrutinib start.⁹ Using these key metrics, investigators then compared patients who newly experienced AF (new AF) during this 12-month episode period with those who did not experience new AF during this period. The results of the analysis showed that patients with claims for new AF discontinued ibrutinib at more than twice the rate of patients without claims for new AF and had significantly higher health care utilization.⁹ These results are explored in detail in a review article, “Real-World Evidence Associated with a First-Generation BTK Inhibitor in Patients With CLL/SLL,” published by The American Journal of Managed Care® (AJMC®) on ajmc.com. In an interview following the review, principal investigator and health care consultant from Milliman, Inc, Kathryn Fitch, RN, MEd, discusses the study’s findings regarding treatment patterns among patients who developed new AF after starting ibrutinib, the costs associated with the development of new AF, and her team’s recent research in this field. In a final interview, Michael Kolodziej, MD, FACP, medical oncologist and Senior Advisor at ADVI Health, LLC, discussed the analysis and its potential implications for managed care.

REFERENCES

1. The American Cancer Society Medical and Editorial Content Team. What is chronic lymphocytic leukemia? American Cancer Society. Updated May 10, 2018. January 13, 2022. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html

2. Chronic lymphocytic leukemia/small lymphocytic lymphoma: FDA updates. Lymphoma Research Foundation. Updated April 21, 2020. Accessed January 13, 2022. https://lymphoma.org/aboutlymphoma/cll/cllfdaupdates/

3. Center for Drug Evaluation and Research. Approval package for application number 205552Orig2s000. Trade name: Imbruvica. United States Food and Drug Administration. February 12, 2014. Accessed January 13, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000Approv.pdf

4. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506. doi:10.1182/blood-2014-10-606038

5. Imbruvica. Prescribing information. Janssen Biotech; 2020. Accessed January 13, 2022. https://www.imbruvica.com/files/prescribing-information.pdf

6. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879. doi:10.3324/haematol.2017.182907

7. Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796-1805. doi:10.3324/haematol.2017.171041

8. Caldeira D, Alves D, Costa J, Ferreira JJ, Pinto FJ. Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis. PLoS One. 2019;14(2):e0211228. doi:10.1371/journal.pone.0211228

9. Fitch KV. Assessing the treatment emergent burden in BTKi therapy: a Medicare analysis in CLL (chronic lymphocytic leukemia). Presented at the Academy of Managed Care Pharmacy Nexus 2021; October 20, 2021; Denver, CO. Accessed January 18, 2022. https://2021.amcpnexus.org/program/science-innovation-theaters

OPDIVO® (nivolumab) + chemotherapy (fluoropyrimidine + platinum-based) for the first-line (1L) treatment of metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma, regardless of PD-L1 status

April 19, 2022April 19, 2022 RR

BMS Sponsored Content

By Dr Rahul Ravilla│Sponsored by Bristol Myers Squibb
Dr Ravilla is a paid consultant for BMS and was compensated for his contribution in drafting this content.

Introduction: Overview of gastroesophageal cancers

Gastroesophageal cancers consist of a group of heterogeneous tumors, including gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal cancer (EC).¹The majority of GC and GEJC are adenocarcinomas, while EC is categorized into 2 main histological subtypes: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC).^2,3 EAC is the predominant histology in the United States, contributing to ~62% of all EC cases.^3,4EAC incidence rates have been increasing over the past 5 decades in Western countries.⁴Recent trends in the United States also suggest increasing incidence rates of GC overall in young adults (<50 years old).⁵

Gastric and esophageal cancers can be aggressive diseases with 5-year relative survival rates of <6% in the metastatic setting in the United States.^7,8 Worldwide, GC and EC represent the fourth and sixth most common causes of cancer-related deaths, respectively.⁵

Approximately 15%–20% of gastroesophageal adenocarcinomas overexpress human epidermal growth factor receptor 2 (HER2)⁹. In this article, we will focus on HER2-negative gastroesophageal adenocarcinomas. Historically, chemotherapy has been the standard of care for the 1L treatment in this setting.¹⁰ In 2021,chemoimmunotherapy combinations were approved for appropriate patients with certain types of gastroesophageal cancers.^11,12

OPDIVO + chemotherapy in 1L metastatic GC/GEJC/EAC

Currently, OPDIVO + fluoropyrimidine- and platinum-containing chemotherapy (chemo) is the only 1L chemoimmunotherapy regimen approved in metastatic non-HER2+ GC, GEJC, and EAC regardless of PD-L1 (programmed death ligand 1) status.^11,13,14 The combination was approved based on the results of Checkmate 649, a global phase 3 study in 1L metastatic GC/GEJC/EAC patients with ECOG performance status 0-1.^11,13 Key exclusion criteria included known HER2+ status and untreated CNS metastases.¹¹ The study recruited all eligible patients regardless of PD-L1 expression.^11,13

Checkmate 649 enrolled 1581 patients randomized 1:1 to OPDIVO + chemo (n=789) or chemo alone (n=792). A total of 473 patients in the OPDIVO + chemo arm and 482 patients in the chemo arm had tumors that expressed PD-L1 combined positive score (CPS) ≥5. The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) in PD-L1 CPS ≥5. Key secondary endpoints included OS in PD-L1 CPS ≥1, OS in all randomized patients, and objective response rate (ORR) in all randomized patients. Checkmate 649 evaluated OPDIVO (10 mg/mL) injection for intravenous (IV) use (q2w or q3w) in combination with physician’s choice of either fluorouracil + oxaliplatin + leucovorin (mFOLFOX6) given q2w or capecitabine + oxaliplatin (CapeOx) given q3w. OPDIVO dosing was aligned with chemotherapy schedule. Treatment continued until disease progression, unacceptable toxicity, or up to 2 years. Baseline characteristics were consistent between all randomized and PD-L1 CPS ≥5 patients.¹³

There are Warnings and Precautions associated with OPDIVO to keep in mind. These include severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity, and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.¹¹ Additional information related to Warnings and Precautions can be found in the Important Safety Information below.

In the primary analysis (minimum[min] follow-up of 12.1 months[mos]), OPDIVO + chemo demonstrated superior OS in all randomized, PD-L1 CPS ≥1, and PD-L1 CPS ≥5 patients as compared to chemotherapy alone. In all randomized patients, mOS was 13.8 mos (95% confidence interval [CI]: 12.6–14.6) with OPDIVO + chemo vs 11.6 mos (95% CI: 10.9–12.5) with chemo (HR=0.80;95% CI: 0.71–0.90; P=0.0002). In PD-L1 CPS≥1 (n=1296), mOS was 14.0 mos (95% CI: 12.6–15.0) with OPDIVO + chemo vs 11.3 mos (95% CI: 10.6–12.3) with chemo (HR=0.77; 95% CI: 0.68–0.88; P<0.0001). In PD-L1 CPS≥5 (n=955), mOS was 14.4 mos (95% CI: 13.1–16.2) with OPDIVO + chemo vs 11.1 mos (95% CI: 10.0–12.1) with chemo (HR=0.71; 95% CI: 0.61–0.83; P<0.0001).¹¹The dual primary endpoint, mPFS in CPS ≥5 patients, was 7.7 mos (95% CI: 7.0–9.2) with OPDIVO + chemo vs 6.0 mos (95% CI: 5.6–6.9) with chemo (HR=0.68; 95% CI: 0.58–0.79; P<0.0001).

*FOLFOX or CapeOx.¹¹†Assessed using blinded independent central review (BICR).¹¹ ‡Based on confirmed response.¹¹§Secondary endpoint.¹³

Exploratory OS analyses were reported for the primary (min follow-up 12.1 months) and follow-up (min follow-up 24 months) analysis. The 12-month OS rate in all randomized patients was 55% with OPDIVO + chemo vs 48% with chemo.¹³The follow-up analysis at 24.0 months reported a mOS of 13.8 mos (95% CI: 12.4–14.5) with OPDIVO + chemo vs 11.6 mos (95% CI: 10.9–12.5) with chemo in all randomized patients (HR=0.79; (95% CI: 0.71–0.88) and 14.4 mos (95% CI: 13.1–16.2) with OPDIVO + chemo vs 11.1 mos with chemo (95% CI: 10.0–12.1) in PD-L1 CPS ≥5 (HR=0.70; (95% CI: 0.60–0.81).¹⁴ The 24.0-month OS rate was 28% vs 19% for OPDIVO + chemo vs chemo, respectively, in all randomized patients.¹⁴

A secondary endpoint (min follow-up of 12.1 mos), ORR in all randomized patients, was 47% (95% CI: 43–50) with OPDIVO + chemo vs 37% (95% CI: 34–40) with chemo alone. Complete response (CR) rates were 10% vs 7% and partial response (PR) rates were 37% vs 30% for OPDIVO + chemo vs chemo, respectively.¹¹

In Checkmate 649, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain. Of the ARs occurring in ≥10% of patients, those which were Grade 3–4 (OPDIVO + chemo vs chemo) were peripheral neuropathy (7% vs 4.8%), headache (0.8 vs 0.3%), nausea (3.2% vs 3.7%), diarrhea (5% vs 3.7%), vomiting (4.2% vs 4.2%), abdominal pain (2.8% vs 2.6%), constipation (0.6% vs 0.4%), stomatitis (1.8% vs 0.8%), fatigue (7% vs 5%), pyrexia (1% vs 0.4%), edema (0.5% vs 0.1%), decreased appetite (3.6% vs 2.5%), hypoalbuminemia (0.3% vs 0.3%), weight decreased (1.3% vs 0.7%), increased lipase (7% vs 3.7%), increased amylase (3.1% vs 0.4%), musculoskeletal pain (1.3% vs 2%), rash (1.7% vs 0.1%), palmar-plantar erythrodysesthesia syndrome (1.5% vs 0.8%), cough (0.1% vs 0%) and upper respiratory tract infection (0.1% vs 0.1%).

OPDIVO and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction. Serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.¹¹

Summary/conclusions

OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is an approved treatment option for 1L metastatic non-HER2+ GC/GEJC/EAC regardless of PD-L1 status.¹¹This approval is based on the Checkmate 649 study, which at the primary analysis demonstrated superior OS with OPDIVO + chemotherapy versus chemotherapy in all randomized patients.¹¹

1L=first line; chemo=chemotherapy; CI=confidence interval; CNS=central nervous system; ECOG=Eastern Cooperative Oncology Group; GEJC=gastroesophageal junction cancer; HR=hazard ratio; mo=month; mOS=median OS; q2w=every two weeks; q4w=every four weeks.

Indication

OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.¹¹

Important Safety Information

Severe and Fatal Immune-Mediated Adverse Reactions
• Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.
• Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
• Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
• OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis
• OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatoxicity
• OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies
• OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.
• In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).
• In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).
• In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).
• In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).
• In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).
• In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction
• OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO® monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions
• OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
• Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
• In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

Other Immune-Mediated Adverse Reactions
• The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.
• Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions
• OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
• Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.
• Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
• Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.
Increased Mortality in Patients with Multiple Myeloma when OPDIVO® is Added to a Thalidomide Analogue and Dexamethasone
• In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Lactation
• There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.
Serious Adverse Reactions
• In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.
Common Adverse Reactions
• In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see US Full Prescribing Information for OPDIVO.

References:
1. Paydary K, Reizine N, Catenacci DVT. Immune-checkpoint inhibition in the treatment of gastro-esophageal cancer: a closer look at the emerging evidence. Cancers (Basel). 2021;13(23):5929.
2. National Cancer Institute. Gastric cancer treatment (PDQ®)–health professional version. National Cancer Institute website. Updated April 22, 2021.Accessed December 3, 2021.
http://cancer.gov/types/stomach/hp/stomach-treatment-pdq.
3. Chen Z, Ren Y, Du XL, et al. Incidence and survival differences in esophageal cancer among ethnic groups in the United States. Oncotarget. 2017;8(29):47037-47051.
4. He H, Chen N, Hou Y, et al. Trends in the incidence and survival of patients with esophageal cancer: a SEER database analysis. Thorac Cancer. 2020;11(5):1121-1128.
5. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021;71(3):209-249.
6. Arnold M, Ferlay J, van Berge Henegouwen MI, Soerjomataram I. Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut. 2020;69(9):1564-1571.
7. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. National Cancer Institute website. Accessed December 3, 2021.
http://seer.cancer.gov/statfacts/html/stomach.html.
8. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: esophageal cancer. National Cancer Institute website. Accessed December 3, 2021.
http://seer.cancer.gov/statfacts/html/esoph.html.
9. Grieb BC, Agarwal R. HER2-Directed Therapy in Advanced Gastric and Gastroesophageal Adenocarcinoma: Triumphs and Troubles. Curr Treat Options Oncol. 2021;22(10):88.
10. ShankaranV, Xiao, H, Bertwistle D, et al. A comparison of real-world treatment patterns and clinical outcomes in patients receiving first-line therapy for unresectable advanced gastric or gastroesophageal junction cancer versus esophageal adenocarcinomas. Adv Ther. 2021;38:
707-720.
11. OPDIVO® (nivolumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
12. KEYTRUDA® (pembrolizumab) [package insert]. Kenilworth, NJ: Merck & Co., Inc; 2021.
13. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastroesophageal junction cancer/oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40.
14. Janjigian YY, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab vs chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/ esophageal adenocarcinoma: CheckMate 649 study. Presentation at ESMO 2021. Abstract LBA7.
15. Data on file. BMS-REF-NIVO-0120. Princeton, NJ: Bristol-Myers Squibb Company; 2021.

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1506-US-2200006 03/22

Efficacy and Safety in the Phase 3 QUAZAR® AML-001 Study of ONUREG® (azacitidine) Tablets

March 23, 2022March 23, 2022 RR

Written by: Thomas E Boyd, MD, Texas Oncology
Content Sponsored by: Bristol Myers Squibb
Dr. Boyd is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Acute myeloid leukemia (AML) is an aggressive hematologic cancer with 5-year relative survival rates less than 30%.¹ The journey for patients diagnosed with AML is very complex, and helping patients achieve remission is a major goal of initial treatment.² Relapse after this initial therapy poses a significant roadblock to survival, as evidenced by high relapse rates and the current 5-year survival rate.^1,3 There remains a critical need for therapies that extend survival.⁴

After a patient enters first remission, continued AML treatment is one avenue for appropriate patients.⁴ ONUREG® is the first and only FDA-approved continued AML treatment for adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.⁵

The efficacy and safety of ONUREG® was evaluated in the Phase 3 QUAZAR®AML-001 trial, where patients who completed intensive induction with or without consolidation therapy were randomized 1:1 to receive ONUREG or placebo orally on Days 1 through 14 of each 28-day cycle.⁵ Randomization was stratified by age at time of induction therapy, cytogenetic risk category at time of induction therapy, prior history of MDS/CMML, and receipt of consolidation therapy following induction therapy.⁵

Median OS, the primary endpoint in the QUAZAR®AML-001 trial, was over 2 years (24.7 months) in the ONUREG® arm and 14.8 months in the placebo arm (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.55-0.86; P=0.0009; Figure 1).⁵ This statistically significant survival benefit of ~10 months for patients with AML in first remission who received ONUREG® compared to placebo demonstrated that QUAZAR® AML-001 trial met its primary endpoint.⁵ Survival estimates were 73% for ONUREG® (n=168; 95% CI: 67, 78) and 56% for placebo (n=127; 95% CI: 49, 62) at 1 year, and 51% for ONUREG® (n=115; 95% CI: 44, 57) and 37% for placebo (n=82; 95% CI: 31, 43) at 2 years.⁶ Analyses of survival estimates at 1 and 2 years were not designed to show a difference between treatment arms.

Additional analyses show the influence of ONUREG® across subgroups vs placebo for median OS (Figure 2). It is important to note that these prespecified analyses should be interpreted with caution because of potential selection bias, insufficient sample size, and a higher probability of making a false positive finding.⁷

The most common adverse reactions (ARs, ≥ 10%) associated with ONUREG® treatment included nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.⁵ Serious ARs occurred in 15% of patients who received ONUREG®, and the most common Grade 3/4 ARs were febrile neutropenia (11%), pneumonia (9%), diarrhea (5%), and fatigue/asthenia (4%).⁵

Efficacy and safety were established by the large, multicenter QUAZAR® AML-001 trial. These results established ONUREG® as a continued treatment for adult patients with AML who achieve first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.

Figure 1: Kaplan-Meier curve for OS: ITT population in QUAZAR® AML-001⁵
KM-for-Overall-Survival

Figure 2: Overall survival select subgroup analysis^6,7
Overall-Survival

*Analysis limitations: These prespecified subgroup analyses should be interpreted with caution to determine a difference between arms in these select subgroups because of potential selection bias, insufficient sample size, and a higher probability of making a false positive finding.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
ONUREG® is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS
Risks of Substitution with Other Azacitidine Products
Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG® are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG® may result in a fatal adverse reaction. Treatment with ONUREG® at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG® for intravenous or subcutaneous azacitidine.
Myelosuppression
New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG®. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS)
In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG® or placebo. 107 received a median of 5 cycles of ONUREG® 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG® arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG® for MDS have not been established. Treatment of MDS with ONUREG® is not recommended outside of controlled trials.
Embryo-Fetal Toxicity
ONUREG® can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 3 months after the last dose.
ADVERSE REACTIONS
Serious adverse reactions occurred in 15% of patients who received ONUREG®. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG®.
Most common (≥10%) adverse reactions with ONUREG® vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION
There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG® and for 1 week after the last dose.

Please see full Prescribing Information for ONUREG®.

References
1. National Cancer Institute. SEER Cancer Statistics Factsheets: Acute Myeloid Leukemia. http://seer.cancer.gov/statfacts/html/amyl.html. Accessed April 21, 2021.
2. Medeiros BC. Interpretation of clinical endpoints in trials of acute myeloid leukemia. Leuk Res. 2018;68:32-29.
3. Wei AH. Maintenance therapy for AML: are we there yet? Blood. 2019;133(13):1390-1392.
4. Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol. 2019;94:803-811.
5. ONUREG® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.
6. Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 in patients with acute myeloid leukemia (AML) in first remission [oral presentation at ASH 2019]. Blood. 2019;134(Suppl 2):LBA-3.
7. Wei AH, Döhner H, Pocock C, et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020;383:2526-2537.

© 2021 Celgene Corporation.
ONUREG is a trademark of Celgene Corporation, a Bristol Myers Squibb company.
QUAZAR® is a registered trademark of Celgene Corporation, a Bristol Myers Squibb company
02/22 2011-US-2100200

General Review: An Approved Treatment Option for Acute Myeloid Leukemia

February 14, 2022February 14, 2022 RR

Written by: Thomas E Boyd, MD, Texas Oncology
Content Sponsored by: Bristol-Myers Squibb
Dr. Boyd is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Acute myeloid leukemia (AML) is a deadly disease that is more common in older adults.¹In 2021, it is estimated that there will be 20,240 new cases of AML in the United States, representing 1.1% of all new cancer cases.¹ Additionally, there will be an estimated 11,400 deaths due to AML, representing 1.9% of all cancer deaths in the US in 2021.¹ Once a patient is diagnosed with AML, beginning treatment as soon as possible is essential for disease management and survival.²

Currently, patients usually follow one of two paths for initial treatment of AML: conventional intensive induction chemotherapy or a less intensive option, with some patients going onto hematopoietic stem cell transplant after either initial treatment.³ The choice of treatment path is based on both patient- and disease-related characteristics such as medical fitness, age, cytogenetic and molecular testing, and risk of adverse events.² With the progress seen in our understanding of the biology of AML, our knowledge of the molecular underpinnings of AML pathology has greatly improved over the years.⁴ This deeper understanding of disease at the molecular level has helped pave the way for a wave of approved therapies, with several new drug approvals beginning in 2017.⁵

A major goal of AML treatment is achieving remission.⁶ However, proliferative AML cells may still persist in remission, leading to a risk of relapse.⁴ Continued treatment of AML in first remission may improve overall survival.⁸

The large, multicenter QUAZAR®AML-001 trial established the efficacy and safety of ONUREG®(azacitidine) tablets, the first and only FDA-approved continued AML treatment for patients in first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.⁸ Eligible patients were ages 55 years or older, diagnosed with AML, were within 4 months of achieving first CR or CRi with intensive induction chemotherapy, and may have received consolidation therapy.⁸ Patients could not enroll in the study if they were candidates for hematopoietic stem cell transplantation at the time of screening.⁸ Additional criteria included an ECOG performance status (PS) 0-3 and intermediate- or poor-risk cytogenetics, defined as normal cytogenetics +8, t(9;11), or other undefined, and complex (≥3 abnormalities): -5; 5q-; -7; 7q-; 11q23 – non t(9;11); inv(3); t(3;3); t(6;9); or t(9;22), respectively.⁸

Quazar-AML-Trial-Design A total of 472 patients were randomized 1:1 to receive either ONUREG® 300 mg or placebo orally on Days 1 through 14 of each 28-day cycle.⁸ Baseline demographics and disease-related characteristics were well balanced between the ONUREG and placebo arms.⁸ Across both arms, 72% of patients were 65 years or older, and most patients (92%) had an ECOG PS of 0 or 1. Additionally, approximately three-quarters of patients received 1 or 2 cycles of consolidation therapy.⁸

With a >2-year median overall survival and a statistically significant survival benefit of ~10 months for patients with AML in first remission compared to placebo, ONUREG met its primary endpoint (24.7 months in the treated arm vs 14.8 months in the placebo arm, hazard ratio (HR) 0.69, 95% confidence interval (CI): 0.55-0.86; P=0.0009).⁸

The most common adverse reactions (ARs, ≥ 10%) associated with ONUREG® treatment included nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.⁸ Serious ARs occurred in 15% of patients who received ONUREG®, with select Grade 3/4 ARs shown in the table below.⁸ Eight percent of patients permanently discontinued ONUREG®, 35% of patients required a treatment interruption due to an AR, and 14% of patients required a dose reduction.⁸

Quazar-Toxicities
ONUREG® is approved for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.⁸ ONUREG® is an oral hypomethylating agent, offering a convenient, once-daily dosing that patients can take at home.⁸ However, it is important to emphasize that ONUREG® should not be substituted for intravenous or subcutaneous azacitidine, because the indications and dosing regimen differ between these formulations.⁸ As the first and only FDA-approved continued AML treatment for patients in first remission, ONUREG® remains an option for appropriate patients.

Please see full Prescribing Information for ONUREG®.

References
1. National Cancer Institute. SEER Cancer Statistics Factsheets: Acute Myeloid Leukemia. http://seer.cancer.gov/statfacts/html/amyl.html. Accessed April 21, 2021.
2. Medeiros BC, Satram S. Real world treatment patterns and comparative effectiveness among elderly patients with acute myeloid leukemia in the United States. Ann Hematol Oncol. 2020;7(1):1283.
3. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
4. Brinda B, Khan I, Parkin B, Konig H. The rocky road to personalized medicine in acute myeloid leukaemia. J Cell Mol Med. 2018;22(3):1411-1427.
5. Lai C, Doucette K, Norsworthy K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol. 2019;12(100):1-20.
6. Medeiros BC. Interpretation of clinical endpoints in trials of acute myeloid leukemia. Leuk Res. 2018;68:32-29.
7. Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol. 2019;94:803-811.
8. ONUREG® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.

© 2021 Celgene Corporation.
ONUREG is a trademark of Celgene Corporation, a Bristol-Myers Squibb company.
QUAZAR is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb company.
1/22 2011-US-2100199

Acute Myeloid Leukemia: Who Is an Appropriate Candidate for ONUREG® (azacitidine) Tablets?

January 10, 2022January 10, 2022 RR

Written by: Thomas E Boyd, MD, Texas Oncology
Content Sponsored by: Bristol-Myers Squibb Company (BMS)

Dr. Boyd is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Acute myeloid leukemia (AML) is a deadly disease with most new cases affecting patients aged 65–74 years old.¹ The 5-year relative survival rate for AML is 29.5%¹, highlighting a need for treatment approaches that improve survival.² Patient- and disease-related characteristics, including medical fitness, age, cytogenetic and molecular testing, and risk of adverse events, often determine treatment options.³

After careful consideration of all factors, patients can be treated with either a higher-intensity chemotherapy option or a lower-intensity therapy option, and in some cases, additional cycles of consolidation therapy may follow the higher-intensity chemotherapy option.⁴ Helping patients achieve remission and keeping them there is a major goal of initial induction therapy. Continued treatment of AML in first remission may improve overall survival; however, relapse due to residual AML cells is still a major concern.² In 764 patients with AML aged 60–85 years old who received induction therapy, ~50% relapsed within 1 year and ~80% relapsed within 5 years.⁵ A goal of continued treatment for AML is extending overall survival (OS) in patients who have achieved first remission.² In some instances, extending OS can be achieved with a hematopoietic stem cell transplant; but not all patients are eligible or choose to go down this treatment route.³

ONUREG® is the first and only FDA-approved therapy indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.⁶ The efficacy and safety of ONUREG® was evaluated in the Phase 3 multicenter, randomized, double-blind placebo-controlled QUAZAR® AML-001 study.⁶ Eligible patients were ages 55 years or older, diagnosed with AML, were within 4 months of achieving first CR or CRi with intensive induction chemotherapy, and may have received consolidation therapy.⁶ Efficacy was established by OS, where ONUREG® demonstrated >2 years median OS for patients with AML in first remission as compared to placebo (24.7 months in the treatment arm vs 14.8 months in the placebo arm, hazard ratio (HR) 0.69, 95% confidence interval (CI): 0.55-0.86; P=0.0009).⁶ The most common adverse reactions (ARs, ≥ 10%) associated with ONUREG® treatment were nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.⁶ Serious ARs occurred in 15% of patients who received ONUREG®, and the most common Grade 3/4 ARs are shown in the table below.⁶

Who is an appropriate candidate for ONUREG®? The following hypothetical examples will review some of the characteristics to consider when deciding if a patient could be appropriate for ONUREG®.

Patient A is a 67-year-old retired accountant who is active and generally healthy. Their hypertension is well managed with medication, and they have no other comorbidities. Despite no family history of leukemia or hematologic abnormalities, Patient A has just been diagnosed with de novo AML not otherwise specified with intermediate-risk cytogenetics and no actionable mutations. Their hematologist prescribes intensive induction chemotherapy with the standard 7+3 regimen, and Patient A went into first remission.

Patient A is generally healthy with a well-managed comorbidity, which results in their treatment with intensive induction chemotherapy followed by first remission. Patient A is a candidate for transplant but declines one due to concerns over graft-versus-host disease. Since Patient A chose not to proceed to transplant, then ONUREG® may be an option for them.

Patient B is a 70-year retired nurse who lives alone, with family nearby. They were recently diagnosed with AML and received 7+3 chemotherapy followed by one round of consolidation. Patient B tolerated their treatment as well as could be expected and achieved first complete remission. While they are eligible for transplant, they declined and have been under observation by their doctor for the past few months. Patient B received and tolerated intensive induction chemotherapy, achieved first remission, and declined transplant, an intensive curative option. This makes them a potential candidate for continued treatment with ONUREG®.

Ultimately, the treating physician will make the final decision, but ONUREG® is indicated as a continued treatment of adult patients with AML who achieved first CR or CRi following intensive induction chemotherapy and are not able to complete intensive curative therapy.⁶ Understanding a patient’s disease and journey can help set them on the path where appropriate towards a continued treatment that has demonstrated an overall survival benefit in the QUAZAR® AML-001 study.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
ONUREG® is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS
Risks of Substitution with Other Azacitidine Products
Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG® are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG® may result in a fatal adverse reaction. Treatment with ONUREG® at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG® for intravenous or subcutaneous azacitidine.
Myelosuppression
New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG®. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS)
In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG® or placebo. 107 received a median of 5 cycles of ONUREG® 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG® arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG® for MDS have not been established. Treatment of MDS with ONUREG® is not recommended outside of controlled trials.
Embryo-Fetal Toxicity
ONUREG® can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m² basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 3 months after the last dose.
ADVERSE REACTIONS
Serious adverse reactions occurred in 15% of patients who received ONUREG®. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG®.
Most common (≥10%) adverse reactions with ONUREG® vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION
There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG® and for 1 week after the last dose.

Please see full Prescribing Information for ONUREG®.

References
1. National Cancer Institute. SEER Cancer Statistics Factsheets: Acute Myeloid Leukemia. http://seer.cancer.gov/statfacts/html/amyl.html. Accessed April 21, 2021.
2. Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol. 2019;94:803-811.
3. Medeiros BC, Satram S. Real world treatment patterns and comparative effectiveness among elderly patients with acute myeloid leukemia in the United States. Ann Hematol Oncol. 2020;7(1):1283.
4. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
5. Büchner T, Berdel WE, Haferlach C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27(1):61-69.
6. ONUREG®® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.

© 2021 Celgene Corporation.
ONUREG® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company.
QUAZAR® is a registered trademark Celgene Corporation, a Bristol-Myers Squibb company.
12/21 2011-US-2100198

Real-world evidence: What can it inform us about the second-line treatment of metastatic squamous NSCLC?

September 14, 2021September 14, 2021 RR

Written by Dr. Solly S. Chedid
Sponsored and developed by Boehringer Ingelheim Pharmaceuticals.

Immunotherapies have changed the way we initiate treatment for many patients with advanced squamous non-small cell lung cancer (NSCLC).¹ As immunotherapy has become a standard first-line treatment, non-immunotherapy options are important to consider for second-line treatment. Currently, there is no clear standard of care for second-line therapy in patients with advanced squamous NSCLC who progress after immuno-chemotherapy. Therefore, an unmet need remains for studies designed to understand the effectiveness and safety of second-line treatments in these patients. Here we will review newly published real-world evidence on second-line treatments of patients with squamous NSCLC with afatinib (GILOTRIF®) following immuno-chemotherapy.

GILOTRIF is the only oral, chemotherapy-free option for treating patients with squamous NSCLC that has progressed after platinum-based chemotherapy.² The efficacy and safety of GILOTRIF were demonstrated in the pivotal LUX-Lung 8 trial. In LUX-Lung 8, treatment with GILOTRIF led to statistically significant improvements in progression-free survival (median 2.4 vs 1.9 months) and overall survival (median 7.9 vs 6.8 months) compared with erlotinib. In LUX-Lung 8, the most common adverse reactions reported in the GILOTRIF treated patients (≥20% all grades) were diarrhea (75%), rash/acneiform dermatitis (70%), stomatitis (30%), decreased appetite (25%), and nausea (21%).

The Real-world Effectiveness of 2L Treatment of Squamous mNSCLC Study is the first to evaluate the real-world use of GILOTRIF following first-line immuno-chemotherapy in patients with squamous NSCLC.¹ It is a retrospective, non-interventional, multisite cohort study using electronic medical records of patients with advanced or metastatic squamous NSCLC treated with pembrolizumab and platinum-doublet chemotherapy in the first line. Patients were treated with either GILOTRIF or physician’s choice chemotherapy in the second line. Study endpoints included patient demographics and clinical characteristics, time on second-line treatment, and incidence of severe (Grade ≥3) immune-related adverse events (irAEs). This study analysis was not powered to compare characteristics or outcomes between the cohorts. In addition, the results of this study are not intended for direct comparison with clinical trials. The main limitations of this study are its retrospective nature, potential for selection bias, and lack of a comparator arm.

A total of 200 patients were included in this study; 99 received GILOTRIF, and 101 received chemotherapy in the second line.¹ More patients in the GILOTRIF cohort had mixed histology, were epidermal growth factor receptor (EGFR) mutation−positive, and were never smokers than those in the chemotherapy cohort. There were geographic differences between the cohorts; more patients from the Northeast received GILOTRIF, and more patients from the South received chemotherapy. In the GILOTRIF cohort, 45% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ranging from 0 to 1, while 55% had an ECOG PS of 2 or higher. In the chemotherapy arm, 50% of patients had ECOG PS 0 to 1, and 50% had ECOG PS of 2 or higher. Other characteristics, such as median age and stage at diagnosis, were similar in both cohorts.

The median time on treatment for the GILOTRIF cohort was 7.3 months. In patients with mixed histology, the median time on treatment was 8.1 months, and for patients with squamous histology it was 5.8 months.¹ EGFR mutation−positive and EGFR mutation−negative patients remained on GILOTRIF for a median of 7.4 and 5.9 months, respectively. The median time on treatment from initiation of second-line chemotherapy was 4.2 months.

Time on Treatment in the Real-World Effectiveness Study¹The most common adverse drug reactions with GILOTRIF were diarrhea (26%), rash (6%), stomatitis, fatigue, and nausea (5% each).¹ Six out of 99 patients experienced a Grade 3/4 irAE during second-line GILOTRIF therapy; each of these patients also experienced a Grade 3 irAE during first-line treatment. The 6 patients in the GILOTRIF cohort who experienced Grade 3/4 irAEs were treated with steroids, and none were hospitalized. Given the real-world nature of the study, adverse event data may be underreported or underdocumented; in addition, censoring may also bias results.

Such real-world evidence (RWE) studies have limitations, including their retrospective nature and potential for selection bias.¹ However, in addition to clinical data collected in registrational clinical trials, data from RWE studies such as this can add important information to help evaluate the clinical utility of a drug in the real-world setting.³ RWE studies can be derived from rich data sources, such as electronic health records, registries, and claims databases, which reflect real-world use, outcomes, and the patient diversity seen in clinical practice.

Despite several limitations highlighted in this paper, the study adds to the body of evidence supporting the effectiveness and safety of GILOTRIF when given as a second-line treatment following immuno-chemotherapy in routine clinical practice.¹

INDICATION AND USAGE

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (AFATINIB) TABLETS
WARNINGS AND PRECAUTIONS

Diarrhea
• GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
• For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
• Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours.
Bullous and Exfoliative Skin Disorders
• GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
• Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
• Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.
Interstitial Lung Disease
• Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
• Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
• Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
• Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.
Gastrointestinal Perforation
• Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials.
• Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, or patients with increasing age or who have an underlying history of GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
• Permanently discontinue GILOTRIF in patients who develop GI perforation.
Keratitis
• Keratitis has been reported in patients taking GILOTRIF.
• Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryo-Fetal Toxicity
• GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
ADVERSE REACTIONS
Adverse Reactions observed in clinical trials were as follows:
Previously Treated, Metastatic Squamous NSCLC
• In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
• Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
• Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
• Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Lactation
• Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.
Females and Males of Reproductive Potential
• GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.
Renal Impairment
• Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.
Hepatic Impairment
• GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

GF PROF ISI 10.21.19

References

1. Kim ES, Kish JK, Cseh A, et al. Second-line afatinib or chemotherapy following immunochemotherapy for the treatment of metastatic, squamous cell carcinoma of the lung: real-world effectiveness and safety from a multisite retrospective chart review in the USA. Clin Lung Cancer. 2021;S1525-7304(21)00029-2.
2. GILOTRIF. Prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2019.
3. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence — what is it and what can it tell us? N Engl J Med. 2016:8;375(23):2293-2297.

Please review the Full Prescribing Information and Patient Information.

Myelodysplastic Syndromes: Managing Anemia due to Ineffective Erythropoiesis in Patients with MDS Requiring RBC Transfusions

August 30, 2021August 30, 2021 RR

Written by: Dr. M. Yair Levy, Texas Oncology
Promotional Content Sponsored by: Bristol Myers Squibb
Dr. Levy is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies characterized by multilineage cytopenias, including anemia.¹ In MDS, stem cells lack the ability for differentiation and maturation, resulting in bone marrow dysfunction and poor blood cell production, in particular red blood cells (RBCs).² Anemia is present in the majority of patients with MDS and, at diagnosis, anemia is the most common cytopenia present in patients with MDS.¹ Anemia in MDS is linked to bone marrow dysfunction characterized by ineffective erythropoiesis.²

Ineffective erythropoiesis in MDS may lead to anemia requiring RBC transfusions and is characterized by increased proliferation of erythroid progenitors, increased death of erythroid precursors, and impaired erythroid maturation.^3,4 In fact, 94% (515/546) of patients with MDS received RBC transfusions in the SEER-Sound registry from 2001 to 2007, 13% of whom had ring sideroblasts.⁵ Ring sideroblasts are erythroblasts with iron-loaded mitochondria associated with anemia that can be identified by iron staining and the results can be found on pathology reports.⁶

The presence of anemia despite increased proliferation of progenitor cells is indicative of ineffective erythropoiesis in MDS.^3,4 There is a need to help address anemia due to ineffective erythropoiesis in patients with MDS requiring RBC transfusions after erythropoiesis stimulating agent (ESA) failure. REBLOZYL® (luspatercept-aamt), the first and only erythroid maturation agent, is approved for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).⁷ REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.⁷ The approval of REBLOZYL by the FDA marked the first new treatment indicated for patients with MDS in 14 years.⁸ In my clinical experience, the results that I’ve seen in patients with lower-risk MDS-RS are consistent with those seen in the MEDALIST clinical trial, as discussed below.

As the first and only erythroid maturation agent, REBLOZYL enhances erythroid maturation through differentiation of late-stage erythroid precursors. REBLOZYL works by binding several TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling and increasing the number and quality of mature RBCs in preclinical models.⁷

REBLOZYL was FDA approved for MDS-associated anemia based on the efficacy and safety outcomes of the pivotal phase 3 MEDALIST trial.^7,9 The MEDALIST trial was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of 229 adult patients with IPSS-R very low-, low-, or intermediate-risk MDS-RS (<5% bone marrow blasts, presence of ring sideroblasts of ≥15% or ≥5% with an SF3B1 mutation) who required RBC transfusions (≥2 RBC units/8 weeks) were randomized 2:1 to REBLOZYL (n = 153) or placebo (n = 76).^7,9 Patients were also required to have had an inadequate response to prior treatment with an ESA (defined as response that is no longer maintained after at least 8 doses of recombinant human erythropoietin or 4 doses of darbepoetin alfa), be intolerant of ESAs, or be ineligible for ESAs (serum EPO >200 U/L).^7,9 The MEDALIST trial excluded patients who had del 5q MDS, a white blood cell count >13 Gi/L, neutrophils <0.5 Gi/L, platelets <50 Gi/L, or who had prior use of a disease-modifying agent for treatment of MDS.⁷

REBLOZYL was administered 1 mg/kg subcutaneously every 3 weeks for at least 24 weeks or until unacceptable toxicity, loss of efficacy, or disease progression. Patients could have their dose increased to 1.33 mg/kg and then to 1.75 mg/kg. Patients received dose increases if they did not achieve transfusion independence after two doses or 6 weeks at 1 mg/kg and 1.33 mg/kg. All patients received best supportive care, which included RBC transfusions as needed.⁷

In MEDALIST, 36% (83/229) of all patients in the trial were 75 years of age or older, including patients up to 95 years.^7,9 95.2% (218/229) of all patients in the trial were ESA-exposed, while only 4.8% (11/229) were ESA-naive, with serum EPO >200 U/L.^7,9 All patients in the trial had ring sideroblasts (≥15% ring sideroblasts or ≥5% ring sideroblasts with an SF3B1 mutation), and the majority (206/229) had an SF3B1 mutation.^7,9 All patients except 1 were classified as having very low- to intermediate-risk MDS by the IPSS-R criteria.⁷ 57% (130/229) of patients had a baseline RBC transfusion burden <6 RBC units/8 weeks.⁷

The primary endpoint in MEDALIST was RBC transfusion independence (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within the first 24 weeks of treatment.⁷ Approximately 3 times greater percentage of patients receiving REBLOZYL achieved the primary endpoint of RBC transfusion independence than placebo: 37.9% (58/153) vs 13.2% (10/76; common risk difference [95% CI]: 24.6 [14.5, 34.6]; P < 0.0001), respectively.⁷ These data support that in patients requiring ≥2 RBC units/8 weeks, REBLOZYL should be started after at least 2 to 3 months of an inadequate response to ESAs.^7,9

Key secondary endpoints in MEDALIST were based on RBC transfusion independence (absence of any RBC transfusions) during any consecutive 12-week period occurring entirely within weeks 1 to 24 and 1 to 48. 28.1% (43/153) of patients receiving REBLOZYL achieved transfusion independence ≥12 weeks occurring entirely within weeks 1 to 24 vs 7.9% (6/76) of patients receiving placebo (common risk difference [95% CI]: 20.0 [10.9, 29.1]; P = 0.0002). For weeks 1 to 48,* 33.3% (51/153) of patients receiving REBLOZYL achieved transfusion independence ≥12 weeks vs 11.8% (9/76) of patients receiving placebo (common risk difference [95% CI]: 21.4 [11.2, 31.5]; P = 0.0003).⁷
*The median (range) duration of treatment was 49 weeks (6–114 weeks) on the REBLOZYL arm and 24 weeks (7-89 weeks) on the placebo arm.

REBLOZYL provided RBC transfusion independence vs placebo in patients with MDS-RS and MDS/MPN-RS-T, based on the WHO 2016 classification. Of patients who were diagnosed with MDS-RS, 34.1% (46/135; 95% CI 26.1, 42.7) of patients receiving REBLOZYL achieved transfusion independence vs 12.3% (8/65; 95% CI 5.5, 22.8) receiving placebo. Of patients who were diagnosed with MDS/MPN-RS-T, 64.3% (9/14; 95% CI 35.1, 87.2) of patients receiving REBLOZYL achieved transfusion independence vs 22.2% (2/9; 95% CI 2.8, 60.0) receiving placebo. Of patients who were diagnosed with other types of MDS (MDS-EB-1, MDS-EB-2, and MDS-U), 75% (3/4; 95% CI 19.4, 99.4) of patients receiving REBLOZYL achieved transfusion independence vs 0% (0/2; 95% CI 0.0, 84.2) receiving placebo.⁷

RBC transfusion independence was also examined by baseline RBC transfusion burden. Of patients requiring 2 to 3 RBC units/8 weeks at baseline,† 80.4% (37/46; 95% CI 66.1, 90.6) of patients receiving REBLOZYL achieved transfusion independence vs 40% (8/20; 95% CI 19.1, 63.9) receiving placebo. Of patients requiring 4 to 5 RBC units/8 weeks at baseline,‡ 36.6% (15/41; 95% CI 22.1, 53.1) of patients receiving REBLOZYL achieved transfusion independence vs 4.3% (1/23; 95% CI 0.1, 21.9) receiving placebo. Of patients requiring ≥6 RBC units/8 weeks, 9.1% (6/66; 95% CI 3.4, 18.7) of patients receiving REBLOZYL achieved transfusion independence vs 3% (1/33; 95% CI 0.1, 15.8) receiving placebo.⁷

†Includes patients who received 3.5 units.
‡Includes patients who received 5.5 units.

The safety of REBLOZYL at the recommended dose and schedule was evaluated in 242 patients with MDS-RS (n = 192) or other myeloid neoplasms (n = 50). The median time on treatment with REBLOZYL was 50.4 weeks (range, 3-221 weeks), with 67% of patients exposed for 6 months or longer and 49% exposed for >1 year.⁷

Among the 242 patients treated with REBLOZYL, 5 (2.1%) had a fatal adverse reaction. 4.5% (11/242) of patients discontinued REBLOZYL due to an adverse reaction and 2.9% (7/242) of patients had their REBLOZYL dose reduced due to adverse reactions. The most common (≥10%) all-grade adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection. The majority of adverse reactions with REBLOZYL were Grade 1 or 2 (mild to moderate). The most common (≥2%) Grade ≥3 adverse reactions included fatigue, hypertension, syncope, and musculoskeletal pain.⁷

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension
Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Embryo-Fetal Toxicity
REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS
Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.

The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection

LACTATION
It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please see full Prescribing Information for REBLOZYL

References:
1. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465.
2. Cazzola M, Malcovati L. Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med. 2005;352(6):536-538.
3. Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol. 2015;52(4):348-356.
4. Fontenay-Roupie M, Bouscary D, Guesnu M, et al. Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction. Br J Haematol. 1999;106(2):464-473.
5. Ramsey SD, McCune JS, Blough DK, et al. Patterns of blood product use among patients with myelodysplastic syndrome. Vox Sang. 2012;102(4):331-337.
6. Malcovati L, Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. Br J Haematol. 2016;174(6):847-858.
7. REBLOZYL [Prescribing Information]. Summit, NJ: Celgene Corporation; 2020.
8. Steensma, D.P. Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J. 2018;8(5):47.
9. Data on file, Celgene Corporation. Summit, New Jersey.

© 2021 Celgene Corporation.
REBLOZYL is a trademark of Celgene Corporation, a Bristol Myers Squibb company.
REBLOZYL is licensed from Acceleron Pharma Inc.
08/21 2007-US-2100270

Advances in Triple Negative Breast Cancer

April 1, 2021April 1, 2021 RR

Written by: Debra Patt, MD, PhD, MBA
Content Sponsored by: Bristol Myers Squibb
Dr. Patt is a paid consultant for BMS and was compensated for her contribution in drafting this article.

Metastatic triple negative breast cancer (TNBC) is a devastating disease, making up 15% of all cancers, and having a limited outcome with an overall survival average of around a year.^1,2 It is a diagnosis of exclusion, as tumor cells do not express the targetable hormone receptors (estrogen or progesterone receptors) or HER2, thus treatment options have historically relied on systemic chemotherapy rather than targeted treatment.³ This aggressive subtype is often associated with an earlier age of onset and an aggressive clinical course. Ethnic disparities have been identified for triple negative disease, with the incidence highest among patients who have a non-Hispanic black ethnic background compared to other ethnic groups.¹ Furthermore, African American women are more likely to develop metastases compared to women of other races. Metastatic progression for triple-negative disease is generally characterized by early relapse and predominantly visceral (including liver, pulmonary and central nervous system) metastases.³

Historically, advances in the treatment of triple negative breast cancer have been rare. Multiple immunotherapy options in combination with chemotherapy are now approved in metastatic TNBC for patients with PD-L1 positive, first-line disease, and today there is much excitement about further evidence supporting its use in the metastatic and early stage settings.⁴ However, no head-to-head data exists to identify the optimal chemotherapy partner for checkpoint inhibition and not all chemotherapy agents appear to provide similar efficacy based on current data, hence more investigations are needed.^5,6 Furthermore, while the incidence of immune-related adverse events such as endocrinopathies are low, the permanence of these side effects, particularly in the early stage setting, is concerning to some and should be closely monitored.

Germline BRCA mutations occur in approximately 10–30% of TNBC cases.⁷ In previously treated metastatic disease, the use of poly (ADP-ribose) polymerase (PARP) inhibitors in germline BRCA mutation positive patients has also shown improvements in survival, with the main reported side effects being hematologic, fatigue and diarrhea.^3,8 In heavily pretreated metastatic TNBC patients, the use of antibody-drug conjugates has also resulted in anti-cancer effects.⁹

While advances in the aggressive and difficult-to-treat triple negative breast cancer subset are promising, all of these recent advances leave us with new treatment options but also unanswered questions. Our knowledge is limited and certainly will improve over time as we understand better predictors of outcome like PD-L1 expression, tumor infiltrating lymphocytes, and other factors as well as the importance of chemotherapy backbone choice. Other agents are now available for previously treated metastatic TNBC patients and further studies will be needed to assess the efficacy of these agents in earlier lines of therapy. Additionally, long-term follow up of studies will also be important to truly understand the impact of these new targeted approaches and the impact of drug tolerability on efficacy and patient quality of life.

References
1. DeSantis CE, Fedewa SA, Sauer AG, Kramer JL, Smith RA, Jemal A. CA Cancer J Clin. 2016;66:31-42.
2. Marra A, Viale G, Curigliano G. BMC Medicine. 2019;17:90-99.
3. Bergin ART, and Loi S. F1000Research. 2019;8: F1000 Faculty Rev-1342. Published online 2019 Aug 2.
4. Simmons CE, Brezden-Masley C, McCarthy J, McLeod D, Joy AA. Ther Adv Med Oncol. 2020;12:1-15.
5. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, et al. DOI: 10.1200/JCO.2020.38.15_suppl.1000 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1000-1000.
6. Miles D, Gligorov J, Andre F, Cameron D, Schneeweiss A, et al. Annals of Oncology. 2020;31 (suppl 4):S1142-S1215. 10.1016/annonc/annonc325.
7. Vagia E, Mahalingam D, Cristofanilli M. Cancers (Basel). 2020 Apr;12:916-941.
8. Madariaga A, Bowering V, Ahrari S, Oza AM, and Lheureux S. Int J Gynecol Cancer. 2020; 30:903-915.
9. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, et al. N Engl J Med. 2019;380:741-751.

Advances with First-Line Dual Immunotherapies in Metastatic Non-Small Cell Lung Cancer

February 22, 2021February 22, 2021 RR

By Dr. David Waterhouse | Sponsored by Bristol Myers Squibb
Dr. Waterhouse is a paid consultant for Bristol Myers Squibb and was compensated for his role in drafting this article.

The American Cancer Society estimates that there will be nearly 229,000 new cases of lung cancer in the United States (US) alone in 2020 and nearly 136,000 lung cancer deaths.¹ Historically, most patients present with metastatic disease and their long-term outlook is grim.² However, significant progress has been made in recent years. In August 2020, Howlader et al reported that the population-level mortality from non-small cell lung cancer (NSCLC) in the US fell sharply from 2013 to 2016.³

Based on the results from Checkmate 227 Part 1a, OPDIVO, in combination with YERVOY, is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.^4-6 In addition, based on the results from Checkmate 9LA, OPDIVO, in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy (chemo), is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.^4,6,7

OPDIVO and YERVOY are associated with the following Warnings and Precautions: severe and fatal immune-mediated reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.⁴ Please see additional Important Safety Information for OPDIVO and YERVOY at the end of the article and US Full Prescribing Information for OPDIVO and YERVOY at https://packageinserts.bms.com/pi/pi_opdivo.pdf and https://packageinserts.bms.com/pi/pi_yervoy.pdf.

OPDIVO® (nivolumab) is a monoclonal antibody targeting programmed death receptor-1 (PD-1) that has been approved for the treatment of lung cancer.⁴ YERVOY® (ipilimumab) is another monoclonal antibody that works to activate the immune system by targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4).^6,8

Figure 1: OPDIVO and YERVOY mechanisms of action^4,6,8-14

OPDIVO+YERVOY-MOA This graphic is for demonstration purposes only.
The illustrated mechanisms may vary for each patient and may not directly correlate with clinical significance.

The phase 3 Checkmate 227 and Checkmate 9LA trials investigated OPDIVO plus YERVOY-based combinations for first-line treatment of certain NSCLC patients.⁴ Part 1a of Checkmate 227 investigated the effects of OPDIVO + YERVOY compared with standard chemo* among patients whose tumors expressed ≥1% programmed death ligand 1 (PD-L1)⁴ (Figure 2).

Figure 2: Checkmate 227 Part 1a study design¹⁵
Checkmate-227-Study-Design *In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.^4,16,17
ALK=anaplastic lymphoma kinase; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EGFR=epidermal growth factor receptor; NSQ=non-squamous; q2w=every 2 weeks; q6w=every 6 weeks; SQ=squamous.

OPDIVO + YERVOY showed a superior survival benefit compared with chemo*, with the primary analysis at a minimum follow-up of 29.3 months revealing a median overall survival (OS) of 17.1 months vs 14.9 months with chemo*, and a hazard ratio (HR) of 0.79, 95% confidence interval (CI): 0.67–0.94, P=0.0066 (Figure 3).^4,16 The median progression-free survival (PFS) was 5.1 months (95% CI: 4.1–6.3) with OPDIVO + YERVOY and 5.6 months (95% CI: 4.6–5.8) with chemo* alone (HR=0.82; 95% CI: 0.69–0.97).⁴

The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure.⁴ The most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%).⁴ Please continue reading for more Important Safety Information for OPDIVO and YERVOY throughout.

Figure 3: Checkmate 227 OS for PD L1 ≥1% (extended 3-year follow-up analysis)^4,15

Median-OS-Primary-Analysis-OPDIVO+YERVOY

At the American Society for Clinical Oncology (ASCO) 2020 Annual Meeting, 3-year follow-up results from this trial were reported. With a median follow-up of more than 3 years (43.1 months), this study represents the longest median follow-up of any dual immuno-oncology (I-O)-based combination in a phase 3 clinical trial in NSCLC.¹⁵ This extended follow-up analysis showed 3-year OS rates of 33% for OPDIVO + YERVOY and 22% for chemo* (Figure 3).¹⁵

At minimum follow-up of 28.3 months, the objective response rate was 36% (95% CI: 31–41), CR=5.8%, PR=30.1% with OPDIVO + YERVOY and 30% (95% CI: 26–35), CR=1.8%, PR=28.2% with chemo*.^4,16,17 The median duration of response from the extended 3-year follow-up analysis was 23.2 months (95% CI: 15.2–32.2) in patients who responded to OPDIVO + YERVOY and 6.7 months (95% CI: 5.6–7.6) with chemo* (Figure 4).¹⁵

Figure 4: Checkmate 227 DOR among responders with PD L1 ≥1% (extended 3-year follow-up analysis)¹⁵

Median-DOR-OPDIVO+YERVOY

Median follow-up of 43.1 months.¹⁵
*In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.^4,16,17

The 3-year data from Checkmate 227 Part 1a show the long-term durable survival of a dual immunotherapy approach.¹⁵ The FDA approved OPDIVO + YERVOY on May 15, 2020, for first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1(≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. With this approval, these patients with NSCLC can now be offered the option of dual I-O therapy.^4,5

Also reported at ASCO 2020 were the results of Checkmate 9LA.¹⁸ Patients were randomized to receive either the combination of OPDIVO + YERVOY and 2 cycles of platinum-doublet chemo† or platinum-doublet chemo† for 4 cycles.⁴ This trial evaluated patients regardless of PD-L1 expression and histology (Figure 5).⁴

Figure 5: Checkmate 9LA study design¹⁸

Checkmate-9LA-Study-Design

†In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm, and up to 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in comparator arm only); SQ: paclitaxel + carboplatin.⁴
q3w=every three weeks.

The trial showed a superior benefit in OS for patients treated with OPDIVO + YERVOY with limited chemo† compared to those who received chemo† alone.¹⁸ At the pre-specified interim analysis at 8.1 months, the median OS was 14.1 months vs 10.7 months (HR=0.69, 96.71% CI: 0.55-0.87, P=0.0006).⁴ Median PFS per blinded independent central review (BICR) at minimum follow-up of 6.5 months was 6.8 months among patients who received OPDIVO + YERVOY with chemo†, and 5.0 months among patients receiving chemo† (HR=0.70, 97.48% CI: 0.57-0.86).4 Confirmed ORR per BICR at minimum follow-up of 6.5 months was 38% (95% CI: 33-43) and 25% (95% CI: 21-30) respectively.^4,18

A follow-up analysis performed at 12.7 months showed median OS of 15.6 months with OPDIVO + YERVOY with chemo† and 10.9 months with chemo† alone with HR of 0.66 (95% CI: 0.55-0.80) (Figure 6).^4,18 OS was consistent across PD-L1 expression levels at minimum follow-up of 8.1 months, with median OS of 14.0 months (95% CI:13.2-NR) and 10.0 months (95% CI: 7.7-13.7) in patients treated with OPDIVO + YERVOY with limited chemo† and chemo† respectively in the PD-L1 <1% sub-population (HR=0.65), and median OS of 14.2 months (95% CI:13.1-NR) and 10.6 months (95% CI: 9.4-12.6) respectively (HR=0.67) in the PD-L1 ≥1% sub-population.¹⁹

Figure 6: Checkmate 9LA overall survival (extended follow-up)¹⁸

Checkmate-9LA-OS
Minimum follow-up of 12.7 months.
†In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm, and up to 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in comparator arm only); SQ: paclitaxel + carboplatin.⁴

In this study, the most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.⁴ The most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).⁴ Please continue reading for more Important Safety Information for OPDIVO and YERVOY throughout. The FDA approved OPDIVO, in combination with YERVOY and 2 cycles of platinum-doublet chemo, for the first-line treatment of adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations in May 2020.^4,7

With the approval of both Checkmate 227 and Checkmate 9LA regimens as first-line therapies, I am pleased to be able to offer metastatic NSCLC patients with additional options. Checkmate 227 provides appropriate mNSCLC patients with a chemo-free, dual I-O option with long-term, durable survival. Additionally, the Checkmate 9LA regimen with dual I-O plus limited chemo† has shown superior OS, and consistent OS, regardless of PD-L1 expression in recurrent/metastatic NSCLC patients.^4,18

*In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.^4,16,17
†In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm, and up to 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in comparator arm only); SQ: paclitaxel + carboplatin.⁴

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-Mediated Hepatitis

OPDIVO and YERVOY can cause immune-mediated hepatitis.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Common Adverse Reactions

In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY:
• https://packageinserts.bms.com/pi/pi_opdivo.pdf
• https://packageinserts.bms.com/pi/pi_yervoy.pdf

References:
1. Key statistics for lung cancer. American Cancer Society. Reviewed October 1, 2019. Revised January 8, 2020. Accessed October 7, 2020. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.
2. Lung and bronchus cancer – cancer stat facts. National Cancer Institute. Accessed October 7, 2020. https://seer.cancer.gov/statfacts/html/lungb.html.
3. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383:640-649.
4. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
5. FDA approval for Checkmate 227. Accessed October 12, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1.
6. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
7. FDA approval for Checkmate 9LA. Accessed October 12, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc.
8. Weber JS, Hamid O, Chasalow SD, et al. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother. 2012;35:89-97.
9. Farber DL, Yudanin NA, and Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014;14(1):24-35.
10. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti–CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non–Hodgkin lymphoma. Clin Cancer Res. 2009;15(20):6446-6453.
11. Felix J, Lambert J, Roelens M, et al. Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response. Oncoimmunology. 2016;5(7):e1136045.
12. Pedicord VA, Montalvo W, Leiner IM, and Allison JP. Single dose of anti–CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA. 2011;108(1):266-271.
13. de Coaña YP, Wolodarski M, Poschke I, et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget. 2017;8(13):21539-21553.
14. Buchbinder EI and Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98-106.
15. Ramalingam S, Ciuleanu T-E, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from Checkmate 227 Part 1. Oral presentation at ASCO 2020. Abstract 9500.
16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.
17. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031. [supplementary appendix].
18. Reck M, Ciuleanu T-E, Cobo M, et al. Nivolumab + ipilimumab + 2 cycles of platinum-doublet chemotherapy vs 4 cycles chemotherapy as first-line treatment for stage IV/recurrent NSCLC: Checkmate 9LA. Oral presentation at ASCO 2020. Abstract 9501.
19. Data on file. NIVO 566. Princeton, NJ: Bristol-Myers Squibb Company.

The Evolution of Therapeutics for Patients with aRCC

January 11, 2021January 11, 2021 RR

Written by Dr. Thomas Hutson, Texas Oncology

Renal cell carcinoma (RCC) is one of the most frequently diagnosed cancers with an incidence of around 400,000 cases worldwide.¹ In the United States alone, RCC accounted for 73,820 new cases and 14,770 deaths in 2019.² In patients with RCC, about 30% present with metastatic disease at the time of initial diagnosis typically requiring systemic therapy, and of those treated for localized RCC, almost 30% develop recurrent disease during the follow-up.³ To address this patient population, multiple targeted therapies focused predominantly on two major molecular pathways, namely angiogenesis and intracellular signal transduction pathways, have gained increasing attention in recent years as prospective therapies for advanced RCC (aRCC).⁴

The Advent of New Therapeutics for RCC

After the approval of high-dose IL2, there was remarkable progress in the treatment of RCC with approval of VEGF inhibitors, as well as mammalian target of rapamycin (mTOR) pathway inhibitors. These agents have gained regulatory approval and have drastically improved the outcome of patients with advanced RCC.⁵ More recently, key insights obtained in regard to the Von Hippel-Lindau (VHL) pathway provided the basis for the development of the VHL-hypoxia pathway-based therapeutic landscape in renal cancers.⁶ For instance, the newer generation tyrosine kinase inhibitors (TKIs) block not only vascular endothelial growth factor receptor (VEGFR) but also fibroblast growth factor receptor (FGFR), and hepatocyte growth factor receptor (C-Met) and Axl, respectively.⁶ These additional targets have been implicated to help escape angiogenesis blockade which may explain their incremental improvement in efficacy demonstrated in pivotal clinical trials.⁶ While significant progress has occurred, there is still room for improvement for targeted therapies as current drug interventions for metastatic RCC (mRCC) have yet to demonstrate the ability to circumvent recurrence and several therapies are accompanied by severe adverse events.⁵

Given that RCC is considered immune-responsive in nature with high numbers of immune cells present in the tumor microenvironment (TME), targeted immunotherapy (IO) was more recently approved as another potential therapy in RCC.⁷ One strategy involves the use of immune checkpoint inhibitors (ICI). In particular, the use of sophisticated ICIs – anti-programmed death receptor-1 (PD-1), anti-programmed death receptor ligand-1 (PD-L1), and anti-cytotoxic T lymphocytes antigen-4 (CTLA-4) – have been studied in large international phase 3 trials demonstrating significant and clinically relevant improvements in efficacy.^4,8 As such, these new therapies have quickly been integrated into the RCC landscape with PD-1 and PD-L1 antibody-based novel ICIs now approved by the FDA as the standard second-line treatment for mRCC as well as in the first-line for moderate to high risk mRCC.^9,10

Recently reported and FDA-approved combinations of ICI or ICI with TKI therapy have been rapidly integrated into the first-line treatment setting based upon recent international phase 3 trials.⁴ It has been proposed that anti-VEGF therapies used in combination with targeted immunotherapies may overcome resistance by modulating the TME. Moreover, inhibition of the VEGF pathway was shown to facilitate access of T-cell population into the TME and decrease the activity of T-regulatory cells and myeloid-derived suppressor cells, thereby enhancing responsiveness to immunotherapy.^9,11,12

Strategizing Therapeutic Approach

When patients with mRCC progress through first-line therapies (TKI-ICI, TKI, ICI-ICI), there are many second-line choices to choose from, including ICI, mTOR pathway inhibitors and TKI-mTOR inhibitor combinations.

Before starting therapy, it is necessary to educate the patient about the possibility of adverse reactions that may ensue in the weeks and months after therapy begins. Setting expectations of therapy will serve to maximize patient compliance through early intervention as adverse reactions emerge. This will require close communication between the clinical treatment team, the patient, and their caregivers. Withholding therapy and dose adjustments may be required in some cases to enable patients to remain on therapy.^13,14

References
1. Bray F, Ferlay J, Soerjomataram I, et al. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2018;68:394-424
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
3. Abara E, Chivulescu I, Clerk N, et al. Recurrent renal cell cancer: 10 years or more after nephrectomy. Canadian Urological Association. 2010;4(2):E45-E49.
4. Wang J, Li X, Wu X, et al. Role of immune checkpoint inhibitor-based therapies for metastatic renal cell carcinoma in the first-line setting: A Bayesian network analysis. EBioMedicine. 2019;47:78-88.
5. Barata P, Ornstein M, Garcia J. The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patinents Progressing after VEGF Inhibition. J Kidney Cancer VHL 2017;4(2):10-18.
6. Jonasch E. Implications of VHL-HIF pathway dysregulation in renal cell carcinoma: current therapeutic strategies and challenges. Kidney Cancer Journal. 2020;18(1):6-10.
7. Leite KR, Reis ST, Junior JP, et al. PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol. 2015;10:189.
8. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813.
9. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-1115.
10. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290.
11. Rini B.I, Plimack E.R, Stus V, et al. Pembrolizumab plus Axitinib versus
Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116-27
12. Suk Lee W, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Experimental and Molecular Medicine. 2020; 52:1475-1485
13. Philip L. Management of Targeted Therapy Adverse Effects. Pharmacytimes. 2020. https://www.pharmacytimes.com/publications/Directions-in-Pharmacy/2019/December2019/featured-article-management-of-targeted-therapy-adverse-effects. Accessed 10/27/2020.
14. Barber FD. Adverse Events of Oncologic Immunotherapy and Their Management. Asia Pac J Oncol Nurs. 2019;6:212-26

This article is sponsored by Eisai Inc.

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