Advances in Triple Negative Breast Cancer

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

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 action4,6,8-14

OPDIVO+YERVOY-MOAThis 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

*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

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

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.

LENV-US4722

Considerations in the Treatment of Metastatic Pancreas Cancer

Written by: Carlos Becerra, MD
Content Sponsored by: Bristol Myers Squibb
Dr. Becerra is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Pancreas adenocarcinoma is a highly aggressive and fatal disease that is projected to become the second leading cause of cancer related death in the US by the year 2030.1 Upon diagnosis, over 50% of the patients present with metastatic disease and we do not have an effective screening tool to detect pancreas cancer at an earlier and potentially curable stage.2-3 Some improvement has been made in median survival for patients with metastatic disease due to better supportive measures and more effective chemotherapy options.3-4 However, the COVID 19 pandemic threatens to disrupt the gains obtained in recent years due to delay in diagnosis and management of this disease.5 In the next paragraphs I will review some key features for the management of patients with metastatic pancreas cancer so that patients can continue to benefit from the current available treatment options in spite of the COVID-19 pandemic.

Key elements to consider at diagnosis and during management of patients with metastatic pancreas cancer include pain control with adequate narcotic analgesics titrated to the patient’s pain and consideration for local treatment modalities, such as palliative radiation therapy and celiac block to help control the pain. Patients should also be closely monitored with early intervention in case of bowel obstruction (consider even surgical intervention with a bypass procedure if the patient has an adequate performance status) and obstructive jaundice (with metal stent preferred over plastic stent; Figure 1). Additional elements include adequate control of nausea and vomiting either due to chemotherapy or to bowel dysfunction, optimal management of the hyperglycemia, and replacement therapy with pancreatic enzymes. Consultation of nutritional services and starting medications to stimulate the appetite should also be considered.3,4,6 Genetic counseling for new patients and testing for germline mutations along with testing the tumor for presence of actionable mutations should also be strongly considered, based on recent advances.7 Patients should also be screened for depression.3,4

Figure 1: Key Elements to Consider at Diagnosis and Follow-Up


The overall goal of systemic chemotherapy should be to improve overall survival of patients while maintaining the best possible quality of life.4 To that end we have several treatment options based on evidence from randomized phase III clinical trials. Keep in mind that at present we do not have a marker that will help select one regimen up front for clinical efficacy and or toxicity but the general consensus is to use a multi-drug regimen for patients with a good to marginal performance status or even a single agent in very frail patients.8,9

In 2011, the results of a phase III clinical trial demonstrated efficacy of 5-FU based combination therapy compared to single agent chemotherapy, at the expense of some increased toxicity.10 Since then, a multi-drug regimen approach has been shown to be effective.11 Today, the gemcitabine-based or 5-FU based treatments are recommended for patients with metastatic disease.12 Choice of treatment is based on overall assessment of the patient with regards to performance status, comorbidities, symptom burden, prior treatments, patient preference, goals of therapy and the patient’s home support system along with consideration of the potential side effects of the therapy.4,12

Once a patient begins treatment, close monitoring of the patient for evidence of disease progression is very important in order to offer patients second line chemotherapy. Thus, evaluation of the patient’s clinical status, restaging scans, and CA19-9 in a timely fashion will help guide the clinician on starting second line therapy.7,3 For patients with tumors that have a mutation in BRCA 1 or 2 gene (~7% of patients) maintenance with a PARP inhibitor, after receiving chemotherapy is recommended. Additional targeted agents are a possible treatment option if the tumors have presence of specific mutations.3,7

Despite advances, metastatic pancreatic cancer can be difficult to treat. The aggressive nature of the disease along with a high symptom burden make diligent patient management of the utmost importance, particularly during today’s challenging times. Recognizing and addressing symptoms proactively along with choosing the optimal treatment to allow for anti-tumor efficacy combined with a side effect profile that best fits the patient’s tolerance remains important.3,8,13

References
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Cancer Res. 2014;74:2913-2921.
2. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed November 2, 2020.
3. Mizrahi JD, Surana R, Valle JW, Shroff RT. Lancet. 2020;395:2008-2020.
4. Moffat GT, Epstein AS, O’Reilly EM. Cancer. 2019;125:3927-3935.
5. Benyon B. Oncology Nursing News. Published online March 31, 2020. https://www.oncnursingnews.com/web-exclusives/to-treat-or-not-to-treat-cancer-during-the-covid-19-pandemic. Accessed November 3, 2020.
6. Gilliland TMVillafane-Ferriol N, Shah KP, Shah RM, Tran Cao HS, Massarweh NN et al. Nutrients. 2017;9:243.
7. Sohal DPS, Kennedy EB, Cinar P, Conroy T, Copur MS, Crane CH et al. J Clin Oncol. 2020;38:3217-3230.
8. Sohal DPS, Mangu PB, Khorana AA, Shah MA, Philip PA, O’Reilly EM, et al. J Clin Oncol. 2016;34:2784-2796.
9. Zhang L, Sanagapalli S, Stoita A. World J Gastroenterol. 2018;24:2047-2060.
10. Conroy T, Desseigne FD, Ychou M, Bouche O, Guimbaud R, Becouarn Y et al. N Engl J Med. 2011;364:1817-1825.
11. Von Hoff DD, Ervin T, Areana FP, Chiorean EG, Infante J, Moore M et al. N Engl J Med. 2013;369:1691-1703.
12. Sohal DPS, Kennedy EB, Khorana A, Copur MS, Crane CH, Garrido-LagunaI et al. J Clin Oncol. 2018;36:2545-2556.
13. Catanese S, Pentheroudakis G, Douillard J-Y, Lordick F. ESMO Open. 2020;5:e000804.

Challenges and Unmet Needs in Squamous Non-Small Cell Lung Cancer

Written by Dr. Irfan A. Mirza
This article is sponsored and developed by Boehringer Ingelheim Pharmaceuticals

Significant strides have been made in the last decade for systemic treatment options for stage IV non-small cell lung cancer (NSCLC), including those tailored for squamous and non-squamous histology.1,2 While non-squamous NSCLC has benefited from advances such as the introduction of personalized, genotyped-directed therapies, and immunotherapy drugs, the treatment options for squamous cell NSCLC remain limited.1,2

Historically, the NCCN guidelines recommended the use of platinum-based chemotherapy in the first line setting, followed by immunotherapy in the second-line.3 However, following the results of the KEYNOTE-407 study, immunotherapy together with platinum doublet chemotherapy is now recommended in the first-line setting.4,5 This leaves an unmet need for patients with metastatic squamous NSCLC who have progressed, where most treatments consist of chemotherapy.2,6

Afatinib is an oral, non-chemotherapy option for patients with metastatic squamous NSCLC who have progressed on platinum-based chemotherapy.7 Afatinib is an irreversible second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor that selectively inhibits homo- and hetero-dimers of the ErbB receptor family (EGFR, ErbB2, and ErbB4).7

LUX-Lung 8 was a multicenter, open label, phase 3, randomized, controlled trial across 23 countries that enrolled 795 patients with advanced (stage III B and stage IV) squamous NSCLC, progressing after at least 4 cycles of platinum-based chemotherapy.8 Patients were randomized (1:1) to either afatinib 40 mg daily or erlotinib 150 mg daily until disease progression.8 The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC), using RECIST v1.1 and secondary endpoints included overall survival (OS) and objective response rates as assessed by an IRC.8

In LUX-Lung 8, significant improvement in PFS and overall survival was observed for afatinib compared with erlotinib.8 The median PFS was reported as 2.4 months with afatinib and 1.9 months with erlotinib [HR, 0.82 (95% CI 0.68-0.99)] (Figure 1).8
LUX-Lung-8-Median-Progression-Free-Survival
After a median follow up of 18.4 months, median OS was 7.9 months in the afatinib group and 6.8 months in the erlotinib group [HR 0.81 (95% CI 0.69-0.95), p = 0.0077].8 Estimates of OS among patients treated with afatinib were 64% at 6 months, 36% at 1 year, and 22% at 18 months (Figure 2).8

LUX-Lung-8-K-M-Estimates-of-Survival
More than half (51%) of patients treated with afatinib were able to achieve disease control (defined as complete response, partial response, stable disease, or non-complete response and non-progressive disease) compared with 40% with erlotinib.8 Excluding patients with non-complete response and non-progressive disease, disease control with afatinib was 37%, vs 29% with erlotinib, in a post hoc analysis.8 The median duration of objective response was 7.3 months with afatinib and 3.7 months with erlotinib.8

The most common adverse effects associated with afatinib were diarrhea, rash/acneiform dermatitis, stomatitis, decreased appetite, nausea, vomiting, paronychia, and pruritus.8,9 Twenty percent of patients discontinued afatinib treatment due to adverse reactions, with the most frequent adverse reactions leading to discontinuation being diarrhea in 4.1% of patients and rash/acne in 2.6%.9 Serious adverse reactions occurred in 44% of patients, with pneumonia (6.6%), diarrhea (4.6%), dehydration, and dyspnea (3.1% each) being the most frequent.9 Fatal adverse reactions in afatinib-treated patients included interstitial lung disease, pneumonia, respiratory failure, acute renal failure, and general physical health deterioration, all occurring in less than 1% of patients.9

Adverse Reactions (ARs) Reported in ≥10% of GILOTRIF-Treated Patients in LUX-Lung 89*:
GILOTRIF (n=392), erlotinib (n=395) – All Grades & Grades 3-4 ARs
Gastrointestinal Disorders
Diarrhea – GILOTRIF all grades: 75%; grades 3-4: 11%; erlotinib all grades: 41%, grades 3-4: 3%
Stomatitis – GILOTRIF all grades: 30%; grades 3-4: 4%; erlotinib all grades: 11%, grades 3-4: 1%
Nausea – GILOTRIF all grades: 21%; grades 3-4: 2%; erlotinib all grades: 16%, grades 3-4: 1%
Vomiting – GILOTRIF all grades: 13%; grades 3-4: 1%; erlotinib all grades: 10%, grades 3-4: 1%
Skin and Subcutaneous tissue disorders
Rash/acneform dermatitis – GILOTRIF all grades: 70%; grades 3-4: 7%; erlotinib all grades: 70%, grades 3-4: 11%
Pruritus – GILOTRIF all grades: 10%; grades 3-4: 0%; erlotinib all grades: 13%, grades 3-4: 0%
Metabolism and nutrition disorders
Decreased appetite – GILOTRIF all grades: 25%; grades 3-4: 3%; erlotinib all grades: 13%, grades 3-4: 0%
Infections
Paronychia§ – GILOTRIF all grades: 11%; grades 3-4: 1%; erlotinib all grades: 5%, grades 3-4: 0%
*NCI CTCAE v 3.0
Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular,

rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
§ Includes paronychia, nail infection, nail bed infection

In summary, LUX-Lung 8 met its primary and secondary endpoints and remains the largest prospective head-to-head trial that compares two TKIs for second-line treatment of patients with squamous NSCLC.8 Future studies should focus on understanding the clinical profile of afatinib within the context of other commonly-used treatment modalities, such as chemotherapy. In a disease setting with few treatment options, and a pandemic which can make delivery of infusions challenging, afatinib offers patients with metastatic squamous NSCLC an opportunity to receive a chemotherapy-free, oral option once they have progressed following treatment with standard, platinum based, first line treatment.8,9

INDICATIONS 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.

REFERENCES
1. Baxevanos P, Mountzios G. Novel chemotherapy regimens for advanced lung cancer: have we reached a plateau? Ann Transl Med. 2018;6(8):139.
2. Santos ES, Hart L. Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib. Onco Targets Ther. 2020 Sep 22;13:9305-9321.
3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.1.2016. ©National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed November 2, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org.
4. Paz-Ares L, et al. Pembrolizumab plus Chemotherapy for Squamous NSCLC. N Engl J Med. 2018;379: 2040-2051; DOI:10.1056/NEJMoa1810865
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.8.2020. ©National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed November 2, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org.
6. Paik PK, et al. New treatment options in advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book. 2019;39:e198-e206.
7. Hirsh V. Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib. BioDrugs. 2015;29(3):167 183.
8. Soria JC, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897 907.
9. GILOTRIF [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.

Please review the Full Prescribing Information and Patient Information at www.gilotrifhcp.com

Minimal Residual Disease Testing in Multiple Myeloma: The Time has Arrived.

Special Written by Dr. Robert Rifkin, Rocky Mountain Cancer Center | Sponsored by Adaptive Biotechnologies

Rising Importance of MRD Testing in Multiple Myeloma

In the early 2000s, the average overall survival rate for patients with multiple myeloma (MM) was only 3 years.1 With the advent of new therapies over the last 5 years, many patients with MM can now expect to achieve clinical complete response (CR). However, while this trend is expected to continue, the majority of these patients who achieve CR will eventually relapse, suggesting that existing therapies are insufficient and more sensitive testing is necessary to identify potentially undetected malignant cells.2

Minimal residual disease (MRD) refers to the small number of cancer cells that can remain in a patient’s body during and after treatment and may eventually cause recurrence of the disease. MRD is commonly assessed in lymphoid malignancies such as B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). In the event of the persistence of malignant B cells, the possibility of recurrence is more likely.3 To address this, MRD testing is now being used to monitor the effectiveness of therapies as well as subsequent treatment decisions by identifying the presence of MRD over time.

The Application of Next-Generation Sequencing

MRD testing in lymphoid malignancies has become increasingly valuable in predicting patient outcomes. While next-generation flow cytometry has been used for MRD testing in B-ALL, and has been standardized for highly sensitive MRD measurements (e.g. 10-6), as reported by Theunissen and Colleagues, standard flow cytometry is limited to a level of detection of 1 malignant cell in 10,000 cells assessed (e.g. 10-4)4. In contrast, next-generation sequencing (NGS) has a level of sensitivity of up to 1 malignant cell in 1,000,000 cells assessed (e.g. 10-6). 5,6

In the era of NGS, it is now possible to assess MRD beyond the standard response criteria for assessment of treatment efficacy. In a review that evaluated the prognostic value of MRD, patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of initial treatment.7

The clonoSEQ® Assay, an in vitro diagnostic (IVD) test that uses multiplex PCR and NGS to identify and quantify disease-associated DNA sequence rearrangements (or clonotypes) of the IgH, IgK and IgL receptor genes, has been FDA-cleared to monitor MRD in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). The assay can accurately and precisely quantify MRD at the DNA-sequence level. According to a recent analysis, clonoSEQ maintains accurate reporting of disease burden down to one malignant cell in 1 million healthy cells provided sufficient sample input.5,6

Patient-specific clonal sequences are identified at the time of diagnosis or high disease burden and can be used as a marker for MRD. Oftentimes, at the conclusion of therapy, MRD measurements can also be used to firmly establish a diagnosis of a molecular complete remission. In order to do this with an NGS assay, it is important to remember to obtain a baseline fresh bone marrow sample at the time of diagnosis. This will facilitate the identification of a dominant clone. In the event such a sample is not available, it is possible to identify the clone utilizing archived or fixed tissue.

Incorporating MRD Testing in Clinical Practice Guidelines

The future of MRD testing in MM, as reviewed by Oliva and colleagues, is clear: MRD testing in MM will be increasingly important as we strive for a cure.8 The course of MM is highly variable, and the clinical behavior is equally diverse. For this reason, MRD testing has been incorporated into clinical practice guidelines as a Standard of Care, as evidenced by the NCCN’s recommendation to assess MRD after each stage of treatment: post-induction, post-high-dose therapy/ASCT, post-consolidation, post-maintenance. NCCN updated their guidelines recently to note that during upfront diagnosis you could consider “baseline clone identification and storage of aspirate samples for future MRD testing by NGS”.9

In short, MRD testing in lymphoid malignancies should be leveraged to track a patient’s disease over time. This approach may aid in key clinical decision-making throughout the course of treatment. For example, if MRD is present in a B-ALL patient, therapy with blinatumomab is suggested over other agents and is now part of guidelines. If MRD is negative, alternative maintenance with the POMP regimen is often employed. Similar guidelines for MM and CLL are on the therapeutic horizon, and I suspect will soon be incorporated into evidence-based guidelines.

As we enter the new area of targeted therapy and the development of novel agents for all the diseases, testing for MRD will become increasingly important. In order to maintain a state-of-the-art clinical practice, and to foster best clinical practice in patient care, it essential that every clinician and stakeholder in the patient’s journey become familiar with these new MRD technologies, and how to integrate them into his or her overall care plan in order to improve clinical outcomes.

Important information

clonoSEQ is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect measurable residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers as a CLIA-validated laboratory developed test (LDT) service. For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit https://www.clonoseq.com/technical-summary/.

References
1) Landgren O, Iskander K. J Intern Med. 2017;281(4):365-382.
2) Munshi NC, Anderson KC. J Clin Oncol. 2013;31 (20):2523-2526.
3) Perrot A, Lauwers-Cances V, Corre J, et al. Blood. 2018;132(23):2456-2464.
4) Theunissen P, Mejstrikova E, et al. Blood. (2017) 129 (3): 347–357.
5) clonoSEQ®. [technical summary]. Seattle, WA: Adaptive Biotechnologies; 2020.
6) Ching T, Duncan ME, et al. BMC Cancer. 2020; 20: 612.
7) Rajkumar SV, Kumar S. Mayo Clin Proc. 2016 Jan;91(1):101-19.
8) Oliva S, D’Agostino M, et al. Front Oncol. 2020; 10: 1.
9) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.1.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March September 22nd, 2020. To view the most recent and complete version of the guideline, go to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use of application and disclaims any responsibility for their application or use in any way.