Tag: Esophageal Cancer

FDA Approves TEVIMBRA® for Advanced Esophageal Squamous Cell Carcinoma

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SUMMARY: The FDA on March 14, 2024 approved TEVIMBRA® (Tislelizumab-jsgr) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. The American Cancer Society estimates that in 2024, about 22,370 new cases of esophageal cancer will be diagnosed in the US and about 16,130 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases. Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

Tislelizumab is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.

The present approval was based on RATIONALE 302 study, which is a global, randomized, open-label, Phase III trial, designed to investigate the efficacy and safety of TEVIMBRA® when compared with investigators choice of chemotherapy as a second-line treatment, for patients with unresectable, locally advanced or metastatic ESCC. In this study, 512 patients (N=512) with advanced or metastatic ESCC who had progressed during or after first-line systemic treatment were randomly assigned 1:1 to receive either Tislelizumab 200 mg IV every 3 weeks or investigator’s choice of chemotherapy. Those in the chemotherapy group received one of the following regimens: Paclitaxel 135-175 mg/m2 IV every 3 weeks or 80-100 mg/m2 IV weekly, Docetaxel 75 mg/m2 IV every 3 weeks or Irinotecan 125 mg/m2 IV Day 1 and Day 8 every 3 weeks. Stratification factors included ECOG PS and choice of chemotherapy. The Primary end point of this trial was Overall Survival (OS) in the Intention-to-Treat (ITT) population. Secondary end points included Progression Free Survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.

The trial met its Primary endpoint with a statistically significant and clinically meaningful survival benefit for TEVIMBRA® compared with chemotherapy. The median OS in the TEVIMBRA® group was 8.6 months compared to 6.3 months in the chemotherapy group (HR=0.70; P=0.0001). This survival benefit was noted across the predefined subgroups, including PD-L1 status, race, and region. In the subset of patients with a PD-L1 CPS of at least 10%, the median OS with Tislelizumab was 10.3 months versus 6.8 months with chemotherapy (HR=0.54; P=0.0006). The 6-month PFS rates in the Tislelizumab and chemotherapy groups were 21.7% and 14.9% respectively, 12-month PFS rates were 12.7% and 1.9%. The Overall Response Rate was higher in the Tislelizumab group versus chemotherapy group (20.3% versus 9.8%) and the median Duration of Response was 7.1 months versus 4.0 months, respectively. The safety profile of Tislelizumab was also favorable over chemotherapy.

It was concluded that Tislelizumab significantly improved Overall Survival compared with chemotherapy as second-line therapy in patients with advanced or metastatic Esophageal Squamous Cell Carcinoma, with a tolerable safety profile. This survival benefit was even more in patients with PD-L1 CPS of 10% or more. Studies are underway, evaluating Tislelizumab in combination with chemotherapy in treatment naïve patients with advanced esophageal carcinoma.

Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. Shen L, Kato K, Kim S-B, et al. J Clin Oncol.2022;40:3065-3076.

FDA Approves OPDIVO® Combination for Advanced Esophageal Carcinoma

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SUMMARY: The FDA on May 27, 2022, approved OPDIVO® (Nivolumab) in combination with Fluoropyrimidine and Platinum-based chemotherapy, as well as OPDIVO® in combination with YERVOY® (Ipilimumab) for the first-line treatment of patients with advanced or metastatic esophageal Squamous Cell Carcinoma. The American Cancer Society estimates that in 2022, about 20,640 new cases of esophageal cancer will be diagnosed in the US and about 16,410 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases.

Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. It has been noted that approximately 50% of patients with advanced esophageal Squamous Cell Carcinoma express tumor-cell Programmed Death Ligand 1 (PD-L1) greater than 1%. In the ATTRACTION-3 multicentre, Phase III trial, treatment with OPDIVO® was associated with a significant improvement in Overall Survival, compared with chemotherapy, in previously treated patients with advanced esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression. In the CheckMate 649 Phase III trial involving patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma, first-line treatment with OPDIVO® plus chemotherapy resulted in a significant Overall Survival (OS) and Progression Free Survival (PFS) benefit, as compared with chemotherapy alone, as well as durable Objective Response Rate (ORR), with an acceptable safety profile.

CheckMate 648 is a global, open-label, Phase III trial in which the efficacy and safety of both an Immune Checkpoint Inhibitor in combination with chemotherapy and a dual Immune Checkpoint Inhibitor combination was evaluated in previously untreated patients with advanced esophageal Squamous Cell Carcinoma. The researchers herein reported the results for OPDIVO® plus chemotherapy and for OPDIVO® plus YERVOY® (Ipilimumab) as compared with chemotherapy alone. In this study, 970 patients with previously untreated, unresectable, advanced, recurrent or metastatic esophageal Squamous Cell Carcinoma were randomly assigned 1:1:1 to receive OPDIVO® plus chemotherapy (N=321), OPDIVO® plus YERVOY® (N=325), or chemotherapy alone. Patients in the OPDIVO® plus chemotherapy group received OPDIVO® 240 mg IV every 2 weeks and chemotherapy consisted of Fluorouracil 800 mg/m2 IV Days 1-5 and Cisplatin 80 mg/m2 IV on Day 1, given every 4 weeks. The OPDIVO® plus YERVOY® group received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. Patients could receive OPDIVO® or OPDIVO® plus YERVOY® for a maximum of 2 years. Demographic and baseline clinical characteristics were balanced across the treatment groups and in patients with tumor-cell PD-L1 expression of 1% or greater (49% of patients in each treatment group had tumor-cell PD-L1 expression of 1% or greater). The Primary end points were Overall Survival (OS) and Progression Free Survival (PFS), as determined by Blinded Independent Central Review (BICR), with hierarchical testing performed first in patients with tumor-cell PD-L1 expression of 1% or greater and then in the overall population. The Secondary end points included Objective Response Rate (ORR), which was also assessed by BICR.

After a minimum follow up period of 13 months, Overall Survival was significantly longer with OPDIVO® plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (15.4 months versus 9.1 months; HR=0.54; P<0.001) and in the overall population (13.2 months versus 10.7 months; HR=0.74; P=0.002). These findings suggested a 46% and 26% lower risk of death respectively with OPDIVO® plus chemotherapy, than with chemotherapy alone. Overall Survival was also significantly longer with OPDIVO® plus YERVOY® than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (13.7 months versus 9.1 months; HR=0.64; P=0.001) and in the overall population (12.7 months versus 10.7 months; HR=0.78; P=0.01).

There was a significant improvement in Progression Free Survival seen with OPDIVO® plus chemotherapy over chemotherapy alone, among patients with tumor-cell PD-L1 expression of 1% or greater (HR=0.65; P=0.002). This PFS benefit was not seen with OPDIVO® plus YERVOY®, as compared with chemotherapy. The incidence of Grade 3 or 4 treatment-related Adverse Events was 47% with OPDIVO® plus chemotherapy, 32% with OPDIVO® plus YERVOY® and 36% with chemotherapy alone.

Treatment with either OPDIVO®-based regimens resulted in a higher Complete Response rate, as well as in more durable responses, than chemotherapy alone. Of the three treatment regimens, OPDIVO® plus chemotherapy led to the highest Objective Response Rate and OPDIVO® plus YERVOY® resulted in the longest median Duration of Response.

It was concluded that first-line treatment of advanced esophageal Squamous Cell Carcinoma with either OPDIVO® plus chemotherapy or OPDIVO® plus YERVOY®, resulted in a significantly longer Overall Survival benefit and durable responses, than chemotherapy alone.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. Doki Y, Ajani JA, Kato K, et al. N Engl J Med 2022;386:449-462

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

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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).1 The 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.3,4 EAC incidence rates have been increasing over the past 5 decades in Western countries.4 Recent 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).11 The 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.13 The 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.11 This 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.

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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

OPDIVO® Combination Improves Overall Survival in Advanced Esophageal Carcinoma

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SUMMARY: The American Cancer Society estimates that in 2022, about 20,640 new cases of esophageal cancer will be diagnosed in the US and about 16,410 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases.

Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. It has been noted that approximately 50% of patients with advanced esophageal Squamous Cell Carcinoma express tumor-cell Programmed Death Ligand 1 (PD-L1) greater than 1%. In the ATTRACTION-3 multicentre, Phase III trial, treatment with OPDIVO® was associated with a significant improvement in Overall Survival, compared with chemotherapy, in previously treated patients with advanced Esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression. In the CheckMate 649 Phase III trial involving patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma, first-line treatment with OPDIVO® plus chemotherapy resulted in a significant Overall Survival (OS) and Progression Free Survival (PFS) benefit, as compared with chemotherapy alone, as well as durable Objective Response Rate (ORR), with an acceptable safety profile.

CheckMate 648 is a global, open-label, Phase III trial in which the efficacy and safety of both an Immune Checkpoint Inhibitor in combination with chemotherapy and a dual Immune Checkpoint Inhibitor combination was evaluated in previously untreated patients with advanced esophageal Squamous Cell Carcinoma. The researchers herein reported the results for OPDIVO® plus chemotherapy and for OPDIVO® plus YERVOY® (Ipilimumab) as compared with chemotherapy alone.

In this study, 970 patients with previously untreated, unresectable, advanced, recurrent or metastatic esophageal Squamous Cell Carcinoma were randomly assigned 1:1:1 to receive OPDIVO® plus chemotherapy (N=321), OPDIVO® plus YERVOY® (N=325), or chemotherapy alone. Patients in the OPDIVO® plus chemotherapy group received OPDIVO® 240 mg IV every 2 weeks and chemotherapy consisted of Fluorouracil 800 mg/m2 IV Days 1-5 and Cisplatin 80 mg/m2 IV on Day 1, given every 4 weeks. The OPDIVO® plus YERVOY® group received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. Patients could receive OPDIVO® or OPDIVO® plus YERVOY® for a maximum of 2 years. Demographic and baseline clinical characteristics were balanced across the treatment groups and in patients with tumor-cell PD-L1 expression of 1% or greater (49% of patients in each treatment group had tumor-cell PD-L1 expression of 1% or greater). The Primary end points were Overall Survival (OS) and Progression Free Survival (PFS), as determined by Blinded Independent Central Review (BICR), with hierarchical testing performed first in patients with tumor-cell PD-L1 expression of 1% or greater and then in the overall population. The Secondary end points included Objective Response Rate (ORR), which was also assessed by BICR.

After a minimum follow up period of 13 months, Overall Survival was significantly longer with OPDIVO® plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (15.4 months versus 9.1 months; HR=0.54; P<0.001) and in the overall population (13.2 months versus 10.7 months; HR=0.74; P=0.002). These findings suggested a 46% and 26% lower risk of death respectively with OPDIVO® plus chemotherapy, than with chemotherapy alone. Overall Survival was also significantly longer with OPDIVO® plus YERVOY® than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (13.7 months versus 9.1 months; HR=0.64; P=0.001) and in the overall population (12.7 months versus 10.7 months; HR=0.78; P=0.01).

There was a significant improvement in Progression Free Survival seen with OPDIVO® plus chemotherapy over chemotherapy alone among patients with tumor-cell PD-L1 expression of 1% or greater (HR=0.65; P=0.002). This PFS benefit was not seen with OPDIVO® plus YERVOY®, as compared with chemotherapy. The incidence of Grade 3 or 4 treatment-related Adverse Events was 47% with OPDIVO® plus chemotherapy, 32% with OPDIVO® plus YERVOY® and 36% with chemotherapy alone.

Treatment with either OPDIVO®-based regimens resulted in a higher Complete Response rate, as well as in more durable responses, than chemotherapy alone. Of the three treatment regimens, OPDIVO® plus chemotherapy led to the highest Objective Response Rate and OPDIVO® plus YERVOY® resulted in the longest median Duration of Response.

It was concluded that first-line treatment of advanced esophageal squamous-cell carcinoma with either OPDIVO® plus chemotherapy or OPDIVO® plus YERVOY® resulted in a significantly longer Overall Survival benefit and durable responses, than chemotherapy alone.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. Doki Y, Ajani JA, Kato K, et al. N Engl J Med 2022;386:449-462

FDA Approves First Line KEYTRUDA® in Combination with Chemotherapy for Esophageal or Gastroesophageal Carcinoma

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SUMMARY: The FDA on March 22, 2021, approved KEYTRUDA® (Pembrolizumab) in combination with Platinum and Fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GastroEsophageal Junction (tumors with epicenter 1 to 5 cm above the GastroEsophageal Junction) carcinoma, who are not candidates for surgical resection or definitive chemoradiation. The American Cancer Society estimates that in the US about 19,260 new esophageal cancer cases will be diagnosed in 2021 and about 15,530 people will die of the disease. Esophageal cancer is more common among men than among women. Majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine. The prognosis for advanced esophageal cancer is poor, with median survival of less than 12 months.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

KEYNOTE-590 is a global, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, in which first line KEYTRUDA® plus chemotherapy was compared with placebo plus chemotherapy, in patients with locally advanced/unresectable or metastatic adenocarcinoma or esophageal Squamous Cell Carcinoma (ESCC) or Siewert type 1 EsophagoGastric Junction adenocarcinoma (EGJ), who were not candidates for surgical resection or definitive chemoradiation. In this study, 749 eligible patients, regardless of PD-L1 expression were randomized 1:1 to KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles (2 years) along with chemotherapy consisting of Cisplatin 80mg/m2 IV given on day 1, plus 5FU 800 mg/m2 IV given on days 1-5, every 3 weeks for 6 cycles, or placebo plus chemotherapy. Treatment was continued until disease progression or unacceptable toxicity, and crossover was not permitted. Approximately 50% of all patients had tumors with a PD-L1 Combined Positive Score (CPS) 10 or more, and half the population was Asian. The dual Primary endpoints of the study were Overall Survival (OS) and Progression Free Survival (PFS). The researchers evaluated outcomes in the overall treatment population, in patients with a PD-L1 CPS 10 or more, and according to histology (Esophageal Squamous Cell Carcinoma versus adenocarcinoma). The Secondary end point was Objective Response Rate (ORR) in all patients. The median follow up was 10.8 months.

There was a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA® with chemotherapy. The median OS among all patients was 12.4 versus 9.8 months (HR=0.73; P<0.0001) and the median PFS among all patients was 6.3 versus 5.8 months, respectively (HR=0.65; P<0.0001). The confirmed ORR in all patients was 45% versus 29.3% (P < 0.0001), with a median Duration of Response of 8.3 versus 6.0 months, respectively. In patients with a PD-L1 CPS 10 or higher, the median OS with the KEYTRUDA® plus chemotherapy was 13.5 months versus 9.4 months with chemotherapy alone (HR=0.62; P<0.0001) and the median PFS was 7.5 months versus 5.5 months, respectively (HR=0.51; P<0.0001). The most common adverse reactions reported in 20% or more of patients who received the KEYTRUDA® combination were nausea, vomiting, constipation, diarrhea stomatitis, fatigue/asthenia, decreased appetite, and weight loss.

It was concluded that treatment with KEYTRUDA® plus chemotherapy combination resulted in superior Overall Survival, Progression Free Survival, and Objective Response Rate, with a manageable safety profile, when compared to chemotherapy alone, in patients with advanced untreated esophageal and EsophagoGastric Junction cancer. These data demonstrate that first line KEYTRUDA® plus chemotherapy is a new standard of care in this patient population.

Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Kato K, Sun J, Shah MA, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.

OPDIVO® (Nivolumab)

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The FDA on June 10, 2020 approved OPDIVO® for patients with unresectable, advanced, recurrent or metastatic Esophageal Squamous Cell Carcinoma (ESCC), after prior Fluoropyrimidine- and Platinum-based chemotherapy. OPDIVO® is a product of Bristol-Myers Squibb Co.