FDA Approves OPDIVO® Combination for Advanced Esophageal Carcinoma

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

FDA Approves KYMRIAH® for Relapsed or Refractory Follicular Lymphoma

SUMMARY: The FDA on May 27, 2022, granted accelerated approval to KYMRIAH® (Tisagenlecleucel) for adult patients with Relapsed or Refractory Follicular Lymphoma after two or more lines of systemic therapy. The American Cancer Society estimates that in 2022, about 80,470 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 22% of all NHLs are Follicular Lymphomas (FL).

Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival of 6-8 years. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments. Patients with Follicular Lymphomas often experience a relapsing and remitting pattern of disease and may be exposed to multiple lines of therapy over the course of their disease. In spite of the availability of multiple systemic therapies for Follicular Lymphoma, the efficacy of these regimens drops off rapidly with later lines of therapy. Novel therapies are therefore being investigated to improve outcomes.

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. KYMRIAH® (genetically engineered T-cells) seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

The present FDA approval was based on the ELARA trial, which is an international, multicenter, single-arm, open-label trial in which the efficacy and safety of KYMRIAH® was investigated in adult patients with Relapsed/Refractory Follicular Lymphoma, after at least two prior therapies. A total of 97 patients received KYMRIAH® (0.6-6×108 CAR+ viable T cells) after lymphodepleting chemotherapy. Bridging therapy was permitted followed by disease assessment prior to KYMRIAH® infusion. Eligible patients had Grades 1-3A Relapsed/Refractory Follicular Lymphoma who had progressed on 2 or more lines of systemic therapy, (including an anti-CD20 antibody and an alkylating agent) or relapsed after Autologous hematopoietic Stem Cell Transplant. The median patient age was 57 years, 85% had Stage III-IV disease, 60% had a FLIPI score 3 or more, 65% had bulky disease, and 42% had LDH above the upper limit of normal. The median number of prior therapies was 4, 78% of patients were refractory to their last treatment and 60% progressed within 2 years of initial anti-CD20 based therapy. The Primary endpoint was Complete Response Rate (CRR) by central review per Lugano 2014 criteria. Secondary endpoints included Overall Response Rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), Safety, and cellular kinetics.

In the primary efficacy analysis, with a median follow up 10.6 months, the Overall Response Rate was 86% with a Complete Response Rate of 66%. The response rates were comparable among key high risk subgroups. The median Duration of Response was Not Reached, with 75% of responders still in response at 9 months. At a median follow up of 17 months, the response rates were maintained and the 12-month PFS was 67% and 9 month Duration of Response was 76%. For patients who had a Complete Response, the 12-month PFS was 86% and the estimated Duration of Response was 87%. Approximately 48% of patients experienced Cytokine Release Syndrome (CRS) within eight weeks of infusion, with no patients experiencing CRS of Grade 3 or higher.

It was concluded that after a median follow up of 17 months, KYMRIAH® demonstrated high Response Rates, as well as durable responses, with remarkable safety profile, thus providing a new treatment option for this difficult-to-treat patient group of patients with Relapsed or Refractory Follicular Lymphoma.

Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study. Thieblemont C, Dickinson M, Martinez-Lopez J, et al. Presented in an oral session at the 63rd American Society of Hematology Annual Meeting & Exposition (ASH) 2021:(Abstract #131).

IMFINZI® in Combination with Chemotherapy Improves Overall Survival in Advanced Biliary Tract Cancer

SUMMARY: Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

Patients with advanced bile tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by bile tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival, has been increasingly explored.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. IMFINZI® in combination with Gemcitabine and Cisplatin showed encouraging antitumor activity in a Phase II study, among patients with advanced bile tract cancers.

TOPAZ-1 is a double-blind, multicenter, global, Phase III trial conducted to evaluate the efficacy of first line immunotherapy given along with Gemcitabine and Cisplatin in patients with advanced metastatic biliary tract cancer. In this study, a total of 685 previously untreated patients with unresectable, locally advanced, recurrent or metastatic biliary tract cancer were randomized 1:1 to receive IMFINZI® (Durvalumab) 1500 mg IV every 3 weeks (N=341) or placebo (N=344), along with Gemcitabine 1000 mg/m2 IV and Cisplatin 25 mg/m2 IV given on Days 1 and 8, every 3 weeks for up to 8 cycles, followed by IMFINZI® 1500 mg IV every 4 weeks or placebo, until disease progression or unacceptable toxicity. Patients with recurrent disease more than 6 months following curative surgery or adjuvant therapy were also included. The median patient age was 64 years and approximately 50% of patients had an ECOG Performance Status of 0. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma versus gallbladder cancer). Approximately 56% had intrahepatic cholangiocarcinoma, followed by gallbladder cancer (25%) and extrahepatic cholangiocarcinoma (19%). The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), and Safety.

The Primary endpoint was met at the first interim analysis and treatment with IMFINZI® plus Gemcitabine and Cisplatin significantly improved Overall Survival compared with placebo plus chemotherapy, with a 20% reduction in the risk of death (HR=0.80; P=0.021). Progression Free Survival was also greatly improved with chemoimmunotherapy vs chemotherapy alone (HR=0.75; P=0.001). The Objective Response Rate was was 26.7% in the IMFINZI® plus chemotherapy group and 18.7% in the placebo plus chemotherapy group. Grade 3 or 4 treatment-related adverse events were almost similar in both treatment groups (62.7% versus 64.9%), and treatment discontinuation due to adverse events was 8.9% in the IMFINZI® plus chemotherapy group and 11.4% in the placebo plus chemotherapy group.

It was concluded that in patients with advanced biliary tract cancers, IMFINZI® in combination with Gemcitabine and Cisplatin significantly improved Overall Survival and Progression Free Survival with manageable safety, when compared to chemotherapy alone, and should therefore be considered first line standard-of- care for this patient group.

A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (gemcis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Oh D-Y, He AR, Qin S, et al. J Clin Oncol. 2022;40(suppl 4):378. DOI:10.1200/JCO.2022.40.4_suppl.378.

Mutations of STK11/KRAS Genes and Efficacy of Immunotherapy in NSCLC

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMpower150 is a multicenter, open-label, randomized, Phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with Stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (ACP-Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (ABCP-Group B), or AVASTIN® plus Carboplatin and Paclitaxel (BCP-Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Among randomized patients with tumors demonstrating no ALK and EGFR mutations, ABCP was associated with significant improvements in Progression Free Survival (PFS) and Overall Survival (OS), compared with BCP, in an updated OS analysis. ABCP also prolonged OS and PFS compared with BCP in an exploratory subgroup analysis of patients with EGFR-sensitizing mutations.

The Serine‐Threonine Kinase 11 (STK11) gene is located on the short arm of chromosome 19 and germline STK11 mutations are often detected in Peutz‐Jeghers syndrome, an Autosomal Dominant disorder resulting in mucocutaneous hyperpigmentation, hamartomas throughout the gastrointestinal tract, and a predisposition for breast, lung, pancreas, and gastrointestinal malignancies including cancers of the colon and small bowel. Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of NSCLC (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. Although immune checkpoint inhibitors with or without chemotherapy have demonstrated survival benefit in patients with KRAS mutated tumors, it remains unclear how co-occurring STK11, KEAP1, and TP53 mutations affect outcomes following immune checkpoint blockade.

The authors in this publication conducted a retrospective exploratory analysis of the efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel), in patients with KRAS mutations and co-occuring STK11, KEAP1, or TP53 mutations, from the IMpower150 nonsquamous NSCLC patient population. Mutation status was determined by circulating tumor DNA Next-Generation Sequencing.

Among the KRAS mutated population, there was numerical improvement in median OS with ABCP compared to BCP (19.8 vs 9.9 months; HR=0.50), as well as PFS (8.1 vs 5.8 months; HR=0.42) respectively. The median OS with ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was 11.7 vs 9.9 months (HR=0.63), and PFS was 4.8 vs 5.8 months (HR=0.80), when compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel). When compared to BCP, the ABCP group showed numerically greater survival than the ACP group among KRAS mutated patients. These results were consistent with reported survival improvements with immune checkpoint inhibitors in KRAS-mutant NSCLC.

In KRAS mutant patients across PD-L1 subgroups, OS and PFS were longer with ABCP when compared with BCP, but in PD-L1-low and PD-L1-negative subgroups, OS with ACP was similar to BCP. Conversely, in KRAS wild type patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups.

KRAS was frequently comutated with STK11, KEAP1, and TP53 and these subgroups conferred different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-wild type and/or KEAP1wild type. In KRAS mutated patients with co-occurring STK11 and/or KEAP1 mutations (44.9%) or TP53 mutations (49.3%), survival was longer with ABCP than with ACP or BCP.

It was concluded that this analysis supported previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. Even though the clinical efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel) and ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was favorable compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel) in these mutational subgroups, survival benefits were greater in the KRAS mutated and KEAP1 and STK11 wild type population versus KRAS mutated and KEAP1 and STK11 mutated population, suggesting both prognostic and predictive value of mutational analysis. The researchers added that these results suggest that TECENTRIQ® in combination with AVASTIN® and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. West JH, McCleland M, Cappuzzo, F, et al. J Immunother Cancer. 2022 Feb;10(2):e003027. doi: 10.1136/jitc-2021-003027.

IMFINZI® Plus Tremelimumab Significantly Improves Overall Survival in Advanced Hepatocellular Carcinoma

SUMMARY: The American Cancer Society estimates that for 2022, about 41,260 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US and 30,520 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is also a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis and only 7% of patients with advanced disease survive five years. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. Tremelimumab is a human monoclonal antibody that targets and blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. In a Phase II study, a single priming dose of Tremelimumab added to IMFINZI® (STRIDE regimen), showed encouraging clinical activity and limited toxicity in patients with unresectable HepatoCellular Carcinoma (HCC), suggesting that a single exposure to Tremelimumab may be sufficient to improve upon activity of IMFINZI®.

HIMALAYA trial is a randomized, open-label, multicentre, global, Phase III study conducted in 190 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. In this study, 1,171 patients with Stage III or IV unresectable hepatocellular carcinoma who had received no prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue), were randomly assigned to receive either the STRIDE regimen which consisted of a single priming dose of Tremelimumab 300 mg IV added to IMFINZI® (Durvalumab) 1500 mg IV, followed IMFINZI® 1500 mg IV by every 4 weeks (N= 393), IMFINZI® monotherapy given at the same dose and schedule (N = 389) or NEXAVAR® (Sorafenib) 400 mg orally BID (N=389). Enrolled patients had ECOG performance status of 0 or 1 and Child-Pugh A disease and could not have main portal vein thrombosis. Patients were stratified based on macrovascular invasion (Yes versus No), etiology of liver disease (Hepatitis B virus versus Hepatitis C virus versus others), and ECOG Performance Status (0 versus 1). The Primary endpoint was Overall Survival (OS) for STRIDE regimen versus NEXAVAR® and key Secondary endpoints included OS for IMFINZI® monotherapy versus NEXAVAR®, Objective Response Rate and Progression Free Survival (PFS) for STRIDE and IMFINZI® monotherapy.

The Primary objective of this study was met at the time of data cutoff. At a median follow up of 16.1 months of treatment with the STRIDE regimen, there was a 22% reduction in the risk of death for patients who received the STRIDE regimen compared to NEXAVAR® alone (HR=0.78; P=0.0035). The median OS with the STRIDE regimen was 16.4 months, compared with 13.8 months with NEXAVAR®, and the 3 year OS rate was 30.7% versus 20.2 % respectively. The Overall Response Rate for the combination STRIDE regimen was 20.1% compared to 5.1% for NEXAVAR®

IMFINZI® monotherapy met the objective of OS non-Inferiority to NEXAVAR® (HR=0.86; 96% CI, 0.73–1.03) and the median OS after 16.5 months of median follow up was 16.6 months with IMFINZI® monotherapy versus 13.8 months with NEXAVAR®, and the 3 year OS rate was 24.7% versus 20.2 % respectively. The Overall Response Rate with IMFINZI® monotherapy was 17% compared to 5.1% for NEXAVAR®. The Secondary endpoint of PFS was not superior in either investigational study group relative to the NEXAVAR® control arm.

It was concluded that HIMALAYA is the first large Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody Tremelimumab, to another checkpoint inhibitor, IMFINZI®. This combination regimen (STRIDE) demonstrated superior efficacy and a favorable benefit-risk profile when compared with NEXAVAR® and should be considered a novel , first-line standard of care systemic therapy, for patients with unresectable Hepatocellular Carcinoma.

Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. Abou-Alfa GK, Chan SL, Kudo M, et al. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379

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

BMS Sponsored Content

By Dr Rahul RavillaSponsored 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.

References:

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

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1506-US-2200006 03/22

FDA Approves Neoadjuvant OPDIVO® and Chemotherapy Combination for Early Stage Non Small Cell Lung Cancer

SUMMARY: The FDA on March 4, 2022, approved OPDIVO® (Nivolumab) with platinum-doublet chemotherapy for adult patients with resectable Non Small Cell Lung Cancer (NSCLC) in the neoadjuvant setting. This represents the first FDA approval for neoadjuvant therapy for early stage NSCLC. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Surgical resection with a curative intent is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease, unless medically unfit. These numbers are likely to increase with the implementation of Lung Cancer screening programs. These patients are often treated with platinum-based adjuvant chemotherapy/immunotherapy following surgical resection, to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

CHECKMATE-816 is an open-label, multicenter, randomized Phase III study which evaluated OPDIVO® plus chemotherapy versus chemotherapy alone as neoadjuvant treatment in patients with resectable Stage IB to IIIA NSCLC. In this trial, 358 patients with clinical Stage IB to Stage IIIA resectable NSCLC, with an ECOG Performance Status of 0 to 1 and no known sensitizing EGFR mutations or ALK alterations, were randomly assigned 1:1 to receive OPDIVO® at a dose of 360 mg IV along with platinum-doublet chemotherapy every 3 weeks for 3 doses (N=179) or chemotherapy alone on the same schedule (N=179). Patients then underwent radiologic staging and surgical resection within 6 weeks of neoadjuvant therapy. They then had the option of adjuvant therapy with or without radiation therapy, and were followed up. Both treatment groups were well balanced with regards to age, sex, histology and smoking status. About two-thirds of the patients had Stage IIIA disease. The median patient age was 65 years and patients were stratified by cancer stage, gender and PD-L1 status (1% or higher versus less than 1%). Tumor Mutational Burden results were available for 50% of patients. The Primary end points of this study were pathologic Complete Response (pCR), defined as the absence of viable tumor cells in lung and lymph nodes, and Event Free Survival (EFS). Secondary endpoints include major pathological response and Overall Survival. Key exploratory endpoints included feasibility of surgery and surgery-related adverse events.

The pCR rate was 24% in the OPDIVO® plus chemotherapy group and 2.2% in the chemotherapy alone group. The pCR improvement was noted with the OPDIVO® plus chemotherapy combination regardless of disease stage and irrespective of radiologic downstaging. Overall, 83% of patients assigned to OPDIVO® plus chemotherapy and 78% of patient’s assigned to chemotherapy alone achieved R0 resection, with 10% versus 74% median residual viable tumor cells noted in the primary tumor bed respectively. Lung-sparing surgery (lobectomy) was performed in 77% of patients assigned to OPDIVO® plus chemotherapy versus 61% among those assigned to chemotherapy alone. The median EFS was 31.6 months in the OPDIVO® plus chemotherapy group and 20.8 months for those receiving chemotherapy alone (HR=0.63; P=0.0052).

The authors concluded that CheckMate 816 is the first Phase III trial to show a benefit for neoadjuvant immunotherapy plus platinum-doublet chemotherapy in earlier stage resectable NSCLC, with marked improvement in pathologic Complete Response rate, without any meaningful increase in toxicity or decrease in the feasibility of surgery. It is likely that the higher pathologic Complete Response rate may translate into higher cure rates, with longer follow up.

Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). Spicer J, Wang C, Tanaka F, et al. J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503

FDA Approves YESCARTA® for Second Line Treatment of Large B-cell Lymphoma

SUMMARY: The FDA on April 1, 2022, approved YESCARTA® (Axicabtagene ciloleucel) for adult patients with Large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy.

What is (CAR) T-cell immunotherapy? Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. It is a therefore a customized treatment created using patient’s own T cells to destroy cancer cells.Chimeric-Antigen-Receptor-T-Cell-Immunotherapy

YESCARTA® is a Chimeric Antigen Receptor (CAR) T cell immunotherapy and consists of autologous T cells that are genetically modified to produce a CAR protein, allowing the T cells to seek out and destroy cancer cells expressing the antigen CD19, which is found uniquely on B cells. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome (CRS), an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum Ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the central nervous system and eradicate cancer cells. CD19 antigen is expressed by majority of the B cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL).

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3 to 4% each year. Outcomes for patients with relapsed/refractory disease, is poor, with an Objective response Rate (ORR) of 26%, Complete Response (CR) rate of 8% and a median Overall Survival (OS) of 6.6 months. There is therefore a significant unmet need in this patient group.

The present FDA approval was based on ZUMA-7, an international, randomized, open-label, multicenter Phase III trial, which compared the safety and efficacy of YESCARTA® with that of the current Standard of Care, as second-line treatment in patients with relapsed or refractory Large B-Cell Lymphoma (LBCL). In this study, 359 enrolled patients were randomized 1:1 to receive either a single infusion of YESCARTA® following Fludarabine and Cyclophosphamide lymphodepleting chemotherapy (N=180) or Standard of Care investigator-chosen second-line therapy, consisting of 2 or 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous Hematopoietic Stem Cell Transplantation (HSCT), in patients who attained Complete Remission or Partial Remission (N=179). Patients randomized to YESCARTA® underwent leukapheresis, and then, lymphodepleting chemotherapy with Fludarabine 30 mg/m2/day and Cyclophosphamide 500 mg/m2/day for 3 days, followed by a single infusion of YESCARTA® at 2 × 106 CAR T cells/kg. Corticosteroid bridging therapy was allowed for patients with high disease burden at screening. Lack of response to chemotherapy was the most common reason for not receiving autologous HSCT, and 35% received on-protocol HSCT. Both treatment groups were well balanced. The median patient age was 59 years, 30% of patients were aged 65 years or older, 79% of patients had Stage III/IV disease, 74% of patients were primary refractory to their frontline therapy, 16% had high-grade B-cell lymphoma (double/triple-hit), and 44% of patients had elevated LDH levels. Key stratification factors included response to frontline therapy and second-line Age-Adjusted International Prognostic Index (sAAIPI) stage. The Primary endpoint was Event Free Survival (EFS), defined as time from randomization to disease progression, start of new lymphoma therapy, or death, and was determined by an Independent Review Committee (IRC). Secondary endpoints included Objective Response Rates (ORR), Overall Survival (OS), Progression Free Survival (PFS), Duration of Response, Safety, and Patient Reported Outcomes (PRO).

At a median follow-up of 24.9 months, the EFS was significantly longer in the YESCARTA® group and the estimated median EFS was 8.3 months in the YESCARTA® group compared with 2.0 months for those receiving Standard of Care chemotherapy (HR=0.40; P<0.0001). The estimated 18-month EFS rate was 41.5% in the YESCARTA® group and 17.0% in the standard therapy group. The IRC-assessed best ORR was statistically significantly higher in the YESCARTA® arm compared to the standard therapy arm (83% versus 50% respectively) and Complete Response rate was 65% versus 32% respectively. EFS was superior with YESCARTA® over Standard of Care across all key patient subgroups, including age, response to first-line therapy at randomization, second-line Age-Adjusted International Prognostic Index (sAAIPI) stage, and prognostic markers.

The authors concluded that ZUMA-7 met its primary EFS end point, demonstrating statistically significant and clinically meaningful improvement in efficacy with YESCARTA® compared to second-line Standard of Care in relapsed/ refractory Large B-Cell Lymphoma, with a 4-fold greater median EFS, a 33% higher Objective Response Rate, a doubling of the Complete Response rate, Event Free Survival improvements across key subgroups, and should therefore be a new standard for patients with second-line relapsed/refractory Large B-Cell Lymphoma. The NCCN updated its clinical practice guidelines to include YESCARTA® as a Category 1 recommendation for patients with early relapsed or primary-refractory Diffuse Large B-Cell Lymphoma.

Primary analysis of ZUMA 7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard of care therapy in patients with relapsed/refractory large B-cell lymphoma. Locke F, Miklos DB, Jacobson CA, et al. Blood. 2021;138(suppl 1):2. doi:10.1182/blood-2021-148039

FDA Approves Single Agent KEYTRUDA® for Advanced Endometrial Carcinoma

SUMMARY: The FDA on March 21, 2022 approved KEYTRUDA® (Pembrolizumab) as a single agent, for patients with advanced endometrial carcinoma that is MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting, and who are not candidates for curative surgery or radiation. The FDA also approved VENTANA MMR RxDx Panel (Ventana Medical Systems/Roche Tissue Diagnostics) as a companion diagnostic device to select patients with dMMR in solid tumors that are eligible for treatment with KEYTRUDA® The FDA previously approved the FoundationOne CDx (F1CDx, Foundation Medicine, Inc.) as a companion diagnostic device to select patients with MSI-H in solid tumors that are eligible for treatment with KEYTRUDA®.

The American Cancer Society estimates that approximately 65,950 new cases of uterine cancer will be diagnosed in 2022 and about 12,550 individuals will die of the disease. Endometrial carcinoma is the second most prevalent gynecologic cancer in women worldwide, and its incidence has been increasing. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, family history, diet and exercise, drugs such as Tamoxifen, etc. Patients with advanced or recurrent endometrial cancer are often treated with a combination of Carboplatin and Paclitaxel. Treatment options following failure of first-line therapy for this patient group however are limited, with single agent response rates of 10-15% and 5-year survival rates of approximately 17%.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an increase in CD3-positive, CD8-positive, and Programmed Death-1 (PD-1) expressing Tumor Infiltrating Lymphocytes and Programmed Death Ligand-1 (PD-L1) expressing intraepithelial and peritumoral immune cells, compared with MicroSatellite Stable cancers. This results in an enhanced antitumor immune response.

MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system. Defective MMR can be a sporadic or heritable event and can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma-HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of Tumor Infiltrating Lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with Immune Checkpoint Inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

KEYTRUDA® (Pembrolizumab) 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. The FDA in 2021 also approved KEYTRUDA® in combination with the multireceptor Tyrosine Kinase Inhibitor LENVIMA® (Lenvatinib) for patients with advanced endometrial carcinoma, irrespective of tumor MSI status based on the KEYNOTE-146 study.

KEYNOTE-158 is a multicenter, nonrandomized, open-label, multicohort, Phase II trial of KEYTRUDA® evaluating predictive biomarkers, in patients with advanced unresectable and/or metastatic solid tumors, who had progressed on standard of care therapy. The present FDA approval was based on the results from a total of 90 patients with MSI-H/dMMR endometrial cancer, who were enrolled in cohort D (11 patients) and cohort K (79 patients) of KEYNOTE-158 trial. This group of previously treated patients received KEYTRUDA® 200 mg IV once every 3 weeks for 35 cycles. The median patient age was 64 years, 48% had received 2 or more lines of prior therapy, and the majority of patients (68%) had received prior radiation therapy. The median duration of treatment was 8.3 months. The Primary end point was Objective Response Rate (ORR) by independent central radiologic review. Secondary end points included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), and Safety.

The Objective Response Rate was 48%, and median Duration of Response was not reached after a median follow up of 42.6 months. The median PFS was 13.1 months, and median Overall Survival was Not Reached. No new safety signals were identified and the immune-mediated adverse events or infusion reactions occurred in 28% of patients and 7% were Grades 3-4, with no fatal events.

It was concluded that KEYTRUDA® demonstrated robust and durable antitumor activity with manageable toxicity in patients with advanced MSI-H/dMMR endometrial cancer, and should be considered as a treatment option for patients with advanced MSI-H/dMMR endometrial cancer, following failure on prior therapy.

Pembrolizumab in Patients With Microsatellite Instability–High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. O’Malley DM, Bariani GM, Cassier PA, et al. DOI: 10.1200/JCO.21.01874 Journal of Clinical Oncology 40, no. 7 (March 01, 2022) 752-761. Published online January 06, 2022.

FDA Approves LAG-3 Inhibitor OPDUALAG® and OPVIDO® in Advanced Untreated Melanoma

SUMMARY: The FDA on March 18, 2022, approved OPDIVO® (Nivolumab) and OPDUALAG® (Relatlimab-rmbw), for adult and pediatric patients 12 years of age or older, with unresectable or metastatic melanoma. The American Cancer Society’s estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® (Ipilimumab), a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 was compared with PD-1 inhibitors, OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab) in patients with advanced melanoma, and both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), and with a better safety profile. In the CheckMate 067, which is a double-blind Phase III study, results from the 6.5 year analysis showed that a combination of OPDIVO® plus YERVOY® demonstrated significant improvement in OS and PFS, when compared to single agent OPDIVO® or single agent YERVOY®.

In an attempt to improve outcomes and enhance the risk-benefit profiles of immunotherapy combinations, alternate Immune checkpoints are being explored. LAG-3 (Lymphocyte-Activation Gene 3 (LAG-3), is a cell-surface receptor expressed on immune cells including activated CD4+ T cells, and negatively regulates T-cell proliferation, inhibits T-cell activation and effector T-cell function. LAG-3 is upregulated in several tumor types, including malignant melanoma.

OPDUALAG® (Relatlimab) is a first-in-class human IgG4 LAG-3–blocking antibody that binds to LAG-3 and restores the effector function of exhausted T cells, resulting in T cell proliferation, activation and a therapeutic response. In preclinical studies, dual inhibition of LAG-3 and PD-1 showed synergistic antitumor activity, and in a Phase I/II trial, the combination of OPDUALAG® and OPDIVO®, demonstrated durable Objective Responses in patients with Relapsed/Refractory melanoma following treatment with PD-1 inhibitors.

RELATIVITY-047 is a Phase II/III, global, multicenter, double-blind, randomized trial in which a fixed-dose combination of OPDUALAG® and OPDIVO® was compared with OPDIVO® alone, in patients with previously untreated metastatic or unresectable melanoma. In this study, 714 patients were randomly assigned 1:1 to receive OPDUALAG® 160 mg and OPDIVO® 480 mg in a fixed-dose combination (N=355) or single agent OPDIVO® 480 mg (N=359). Both regimens were administered as an IV infusion over 60 minutes every 4 weeks, and treatment was continued until disease progression, unacceptable toxicities, or withdrawal of consent. Both treatment groups were well balanced and patients were stratified according to LAG-3 expression (1% or more versus less than 1%), PD-L1 expression (1% or more versus less than 1%), BRAF V600 mutation status, and metastasis stage (M0 or M1 with normal LDH levels versus M1 with elevated LDH levels). More patients in the OPDUALAG®- OPDIVO® group had Stage M1c disease, and a larger proportion had three or more sites with at least one metastatic lesion. The Primary end point was Progression Free Survival (PFS) as assessed by blinded Independent Central Review. Secondary end points included Overall Survival and Objective Response Rate (ORR). The median follow up was 13.2 months and the use of subsequent therapies upon progression was similar in the two treatment groups.

The median PFS was 10.1 months with OPDUALAG®- OPDIVO® as compared with 4.6 months with OPDIVO® (HR=0.75; P=0.006). The PFS benefit at 12 months with OPDUALAG®- OPDIVO® was 47.7% compared to 36.0% with OPDIVO®. The PFS benefit was more so with Relatlimab- OPDIVO® across key prespecified subgroups, compared to single agent OPDIVO®. Patients with poor prognosis characteristics, such as visceral metastases, high tumor burden, elevated levels of serum LDH, or mucosal or acral melanoma, had better outcomes with OPDUALAG®- OPDIVO® combination, than with single agent OPDIVO®. Further, a benefit with OPDUALAG®- OPDIVO® was also noted across BRAF mutant and wild-type subgroups, compared to OPDIVO®. Expression of LAG-3 or PD-L1 was not useful in predicting a benefit of OPDUALAG®- OPDIVO® over single agent OPDIVO® and appears to NOT have a clear role in treatment selection.

Grade 3 or 4 toxicities occurred in 18.9% of patients in the OPDUALAG®- OPDIVO® group and in 9.7% of patients in the single agent OPDIVO® group. The Safety profile of OPDUALAG®- OPDIVO® appeared favorable, when compared with dual checkpoint inhibition with a CTLA-4 inhibitor and PD-1 inhibitor combination (YERVOY®- OPDIVO®) in the CheckMate 067 trial, in which Adverse Events were noted in 59% of patients.

It was concluded that inhibition of two immune checkpoints, LAG-3 and PD-1, provided greater benefit with regards to Progression Free Survival, than inhibition of PD-1 alone, in patients with previously untreated metastatic or unresectable melanoma. The authors added that these results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma, and establishes LAG-3 as the third immune checkpoint pathway, thus providing more treatment options for patients with advanced melanoma.

Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. Tawbi HA, Schadendorf D, Lipson EJ, et al. for the RELATIVITY-047 Investigators. N Engl J Med 2022;386:24-34.