Category: Immuno Oncology

FDA Approves Bispecific Antibody LUNSUMIO® for Follicular Lymphoma

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SUMMARY: The FDA on December 22, 2022, granted accelerated approval to LUNSUMIO® (Mosunetuzumab-axgb), a bispecific CD20-directed CD3 T-cell engager for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2022, about 80,470 people were diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals died 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.

LUNSUMIO® is a first-in-class CD20 x CD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.

This FDA approval was based on the positive results from the Phase II GO29781 study, which is a multicenter, open-label, dose-escalation and dose-expansion trial evaluating the safety, efficacy, and pharmacokinetics of LUNSUMIO® in patients with heavily pretreated Follicular Lymphoma, including those who were at high risk of disease progression or whose disease was refractory to prior therapies. The efficacy population consisted of 90 enrolled patients with Relapsed or Refractory FL (Grade 1-3a) who had received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

LUNSUMIO® was administered IV in 21-day cycles with Cycle 1 step-up dosing of 1 mg on Cycle 1, Day 1, 2 mg on Cycle 1 Day 8, 60 mg on Cycle 1 Day 15, 60 mg on Cycle 2 Day 1, and 30 mg on Day 1 in subsequent cycles. Patients with a Complete Response discontinued therapy after 8 cycles. Patients with a Partial Response or Stable disease continued treatment for up to 17 cycles unless they experienced progressive disease or unacceptable toxicity. The Primary endpoint was Objective Response Rate (ORR) assessed by an Independent Review Committee according to standard criteria for Non-Hodgkins Lymphoma.

The ORR was seen in 80% of patients treated with LUNSUMIO® with 60% achieving Complete Responses. A majority of patients (57%) maintained responses for at least 18 months. With a median follow up of 14.9 months among responders, the estimated median Duration of Response was 22.8 months and the estimated Duration of Response at 12 months and 18 months was 62% and 57%, respectively. Among 218 patients with hematologic malignancies who received LUNSUMIO® at the recommended dose, the most common Adverse Event was Cytokine Release Syndrome (CRS) seen in 39% of patients, which can be severe and life-threatening. The median duration of CRS events was 3 days. Other common Adverse Events included fatigue, rash, fever and headache.

It was concluded from this study that in patients with heavily pretreated Follicular Lymphoma, chemotherapy-free, fixed-duration treatment with LUNSUMIO® induced high rates of Complete Remissions with favorable safety profile, allowing potential administration as an outpatient regimen.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Budde LE, Sehn LH, Matasar M, et al. The Lancet Oncology 2022; 23:1055-1065.

Tumor-Infiltrating Lymphocyte Therapy in Advanced Refractory Melanoma

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SUMMARY: The American Cancer Society estimates that in 2022, about 99,780 new cases of melanoma of the skin were diagnosed in the United States and 7,650 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. They are therefore frequently used first-line treatment in patients with metastatic melanoma.

Over 50% of untreated patients receiving a combination of PD-1 and CTLA-4 inhibitors are alive after five years. However, combination immunotherapy with YERVOY® and OPDIVO® is associated with a high incidence of severe adverse events and is currently recommended primarily for a subgroup of patients with poor prognostic factors such as a high serum LDH levels or liver or brain metastases. Approximately 50% of melanomas harbor BRAF V600E mutation and are often treated with a combination of BRAF and MEK inhibitors. This combination is associated with a high response, but resistance develops in most patients over time. YERVOY® is presently often used as second line therapy, but only 15-30% of patients benefit from this intervention. There is an unmet need for this group of patients.

Adoptive immunotherapy, also known as cellular immunotherapy, is a form of treatment in which naturally occurring or gene-engineered T cells with antitumor activity are transferred to a tumor-bearing host to eliminate cancer. These killer T cells bind to antigens on the surface of cancer cells and destroy them. Cellular immunotherapies include Tumor-Infiltrating Lymphocyte (TIL) Therapy, Engineered T Cell Receptor (TCR) Therapy, Chimeric Antigen Receptor (CAR) T Cell Therapy and Natural Killer (NK) Cell Therapy.

Adoptive immunotherapy with Tumor-Infiltrating Lymphocytes (TILs) is a personalized autologous therapy in which lymphocytes which have infiltrated the tumor are expanded in vitro and administered intravenously following nonmyeloablative, lymphodepleting chemotherapy, and supported by the IV administration of Interleukin-2 (IL-2) to enhance the in vivo expansion of the cells and augment antitumor responses. In contrast to Lymphokine-Activated Killer cells (LAK), human TILs demonstrate cytolytic specificity against only the tumor from which they were derived or against closely related tumors, and in preclinical models have proved to be 50 to 100 times more potent than LAK cells. Evidence of clinical activity of TIL therapy in patients with advanced melanoma was initially reported by Rosenberg and colleagues in the 1990s and subsequent Phase 1-2 trials showed responses in 30-70% of patients, with responses noted even among those who had disease progression while receiving anti-PD1 treatment. Nonetheless, there has been no direct comparison of TILs with standard treatment.

This multicenter, open-label, Phase III, randomized trial was conducted to compared TILs with Yervoy® as first or second-line treatment in patients with advanced melanoma. In this study, a total of 168 patients with unresectable Stage IIIC or IV melanoma were randomly assigned in a 1:1 ratio to receive either TILs (N=84) or YERVOY® (N=84). Patients assigned to receive TILs underwent metastasectomy for the retrieval and expansion of TILs, followed by inpatient administration of nonmyeloablative, lymphodepleting chemotherapy, which consisted of Cyclophosphamide 60 mg/kg IV QD for 2 days and Fludarabine 25 mg/m2 IV QD for 5 days, single adoptive transfer of 5×109 to 2×1011 TILs intravenously, and subsequent high-dose IL-2, 600,000 IU/kg IV every 8 hours, for a maximum of 15 doses. Patients in the YERVOY® group received 3 mg/kg IV every 3 weeks, for a maximum of 4 doses. Administration of YERVOY® could be delayed or discontinued if adverse events occurred, and no dose reductions were allowed. Both treatment groups were well balanced and 86% of patients were refractory to PD-1 inhibitor therapy, mostly adjuvant or first line therapy. The median patient age was 59 years and patients were stratified according to BRAF V600-mutation status, line of treatment, and treatment center. The Primary end point was Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR), Complete Response (CR), Overall Survival (OS), Health-Related Quality of Life and Safety.The median follow-up was 33.0 months.

The median PFS was 7.2 months in the TIL group and 3.1 months in the YERVOY® group (HR=0.50;P<0.001).The Objective Response Rate was 49% in the TIL group and 21% in the YERVOY® group, with a Complete Response rate of 20% in the TIL group and 7% in the YERVOY® group, with durable Complete Responses in both treatment groups. The median Overall Survival was 25.8 months in the TIL group and 18.9 months in the YERVOY® group(HR=0.83). The 2-year OS was 54.3% in the TIL group and 44.1% in the YERVOY® group. Treatment-related adverse events of Grade 3 or higher occurred in all patients in the TIL group and in 57% of those in the YERVOY® group, and these events were mainly chemotherapy-related myelosuppression. Treatment-related serious adverse events occurred in 15% of the patients in the TIL group and 27% of those in the YERVOY® group.

It was concluded that in patients with advanced melanoma including those patients refractory to PD-1 inhibitor therapy, treatment with TILs was associated with significantly longer Progression Free Survival than treatment with YERVOY®.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. Rohaan MW, Borch TH, Van den Berg JH, et al. N Engl J Med 2022; 387:2113-2125

Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in Advanced NSCLC

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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. 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.

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 immune system T cells. 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. 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. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. This study consisted of Part 1a/Part 1b and Part 2. In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere.

Part 1a: Patients received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks (N=396), OPDIVO® monotherapy 240 mg IV every 2 weeks (N=396) or chemotherapy alone given every 3 weeks for up to four cycles (N=397), in patients whose tumors had PD-L1 expression of 1% or more.
Part 1b: Patients received OPDIVO® plus YERVOY® (N=187), OPDIVO® 360 mg IV every 3 weeks plus chemotherapy IV every 3 weeks for up to four cycles (N=177), or chemotherapy alone IV every 3 weeks for up to four cycles (N=186), in patients whose tumors did not express PD-L1 (less than 1%)

Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

There were two independent Primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Part 1a and Part 1b). Other assessments included Objective Response Rate (ORR), Duration of Response (DOR), and treatment-free interval. Treatment-free interval was measured in patients who discontinued study therapy and was defined as the time from last study dose to start of subsequent systemic therapy.

The Overall Survival (OS) data was previously reported at a minimum follow up of 29 months, and the median OS was of 17.1 months for the OPDIVO® plus YERVOY® group, compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rate of 40.0% and 32.8%, respectively. The researchers here in presented data after a minimum follow up of 61.3 months (5 years).

Patients whose tumors had PD-L1 expression of 1% or more continued to have sustained long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR=0.77), and the 5-year OS rates were 24% with OPDIVO® plus YERVOY® compared to 14% with chemotherapy alone.

Patients with a PD-L1 expression of less than 1% also demonstrated continued long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR = 0.65), and the 5-year OS rates were 19% for OPDIVO® plus YERVOY&reg compared to 7% for chemotherapy alone.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 months for PD-L1–negative patients who received OPDIVO® plus YERVOY®, compared to 9.5 months and 24.9 months respectively, for those who received chemotherapy.

Among those who responded to treatment, more patients who received OPDIVO® plus YERVOY® remained in response at five years, compared to chemotherapy, in both PD-L1 expression of 1% or more group (28% versus 3%) and PD-L1 expression of less than 1% group (21% versus 0%), respectively.

Among patients treated with OPDIVO® plus YERVOY® who were alive at five years, approximately two-thirds of patients did not receive any subsequent therapy for more than three years after stopping treatment, regardless of PD-L1 expression.

It was concluded that in this longest reported follow up of a Phase III trial of first line, chemotherapy free, combination immunotherapy, in metastatic Non Small cell Lung Cancer, a combination of OPDIVO® plus YERVOY® continued to provide long term durable clinical benefit and increased 5-year survivorship, when compared to chemotherapy, in previously untreated patients with metastatic NSCLC, regardless of PD-L1 expression.

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. DOI: 10.1200/JCO.22.01503 Journal of Clinical Oncology. Published online October 12, 2022.

FDA Approves LIBTAYO® in Combination with Chemotherapy for Non-Small Cell Lung Cancer

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SUMMARY: The FDA on November 8, 2022, approved LIBTAYO® (Cemiplimab-rwlc) in combination with platinum-based chemotherapy for adult patients with advanced Non-Small Cell Lung Cancer (NSCLC) with no EGFR, ALK, or ROS1 aberrations. 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. Immuno-Oncology (IO) therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced NSCLC. It is now standard therapy for patients with lung cancer.

KEYTRUDA® (Pembrolizumab; anti PD-1) and TECENTRIQ® (Atezolizumab; anti PD-L1) are both approved in combination with platinum-based chemotherapy for the first-line treatment of patients with metastatic NSCLC. The FDA approval of TECENTRIQ® with platinum-doublet chemotherapy is however limited to non-squamous histology.

LIBTAYO® is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1. LIBTAYO® monotherapy was approved by the FDA in 2021 after it demonstrated significantly improved Overall Survival and Progression Free Survival compared with chemotherapy, in patients with advanced Non-Small Cell Lung Cancer with PD-L1 of at least 50%. The researchers in EMPOWER-Lung 3 evaluated the efficacy of first line LIBTAYO® in combination with investigator’s choice of platinum-doublet chemotherapy, among patients with advanced NSCLC, with either squamous or non-squamous histology, and any level of PD-L1 expression.

EMPOWER-Lung 3 is a randomized, multicenter, multinational, double-blind, active-controlled Phase III trial in which 466 patients with advanced NSCLC who had not received prior systemic treatment were randomized (2:1) to receive either Cemiplimab 350 mg IV once every 3 weeks (N=312) or placebo (N=154) every 3 weeks, in combination with four cycles of chemotherapy. Investigators’ choice of histology-specific chemotherapy options included Paclitaxel plus Carboplatin, Paclitaxel plus Cisplatin, Pemetrexed plus Carboplatin and Pemetrexed plus Cisplatin. Patients were treated for a maximum of 108 weeks, or until disease progression or unacceptable toxicity. For patients with non-squamous histology assigned to a Pemetrexed-containing regimen, maintenance Pemetrexed was mandatory. Patients were enrolled irrespective of PD-L1 expression or tumor histology and had advanced or metastatic NSCLC, with no ALK, EGFR or ROS1 aberrations. Among those enrolled, 43% had tumors with squamous histology, 67% had tumors with less than 50% PD-L1 expression, 15% had inoperable locally advanced disease not eligible for definitive chemoradiation, and 7% had pretreated and clinically stable brain metastases. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR).

The trial was stopped early upon recommendation by the Independent Data Monitoring Committee (IDMC) after the LIBTAYO® combination demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, compared to placebo plus chemotherapy. The median OS was 21.9 months in the LIBTAYO® plus chemotherapy group and 13.0 months in the placebo plus chemotherapy group (HR=0.71; P=0.0140). This represented a 21% relative reduction in the risk of death in the LIBTAYO® plus chemotherapy group. The 12-month probability of survival was 66% for the LIBTAYO® combination versus 56% for chemotherapy.

The median PFS per BICR was 8.2 months in the LIBTAYO® plus chemotherapy group and 5.0 months in the placebo plus chemotherapy group (HR=0.56; p<0.0001). This represented a 44% reduction in the risk of disease progression in the LIBTAYO® plus chemotherapy group. The 12-month probability of PFS for the LIBTAYO® combination was 38%, versus 16% for chemotherapy. The confirmed ORR per BICR was 43% and 23% in the respective treatment groups and the median Duration of Response was 16 months versus 7 months respectively. The most common (15% or more) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

It was concluded that LIBTAYO® is only the second anti-PD-1/PD-L1 agent to show efficacy in advanced Non-Small Cell Lung Cancer either as monotherapy in those with PD-L1 expression 50% or more, or in combination with chemotherapy, irrespective of PD-L1 expression or tumor histology.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Gogishvili M, Melkadze T, Makharadze T, et al. Nature Medicine 2022;(28):2374-2380.

TAFINLAR® and MEKINIST® versus OPDIVO® plus YERVOY® for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial

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SUMMARY: The American Cancer Society 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.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and results in constitutive activation of the MAPK pathway.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. TAFINLAR® plus MEKINIST® led to long-term survival benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, from two randomized Phase III COMBI-d and COMBI-v trials.

A combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) showed durable improved outcomes among patients with unresectable or metastatic melanoma and approximately 50% of patients were alive at 6.5 years (J Clin Oncol 39, 2021. suppl 15; abstr 9506). The FDA granted approval for this combination in 2015 for the treatment of patients with metastatic melanoma, regardless of tumor BRAF mutation status.

It has been noted that BRAF/MEK inhibitor therapy tends to produce high tumor response rates and prolonged median Progression Free Survival (PFS), whereas OPDIVO® /YERVOY® tends to have its major impact on Duration of Response. However, the optimal treatment sequence for patients with treatment-naive BRAFV600-mutant metastatic melanoma, between combination OPDIVO®/YERVOY® checkpoint inhibitor immunotherapy and combination TAFINLAR® plus MEKINIST® molecularly targeted therapy, has remained unclear. Recently published tumor biology studies have suggested that resistance to BRAF/MEK-inhibitor therapy results in an immunosuppressive tumor microenvironment that is void of functional CD103+ dendritic cells, preventing effective antigen presentation to the immune system, and that immunotherapy may enhance BRAF-mutated melanoma responsiveness to targeted therapy.

DREAMseq (EA6134) is a two-arm, two-step, open-label, randomized Phase III trial, which investigated the anti PD-1/CLTA-4 immunotherapy combination of OPDIVO® plus YERVOY® followed by the anti-BRAF/MEK targeted therapy combination of TAFINLAR® plus MEKINIST®, versus the reverse sequence, in patients with advanced BRAF V600-mutant melanoma. This study was conducted to determine which treatment sequence produced the best efficacy.

In this study, 265 patients with treatment-naive BRAF V600-mutant metastatic melanoma were randomly assigned to receive either combination OPDIVO® plus YERVOY® (arm A=133) or TAFINLAR® plus MEKINIST® (arm B=132) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, TAFINLAR® plus MEKINIST® (arm C=27) or OPDIVO® plus YERVOY® (arm D=46). The two initial treatment arms were balanced and more patients on arm B had BRAF V600K-mutant tumors than those on arm A (25.2% versus 12.1%). The median patient age was 61 years and eligible patients had histologically confirmed, BRAF V600-mutant unresectable Stage III or IV melanoma with measurable disease. The Primary end point was 2-year Overall Survival (OS). Secondary end points included 3-year OS, Objective Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), crossover feasibility, and Safety.

The study was stopped early by the Independent Data Safety Monitoring Committee because statistical significance was achieved for the Primary endpoint. The 2-year OS for those starting on arm A was 71.8% and arm B was 51.5% (P=0.01). Step 1 Progression Free Survival favored arm A (P=0.054). The Objective Response Rates were arm A: 46%, arm B: 43%, arm C: 47.8%, and arm D: 29.6%. The median Duration of Response was not reached for arm A, and 12.7 months for arm B (P<0.001). Crossover occurred in 52% of patients following documented disease progression. Grade 3 or more toxicities occurred with similar frequency between treatment groups and adverse events related to regimens were as expected.

It was concluded from this study that for patients with advanced BRAF V600-mutant metastatic melanoma, the treatment sequence beginning with the immune checkpoint inhibitor combination of OPDIVO® plus YERVOY® resulted in superior Overall Survival and longer Duration of Response, compared with the treatment sequence beginning with TAFINLAR® plus MEKINIST®, and should therefore be the preferred treatment sequence for most of these patients.

Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134. Atkins MB, Lee SJ, Chmielowski B, et al. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763

Association of Gut Microbiome with Immune Checkpoint Inhibitor Response in Advanced Melanoma

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SUMMARY: The American Cancer Society estimates that in 2022, there will be an estimated 1.92 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years. Nonetheless, less than 50% of the patients respond to single-agent ICI and a higher response to targeting both PD-1 and CTLA-4 is associated with significant immune-related Adverse Events.

Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD-L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL- Interferon-gamma, Neutrophil-to-ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The gut microbiome is unique in each individual, including identical twins. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. It should be noted however that the relationship between gut bacteria and immune response is influenced by several factors and may be partially cancer type specific and it is unlikely that the same microbiome features can reflect the uniqueness of the genetic and immune characteristics of each tumor.

Even though the composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, there is a lack of consistency of results between the published studies, and there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. The Predicting Response to Immunotherapy for Melanona with Gut Microbiome and Metabolomics (PRIMM) studies are two separate prospective observational cohort studies that has been recruiting patients in the UK (PRIMM-UK) and the Netherlands (PRIMM-NL) since 2018. These cohorts of previously ICI-naive patients with advanced melanoma have provided extensive biosamples, including stool, serum and peripheral blood mononuclear cells, before and during ICI treatment, with detailed clinical and dietary data collected at regular intervals longitudinally.

The authors therefore performed a meta-analysis on existing publicly available datasets to produce the largest study to date. In order to study the role of the gut microbiome in ICI response, the researchers recruited ICI-naive patients with advanced cutaneous melanoma from the PRIMM cohorts, as well as three additional cohorts of ICI-naive patients with advanced cutaneous melanoma, originating from Barcelona, Leeds and Manchester (N = 165), and performed shotgun metagenomic sequencing on a total of 165 stool microbiome samples collected before initiating ICI treatment. Shotgun sequencing is a laboratory technique for determining the DNA sequence of an organism’s genome. This dataset was integrated with 147 metagenomic samples from smaller publicly available datasets. This methodology provided the largest assessment of the potential of the gut microbiome as a biomarker of response to ICI, in addition to allowing for investigation of specific microbial species or functions associated with response. Patient demographics including age, gender, BMI, previous non-immunotherapy treatments, previous drug therapies such as antibiotics, Proton Pump Inhibitors (PPIs) and steroids, as well as dietary patterns, were collected in these cohorts for the majority of patients, and were considered in the multivariate analysis.

The researchers used machine learning analysis to understand the association between gut microbiome and response to ICIs. This analysis confirmed the link between the microbiome and Overall Response Rates (ORRs), as well as Progression Free Survival (PFS) with ICIs. This analysis also revealed limited reproducibility of microbiome-based signatures across cohorts. A panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansiamuciniphila were associated with responders, but no single species could be regarded as a fully reliable biomarker across studies. Based on these findings from this large set of real-world cohorts, the authors noted that the relationship between human gut microbiome and response to ICIs is more complex than previously understood, and extends beyond the presence or absence of different microbial species in responders and nonresponders.

It was concluded that future studies should include large samples and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course. Until then, the authors recommend high-quality, diverse, whole-foods diet to optimize gut health, rather than consumption of commercial probiotics.

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022;28:535-544.

FDA Approves TECVAYLI® for Relapsed or Refractory Multiple Myeloma

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SUMMARY: The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma. At the time of writing, there are three BCMA-targeted therapies approved by the FDAfor patients with Relapsed or Refractory multiple myeloma with triple-class exposure. They include CARVYKTI® (Ciltacabtageneautoleucel) and ABECMA® (Idecabtagenevicleucel),which are B-Cell Maturation Antigen (BCMA)-directed genetically modified autologous T cell immunotherapies (CART-Cell therapies), and BLENREP® (Belantamabmafodotin-blmf), which is a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor drug conjugate (Antibody Drug Conjugate). Even though CAR T-cell therapies have resulted in remarkable clinical responses, logistic challenges include at least 2 weeks of hospital stay, long manufacturing times, need for bridging therapy, and high cost of treatment.

TECVAYLI® is a bispecific antibody with dual binding sites, that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, and thereby mediates T-cell activation and lysis of BCMA-expressing myeloma cells. This effect occurs regardless of T-cell–receptor specificity or Major Histocompatibility Complex class I molecules on the surface of myeloma cells. This mechanism of action of TECVAYLI® is distinct from that of other available therapies for this patient group.

The present FDA approval was based on the efficacy and safety results from the pivotal, single-arm, multi-cohort, open-label, multi-center Phase 1/2 portion of MajesTEC-1 study, which enrolled 165 patients, who had Relapsed or Refractory myeloma after at least three therapy lines, including triple-class exposure to an Immunomodulatory drug, a Proteasome Inhibitor, and an anti-CD38 antibody. Patients received TECVAYLI® 1.5 mg/kg subcutaneously once weekly, after receiving step-up doses of 0.06 and 0.3 mg/kg separated by 2- 4 days and completed 2-4 days before the administration of the first full TECVAYLI® dose. Patients were hospitalized and premedicated with Dexamethasone, Acetaminophen, and Diphenhydramine for each step-up dose and for the first full dose of TECVAYLI®. Treatment was continued until disease progression, unacceptable toxicity, or the end of the study. The median age was 64 years, the median time between diagnosis and the first treatment dose was 6 years, 26% had at least one high-risk cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16) among those with available cytogenetic data (N=148), 77.6% had triple-class refractory disease, and patients had received a median of 5 previous lines of therapy. The Primary end point was the Overall Response Rate (ORR), which was defined as a Partial Response or better according to the International Myeloma Working Group criteria, as assessed by an Independent Review Committee. Secondary end points included Duration of Response, Very Good Partial Response (VGPR) or better, Progression Free and Overall Survival, Minimal Residual Disease (MRD) status and Safety.

At a median follow-up of 14.1 months, the Overall Response Rate was 63%, with 39.4% having a Complete Response or better. Close to 60% of patients had a Very Good Partial Response or better. Approximately, 27% of patients had negative results for Minimal Residual Disease in bone marrow (<1 myeloma cell in 100,000 cells), and the MRD-negativity rate among the patients with a Complete Response or better was 46%. The median Duration of Response was 18.4 months, and the median duration of Progression Free Survival was 11.3 months. Common adverse events included Cytokine Release Syndrome (CRS) noted in 72% and were mostly Grade 1 or 2 and fully resolved. None of the patients discontinued TECVAYLI® due to CRS. Other common adverse events included neutropenia, anemia, and thrombocytopenia, as well as immune effector cell–associated neurotoxicity syndrome, but none of the patients discontinued therapy because of neurotoxic events.

It was concluded from this study that TECVAYLI® had substantial clinical activity, with a high rate of deep and durable response in patients with triple-class-exposed Relapsed or Refractory multiple myeloma. Toxic effects were common but were mainly of low grade and reversible. The researchers added that the efficacy of TECVAYLI® compared favorably with other FDA approved treatments that are currently available for later lines in multiple myeloma, including BLENREP® (Belantamabmafodotin-blmf), XPOVIO® (Selinexor), and CAR T-cell therapies.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Moreau P, Garfall AL,van de DonkNW,et al. N Engl J Med 2022; 387:495-505

FDA Approves IMJUDO® plus IMFINZI® for Patients with Advanced Hepatocellular Carcinoma

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SUMMARY: The FDA on October 21, 2022, approved IMJUDO® (Tremelimumab) in combination with IMFINZI® (Durvalumab), for adult patients with unresectable HepatoCellular Carcinoma (HCC). 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. IMJUDO® 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 IMJUDO® 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 IMJUDO® may be sufficient to improve upon activity of IMFINZI®.

HIMALAYA trial is a randomized, open-label, multicenter, 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 IMJUDO® 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 present FDA approval was based on a comparison of the 782 patients randomized to IMJUDO® plus IMFINZI® (STRIDE regimen) to NEXAVAR®.

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), 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. The most common adverse reactions occurring in patients were rash, diarrhea, fatigue, pruritis, musculoskeletal pain and abdominal pain.

It was concluded that HIMALAYA is the first large Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody IMJUDO®, 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.

Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. Abou-Alfa GK, Lau G, Kudo M, et al. Published June 6, 2022. NEJM Evid 2022; 1 (8) DOI:https://doi.org/10.1056/EVIDoa2100070.

OPDIVO® (nivolumab) for the Adjuvant Treatment of High-Risk Urothelial Carcinoma*

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*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.
Written by: Terence Friedlander, MD
Professor of Medicine, Division of Hematology/Oncology, Zuckerberg San Francisco General Hospital, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

Content sponsored by: Bristol Myers Squibb
Dr Friedlander is a paid consultant for BMS and was compensated for his contribution in drafting this content.

Overview of High-Risk Urothelial Carcinoma*
Currently, radical resection with or without perioperative therapy is the standard of care for treating high-risk urothelial carcinoma (UC).1* However, there is still a high chance of recurrence within 2 years of radical resection, with less favorable survival rates for the high-risk patient population.1 While neoadjuvant therapy has an established role in treating high-risk UC,* data are less clear regarding the role of adjuvant therapy.2 In a retrospective observational cohort study of patients 65 years or older with UC at high risk of recurrence after radical resection, including patients who received neoadjuvant chemotherapy, median disease-free survival (mDFS) was determined to be 13.5 months.1 Cisplatin-based chemotherapy is the neoadjuvant standard of care, but prior to 2021 there were no FDA-approved adjuvant therapy options.1-3 Studies have shown that adjuvant chemotherapy may delay recurrence and improve overall survival (OS), but these studies have not definitively shown a survival benefit, largely due to inadequate sample sizes.2 Additionally, approximately 50% of patients are ineligible for cisplatin-based treatment.1 As a result, there is a high unmet need for this difficult-to-treat population, and it is important for the urologist, oncologist, and patient to discuss and align on perioperative treatments at the time of diagnosis and early in the patient journey.1,2,4 Entering the adjuvant treatment landscape, immune checkpoint inhibitors may be an additional treatment option for HCPs to consider for their patients with high-risk UC.1,2*

Adjuvant OPDIVO in High-Risk Urothelial Carcinoma*
OPDIVO is approved and indicated for the adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5 The approval is based on Checkmate 274, a phase 3, multicenter, double-blind, randomized trial of adjuvant OPDIVO versus placebo.6 More information on the study design can be found in the images below. Baseline characteristics were balanced across treatment arms.6
Checkmate 274Important Safety Information
Select Important Safety Information
In Checkmate 274, serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). The most-common adverse reactions reported in ≥20% of patients were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and UTI. OPDIVO was discontinued or delayed due to adverse reactions in 18% and 33% of patients, respectively.5

OPDIVO is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; 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.

OPDIVO may cause severe infusion-related reactions. In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.5 For additional information regarding infusion-related reactions, please see Important Safety Information for OPDIVO.
Checkmate-274-Defined-High-Risk-PatientsDouble-median-DFS-with-OPDIVOCheckmate 274 was not powered to detect differences in the treatment effect at extended follow-up analysis; therefore, results from this exploratory analysis should be interpreted with caution.

Adjuvant OPDIVO demonstrated superior disease-free survival (DFS) compared with placebo at the primary analysis (minimum follow-up of 5.9 months).5,6 Median DFS was 20.8 months with OPDIVO versus 10.8 months with placebo (HR=0.70 [95% CI: 0.57–0.86];P=0.0008).5 OS was also evaluated as a secondary endpoint, but at the time of the planned interim analysis, these data were immature with 33% of deaths in the ITT population; in the UTUC subpopulation, 37 deaths occurred, 20 of which occurred with OPDIVO versus 17 with placebo.5 Although the subgroup analyses were not statistically powered, for patients with prior neoadjuvant cisplatin therapy (n=308), the DFS hazard ratio was 0.52 [95% CI: 0.38–0.71] and for patients without prior neoadjuvant cisplatin therapy (n=401), the DFS hazard ratio was 0.92 [95% CI: 0.69–1.21].6 In additional exploratory subgroup analyses, no improvement in DFS was observed with nivolumab compared to placebo in patients with UTUC (n=149) the unstratified DFS hazard ratio was 1.15 (95% CI: 0.74–1.80); in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio was 0.83 (95% CI: 0.64–1.08).5

At the extended follow-up analysis (minimum follow-up of 11.0 months), mDFS was doubled with adjuvant OPDIVO compared with placebo. Median DFS was 22.0 months with OPDIVO versus 10.9 months with placebo (HR=0.70 [95% CI: 0.57–0.85]).12

Summary/conclusions
Given the high unmet need in this difficult-to-treat population, the call for approved adjuvant treatment options continues to rise.1,2 Adjuvant OPDIVO offers a chance to change the future for patients with high-risk UC as the only FDA-approved adjuvant option for adult patients with UC at high risk of recurrence after radical resection regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5,6,12 In Checkmate 274, OPDIVO significantly extended mDFS at the time of primary analysis and doubled mDFS at the time of extended follow-up analysis.5,6,12 Further data will be generated for the secondary endpoint of OS, which may provide greater insight into the efficacy of OPDIVO in this context.6,8 Given the clinical profile of Checkmate 274 and subsequent FDA approval, OPDIVO may help extend DFS for appropriate patients in need of treatment in the adjuvant UC setting.5,6,12

*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.

Additional Definitions
CI=confidence interval; HCP=healthcare provider; HR=hazard ratio; ITT=intent to treat; PD-L1=programmed death ligand 1; UTUC=upper tract urothelial carcinoma.

Indication
OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

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 Hepatotoxicity
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 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%).

Common Adverse Reactions
In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

Please see US Full Prescribing Information for OPDIVO.

References
1. Drakaki A, Pantuck A, Mhatre SK, et al. “Real-world” outcomes and prognostic indicators among patients with high-risk muscle-invasive urothelial carcinoma. Urol Oncol. 2021;39:76.e15-76.e22.
2. Referenced without permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed August 4, 2022. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
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Late Breaking Abstract – ESMO 2022: PADCEV® plus KEYTRUDA® in Previously Untreated Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic Urothelial Carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-103 is a clinical trial conducted to examine the safety and efficacy of Enfortumab vedotin given as monotherapy, and in combination with other anticancer therapies, as first line and second line treatment, for patients with urothelial cancer. This study was conducted in multiple parts for both locally advanced or metastatic urothelial cancer and muscle invasive bladder cancer.

EV-103/KEYNOTE-869 Cohort K is a randomized cohort investigating Enfortumab vedotin alone or in combination with Pembrolizumab as first line treatment in patients with unresectable locally advanced or metastatic urothelial cancer, who are ineligible to receive Cisplatin-based chemotherapy. In this Phase Ib/II randomized study, 149 eligible patients (N=149) were randomly assigned to receive a combination of Enfortumab vedotin 1.25 mg/kg given intravenously on days 1 and 8, and Pembrolizumab 200 mg given intravenously on day 1, every 21 days (N=76) or Enfortumab vedotin monotherapy given on the same schedule (N=73). Ineligibility for Cisplatin-based chemotherapy could be due to at least one of the following: Glomerular filtration rate (GFR) less than 60 mL/min, ECOG Performance Status of 2, Grade 2 or more hearing loss, or New York Heart Association Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease, and adjuvant/neoadjuvant Platinum-based therapy within 12 months prior to randomization, were allowed. The Primary endpoint was confirmed Objective Response Rate (ORR) by BICR (Blinded Independent Central Review). Secondary endpoints included Duration of Response (DOR), Safety, Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 14.2 months, the confirmed Objective Response Rate was 64.5% with the Enfortumab vedotin and Pembrolizumab combination, with 10.5% of patients experiencing a Complete Response and 53.9% of patients experiencing a Partial Response. The median Duration of Response was not reached. The most common Treatment-Related Adverse Events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%).

It was concluded that in Cisplatin-ineligible patients with unresectable locally advanced or metastatic urothelial cancer, treatment with Enfortumab vedotin and Pembrolizumab combination in chemo naïve patients, resulted in high Overall Response Rate, along with a safety profile that was tolerable. The authors added that Antibody-Drug Conjugates have the potential to make a greater impact in treating bladder cancer, especially in combination with checkpoint inhibitors, as shown in this trial and these data support ongoing investigations of first line Enfortumab vedotin and Pembrolizumab in patients with locally advanced or metastatic urothelial cancer.

Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Rosenberg JE, Milowsky M, Ramamurthy C, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA73