Category: Immuno Oncology

Five Year Outcomes with First Line OPDIVO® plus YERVOY® and a Limited Course of Chemotherapy

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SUMMARY: The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States and accounts for about 13% of all new cancers and 21% of all cancer deaths. 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.

Nivolumab (OPDIVO®) 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. Ipilimumab (YERVOY®) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. In the CheckMate-227, Part 1, Phase III trial, a combination of Nivolumab plus Ipilimumab significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with Nivolumab plus Ipilimumab could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition, as well as minimizing the toxicities associated with a full course of chemotherapy.

CheckMate-9LA is a pivotal, randomized, open-label, global, multi-center, Phase III trial, designed to evaluate the long-term efficacy and safety of a combination of immunotherapy and chemotherapy compared to chemotherapy alone in patients with metastatic NSCLC. In this study, 719 adults treatment naïve patients with histological confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive either Nivolumab 360 mg every 3 weeks IV plus Ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. Crossover between treatment groups was not permitted. However, at physician discretion, patients could receive subsequent immunotherapy upon discontinuation of study treatment in either group. The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and efficacy by PD-L1 subgroups. Exploratory Endpoints included Treatment-Free Interval (TFI), efficacy in patients who discontinued due to Treatment-Related Adverse Events (TRAEs), and outcomes among 5-year survivors. This trial met its Primary and Secondary endpoints, showing statistically significant improvements in OS, PFS, and Objective Response Rate (ORR), when compared to chemotherapy alone. This clinical benefit was noted across tumor PD-L1 expression levels and histology. The researchers herein reported updated efficacy and safety data with a 5-year follow up, and outcomes in 5-year survivors.

At a median follow up of 64.5 months, the combination of Nivolumab, Ipilimumab, and chemotherapy demonstrated a continued survival benefit over chemotherapy alone. The 5-year OS rate was 18% for the experimental group compared to 11% for the control group, with a Hazard Ratio (HR) of 0.73. In patients with tumor PD-L1 expression less than 1%, a subgroup with historically poorer outcomes, the 5-year OS rate was 22% in the experimental group versus 8% in the control group (HR=0.63). The 5-year PFS rate in this subgroup was also significantly better with Nivolumab plus Iipilimumab and chemotherapy (9% versus 3%).

The median DOR in the experimental arm was 12.4 months compared to 5.6 months in the control arm. The 5-year DOR rates were 19% for the experimental group and 8% for the control group. Regarding Treatment-Free Interval (TFI), among patients who survived to 5 years, 72% of those in the experimental group were treatment-free compared to 35% in the control group. The TFI rates underscore the durability of the response achieved with the combination therapy.

In Squamous NSCLC patients, the median OS was 14.5 months with the experimental regimen compared to 9.1 months with chemotherapy alone (HR, 0.63). For non-squamous NSCLC patients, the median OS was 17.8 months versus 12.0 months (HR, 0.77). In patients with PD-L1 expression less than 1%, the experimental regimen had a median OS of 17.7 months compared to 9.8 months for the control group. For those with PD-L1 expression 1% or greater, the median OS was 15.8 months versus 10.9 months. Among patients who discontinued the experimental regimen due to TRAEs (N=61), 37% were alive at 5 years. The median OS in this subgroup was 27.5 months, with a 5-year OS rate of 37%.

No new safety signals emerged with extended follow up. Grade 3 and 4 immune-mediated AEs were relatively low across different Ipilimumab dosing groups. The most common severe AEs were hepatitis, rash, pneumonitis, and adrenal insufficiency, with incidence varying by the number of Ipilimumab doses.

Exploratory Analyses suggested that among the 5-year survivors, the median PFS was not reached in the experimental group compared to 16.8 months in the control group (HR, 0.52). The ORR at 5 years was 73% in the experimental group versus 60% in the control group.

In conclusion, the 5-year follow-up results from the CheckMate -9LA trial reinforce the long-term efficacy of Nivolumab plus Ipilimumab combined with chemotherapy as a first-line treatment for metastatic NSCLC. The combination therapy not only improved OS and PFS compared to chemotherapy alone, but also showed a significant benefit in patients with low PD-L1 expression and Squamous histology. The extended follow-up underscores the durability of the response and supports the combination as a robust treatment option for patients with metastatic NSCLC, with manageable safety profiles over the long term.

Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA. Reck M, Ciuleanu TE, Schenker M, et al. J Clin Oncol. 2024;42(suppl 16):8560-8560. doi:10.1200/JCO.2024.42.16_suppl.8560.

Late Breaking Abstract – ASCO 2024: Sustained Improvement in Relapse Free Survival with Personalized mRNA Cancer Vaccine plus KEYTRUDA® in Resected High Risk Melanoma

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SUMMARY: The American Cancer Society estimates that for 2024, about 100,640 new cases of melanoma of the skin will be diagnosed in the United States and 8,290 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. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.

Patients with resected Stage IIB/C disease comprise a significant group of patients at significant risk of recurrence. Patients with Stage IIB disease have primary tumors that are more than 2 mm, and 4 mm or less in thickness, with ulceration (T3b), or more than 4 mm in thickness without ulceration (T4a). Patients with Stage IIC disease have primary tumors more than 4 mm in thickness with ulceration (T4b). Although Stage II melanoma is less advanced than Stage III, the 5-year risk of recurrence in patients with Stage IIB or Stage IIC disease without adjuvant therapy is approximately 35% and 50% respectively. The 5-year Melanoma-Specific Survival (MSS) rates for patients with Stage IIB/IIC disease are similar to those for Stage IIIA, Stage IIIB and Stage IIIC disease.

Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk resected melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab (KEYTRUDA®) was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab (OPDIVO®) versus 41.2% for ipilimumab (YERVOY®). Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

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. 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.

mRNA-4157 (V940) is a novel messenger RiboNucleic Acid (mRNA)-based individualized neoantigen therapy consisting of a single synthetic mRNA coding for up to 34 neoantigens, that is designed and produced based on the unique mutational signature of the DNA sequence of the patients tumor. Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) was designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patients tumor. Early clinical studies demonstrated that combining mRNA-4157 (V940) with Pembrolizumab may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.

KEYNOTE-942 is an ongoing randomized, open-label, Phase IIb trial, designed to evaluate the efficacy and safety of mRNA-4157, an individualized neoantigen therapy, in combination with Pembrolizumab, in patients with completely resected high-risk Stage III/IV cutaneous melanoma. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157 in combination with Pembrolizumab (N=107) or Pembrolizumab alone (N=50). The vaccine was administered 1 mg every three weeks for a total of nine doses, and Pembrolizumab was given at 200 mg IV every three weeks for up to 18 cycles (approximately one year). All patients had tumor sample (Formalin Fixed Paraffin Embedded-FFPE) available for Next Generation Sequencing and patients were stratified by disease stage. mRNA-4157 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patients had Stage IIIC disease. Approximately 64% of patients were PD-L1 positive and 74% had high Tumor Mutational Burden-TMB (10 or more mutations/Mb) in the combination treatment group, whereas 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. HLA genotyping was performed to explore associations between specific HLA alleles and treatment response. Additionally, subgroup analyses were conducted based on TMB, PD-L1 expression, and circulating tumor DNA (ctDNA) status.

The Primary endpoint was Relapse Free Survival (RFS), defined as the time from first dose of Pembrolizumab until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause. Secondary endpoints included Distant Metastasis-Free Survival and Safety. Exploratory endpoints included distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint.

At a median follow up of 23 months for the mRNA-4157/V940 plus Pembrolizumab group, and 24 months for Pembrolizumab alone group, the Relapse Free Survival at 18 months was 78.6% for the immunotherapy combination versus 62.2% for Pembrolizumab alone (HR=0.56; P=0.0266), and this equated to a 44% reduction in the risk of recurrence or death with 2 years of follow-up. mRNA-4157/V940 and Pembrolizumab combination treatment demonstrated an improvement in RFS, irrespective of PD-L1 status and TMB status.

In the recent data presented at ASCO 2024, with an additional year of planned follow-up, at a median of approximately 34.9 months, the combination of mRNA-4157 and Pembrolizumab demonstrated a significant clinically meaningful and durable improvement in RFS, the Primary endpoint of the study, compared to Pembrolizumab alone. The risk of recurrence or death was reduced by 49% (HR=0.51; P=0.019), compared to Pembrolizumab monotherapy. The 2.5-year RFS rate for the combination group was 74.8% compared to 55.6% in the Pembrolizumab alone group. The RFS improvement was observed across subgroups irrespective of TMB and PD-L1 levels.

The combination therapy also showed a meaningful improvement in Distant Metastasis-Free Survival, which was a key Secondary endpoint, compared to Pembrolizumab alone (HR=0.38; P=0.015). This represented a 62% reduction in the risk of developing distant metastases or death compared to Pembrolizumab alone.

While not formally tested as a Primary endpoint, Overall Survival trended favorably with the combination therapy, with a 2.5-Year OS Rate of 96.0% for combination versus 90.2% for Pembrolizumab alone (HR=0.425).

The safety profile of mRNA-4157 in combination with Pembrolizumab was consistent with previous analyses and the common adverse events were fatigue (60.6%), injection site pain (56.7%), and chills (49.0%). Grade 3 or higher adverse events occurred in 25% of patients receiving combination therapy and 18% in the Pembrolizumab alone group. Immune-related adverse events were reported by approximately 37.5% of patients in the combination group and 36% in the Pembrolizumab alone group, with no new safety signals identified.

The KEYNOTE-942 trial demonstrated that mRNA-4157 in combination with Pembrolizumab significantly improved Recurrence-Free Survival and Distant Metastasis-Free Survival in patients with resected high-risk Stage III/IV melanoma, compared to Pembrolizumab alone. These findings suggest a potential benefit across various patient subgroups based on TMB, PD-L1 expression, and ctDNA status. The safety profile was manageable and consistent with expectations for both treatments. Based on these positive results, further investigation in the Phase III INTerpath-001 trial is underway to validate these findings and potentially transform the adjuvant treatment landscape for melanoma patients.

Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial.Weber JS, Khattak MA, Carlino MS, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA9512). DOI 10.1200/JCO.2024.42.17_suppl.LBA9512

FDA Approves Bispecific T-Cell Engager IMDELLTRA® for Small Cell Lung Cancer

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SUMMARY: The FDA on May 16, 2024, granted accelerated approval to IMDELLTRA® (Tarlatamab-dlle) for Extensive Stage-Small Cell Lung Cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 13-15% of all lung cancers. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis. Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab is a first-in-class bispecific T-cell engager immunotherapy that directs the patient’s T cells to cancer cells expressing delta-like ligand 3 (DLL3), independent of major histocompatibility complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

The present FDA approval was based on the efficacy of Tarlatamab in the open-label, global, multicenter, multi-cohort, Phase 2 DeLLphi-301 trial, which included patients with Relapsed/Refractory Extensive Stage Small Cell Lung Cancer with disease progression after platinum-based chemotherapy. In this Phase 2 study, patients received a step dose of Tarlatamab 1 mg IV on day 1 of cycle 1, after which they received the target dose of either 10 mg or 100 mg on day 8 and day 15 of cycle 1 and every 2 weeks thereafter in 28-day cycles (two doses per cycle) until disease progression or unacceptable toxicity. Overall 134 patients received Tarlatamab 10 mg IV, the median age in this group was 64 years and the median duration of treatment in this group was 5.1 months. Positivity for DLL3 expression on tumor cells was not required for trial entry and patients with symptomatic brain metastases, interstitial lung disease or non-infectious pneumonitis, and active immunodeficiency were excluded.

The Primary end point was Objective Response Rate (Complete or Partial Response), as assessed by Blinded Independent Central Review. Secondary end points included Duration of Response, Progression-Free Survival and Overall Survival. Efficacy was evaluated in 99 patients with disease progression enrolled in this study, who received Tarlatamab 10 mg IV, following platinum-based chemotherapy.

The Objective Response Rate was 40% and median Duration of Response was 9.7 months. The researchers noted that this Objective Response Rate far exceeded the historical control benchmark of 15% for the Primary end point. Of the 69 patients with available data regarding platinum sensitivity status, the ORR was 52% in 27 patients with platinum-resistant Small Cell Lung Cancer (defined as progression less than 90 days after last dose of platinum therapy) and 31% in 42 patients with platinum-sensitive Small Cell Lung Cancer (defined as progression 90 or more days after last dose of platinum therapy). The median Overall Survival was 14.3 months, with final and complete survival data still not mature. The most common adverse reactions were Cytokine Release Syndrome (CRS), fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, and constipation, anemia and nausea.

It was concluded that Tarlatamab represents a new immunotherapeutic approach for Small Cell Lung Cancer. It is the first and only DLL3-targeting Bispecific T-cell Engager therapy, establishing itself as an effective and innovative treatment option for patients with previously treated Small Cell Lung Cancer.

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. Ahn M-J, Cho BC, Felip E, et al. for the DeLLphi-301 Investigators. N Engl J Med 2023;389:2063-2075

FDA Approves BREYANZI® for Relapsed/Refractory Follicular Lymphoma

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SUMMARY: The FDA on May 15, 2024, granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel) for adults with Relapsed or Refractory Follicular Lymphoma who have received two or more prior lines of systemic therapy. The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 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 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. 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 (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Despite advances in treatment for Follicular Lymphoma, there remains an unmet need for additional options that offer treatment-free intervals with durable, complete responses.

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 body of patients and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

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.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® contains a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. BREYANZI® was previously approved in the US for the treatment of Relapsed or Refractory Large B-Cell Lymphoma (LBCL) after at least one prior line of therapy, and also received accelerated approval for the treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma after at least two prior lines of therapy.

TRANSCEND-FL is a global, multicenter, open-label, single-arm Phase II trial which included patients with Relapsed or Refractory Follicular Lymphoma after two or more lines of systemic therapy including an anti-CD20 antibody and an alkylating agent. This study included 94 eligible patients (N=94) and these patients also needed to have an ECOG PS of 1 or less, as well as adequate bone marrow function to receive lymphodepleting chemotherapy. Eligible patients had PET-positive disease at baseline or after bridging therapy and had at least 9 months of follow up from first response. Patients were excluded if they had evidence or a history of composite Diffuse Large B-Cell Lymphoma and Follicular Lymphoma, or transformed Follicular Lymphoma, a WHO subclassification of duodenal-type Follicular Lymphoma, CNS-only involvement by malignancy, or prior CAR T-cell therapy or other genetically modified cell therapy. Following apheresis and collection of T cells, patients received lymphodepleting chemotherapy consisting of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV daily for 3 days. Patients could receive bridging therapy for disease control following apheresis and prior to lymphodepletion and subsequent administration of BREYANZI®. Patients received a single dose of BREYANZI® 2-7 days, following the completion of lymphodepleting chemotherapy at a target dose of 100 x 106 CAR-positive T cells.

The Primary efficacy endpoint was the Overall Response Rate (ORR), defined as the percentage of patients achieving a Partial or Complete Response per Lugano criteria as assessed by an Independent Review Committee (IRC). Secondary endpoints included Complete Response (CR) rate, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and Safety. Responses were evaluated using PET scans, providing a comprehensive assessment of treatment efficacy.

The study demonstrated impressive efficacy outcomes, with an ORR of 95.7% and a CR rate of 73.4% in the primary analysis set. Responses were rapid, with a median time to response of one month. After a median follow up of 16.8 months, the median Duration of Response was Not Reached. Approximately 81% of responders remained in response at 12 months, and 77% of responders remained in response at 18 months, underscoring the potential of this therapy to induce long-lasting remissions. The most common non-laboratory adverse reactions were Cytokine Release Syndrome (CRS), headache, musculoskeletal pain, fatigue, constipation, and fever.

In this largest primary analysis assessing CAR T-cell therapy for Relapsed or Refractory Follicular Lymphoma, a treatment option with a one-time infusion of BREYANZI® with the potential for lasting remission, addresses the unmet need of these patients, heralding a new era in the management of this challenging disease.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma

Bispecific Immune Checkpoint Inhibitor Improves Survival in Gastric and GEJ Cancer Regardless of PD-L1 Status

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SUMMARY: The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 15%. These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

Cadonilimab (AK104) is a human, bispecific IgG1 antibody with high binding avidity especially to high density of PD-1 and CTLA-4 due to its tetravalent design, and could simultaneously bind different cells expressing PD-1 and CTLA-4, respectively. By effective blocking both PD-1 and CTLA-4 pathways, Cadonilimab activates T cells by increasing interleukin-2 (IL-2) and interferon-gamma secretion to similar extent, as compared with anti-PD-1 and anti-CTLA-4 combination.

COMPASSION-15 is a double-blind, randomized, multicenter, Phase III trial that enrolled 610 patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. They were randomly assigned 1:1 to receive either Cadonilimab in combination with Oxaliplatin and Capecitabine chemotherapy, or placebo plus the same chemotherapy. Chemotherapy with Oxaliplatin and Capecitabine was given every 3 weeks for up to six cycles. Capecitabine was administered at 1000 mg/m2 orally twice daily on days 1 through 14 every 3 weeks and Oxaliplatin IV at 130 mg/m2 every 3 weeks. Cadonilimab 10 mg/kg IV or placebo was given on day 1 of each cycle every 3 weeks. Following the 6 cycles, patients then received Cadonilimab 10 mg/kg IV monotherapy or placebo every 3 weeks. Stratification factors included ECOG performance status (0 versus 1), PD-L1 expression (CPS 5% or more, or less than 5%), and the presence or absence of liver metastasis. The Primary endpoint was Overall Survival (OS) in the Intent to Treat (ITT) population.

The researchers herein presented the interim analysis data of COMPASSION-15 trial. The results revealed a significant improvement in Overall Survival with Cadonilimab combination therapy compared to placebo. The median OS was 15.0 months with Cadonilimab combination, compared with 10.8 months for those in the placebo arm (HR=0.60; P<0.001). The 18-month Overall Survival rate was 45.8% in the Cadonilimab group versus 25.5% in the placebo group.

Subgroup analysis based on PD-L1 expression levels (CPS 5% or more, or less than 5%) also demonstrated favorable outcomes with Cadonilimab across all strata. Among patients with a PD-L1 CPS of less than 5%, Cadonilimab combination achieved a median OS of 14.8 months, compared with 11.1 months in the placebo group. The 18-month OS rates were 44.1% compared with 27.5%, respectively.

Progression-Free Survival (PFS), another critical measure of treatment efficacy, showed consistent benefits with Cadonilimab combination compared to placebo plus chemotherapy, irrespective of PD-L1 expression. Median PFS was 7 months versus 5.3 months in the ITT population, with similar trends observed in CPS 5% or more, and less than 5% subgroups.

The safety analysis revealed no new safety signals. However, Grade 3 or higher treatment-related adverse events were more commonly reported in the combination therapy group compared to the placebo group. Treatment-related adverse events leading to therapy discontinuation were also more frequent in the Cadonilimab group.

It was concluded from this study that Cadonilimab is the first PD-1/CTLA-4 bispecific antibody to demonstrate substantial improvements in Overall Survival and Progression-Free Survival benefit in combination with chemotherapy, offering a potential new standard of care for patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. This study represents a significant milestone in the quest for improved first-line treatments for gastric and GEJ cancers, even for patients with low PD-L1 expression tumors.

Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): A randomized, double-blind, phase 3 trial. Ji J, Shen L, Li Z, et al. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA.

Benefits of Neoadjuvant Chemoimmunotherapy in Early Stage Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 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.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Approximately 50% of NSCLC patients are diagnosed at an early stage, when surgical resection is a viable treatment option. Among patients with early stage disease, 20% present with Stage I or II disease, while 30% present with Stage IIIA or IIIB disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

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. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Combining cytotoxic chemotherapy with a PD-1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.

Neoadjuvant Immune Checkpoint Inhibitors (ICIs) have emerged as a promising approach to enhance the surgical resectability of tumors and reduce the risk of distant relapse. Clinical trials investigating the combination of neoadjuvant ICIs with platinum-based chemotherapy (ICI-chemotherapy) in resectable NSCLC have demonstrated improvements in Event-Free Survival (EFS) and a notable increase in pathologic Complete Response (pCR), which is considered a potential surrogate for Overall Survival. Consequently, regulatory agencies such as the US FDA and the European Medicines Agency have approved neoadjuvant ICI regimens for resectable NSCLC.

Several studies have suggested greater benefits in EFS and/or pCR in patients with higher PD-L1 expression in tumor cells. As a result, the European Medicines Agency has limited the use of neoadjuvant ICI therapy in combination with platinum-based chemotherapy to NSCLC patients with tumor cell PD-L1 expression of at least 1%. Other factors potentially influencing treatment outcomes include histologic features, disease stage, and smoking history. However, uncertainties remain regarding the necessity of adjuvant postoperative ICI treatment for all patients receiving neoadjuvant ICIs with chemotherapy, and the optimal duration of preoperative treatment.

The researchers therefore conducted a systematic review and meta-analysis of Randomized Clinical Trials with neoadjuvant Immune Checkpoint Inhibitors (ICIs) plus chemotherapy (ICI-chemotherapy) with or without adjuvant ICIs, to evaluate the collective benefits of neoadjuvant ICI-chemotherapy in Event-Free Survival (EFS) and pathologic Complete Response (pCR) among early-stage NSCLC patients, and additionally investigate the impact of various clinical, pathologic, and treatment-related factors. The analysis included 8 Phase II and III Randomized Clinical Trials involving 3387 previously untreated Stage IB-IIIB NSCLC patients. It compared 2-year EFS and pCR rates between patients receiving neoadjuvant chemoimmunotherapy and those patients receiving neoadjuvant chemotherapy alone. The current analysis unlike other meta-analyses that aimed to compare different perioperative ICI-based therapies, focused on limiting heterogeneity and providing consistent and clinically helpful evidence from the subgroup analysis.

The results indicated that neoadjuvant chemoimmunotherapy significantly improved both 2-year EFS and pCR rates, compared to chemotherapy alone. Neoadjuvant chemoimmunotherapy was associated with improved 2-year EFS (HR=0.57; P<0.001) and increased pCR rate (RR=5.58; P<0.001), compared to neoadjuvant chemotherapy alone. This benefit was noted regardless of age, sex, ECOG performance status, smoking history, histologic features including tumor PD=L1 status, tumor stage, type of platinum-compound chemotherapy, number of cycles of neoadjuvant chemoimmunotherapy, or addition of adjuvant Immune Checkpoint Inhibitors. Patients with tumor cells negative for PD-L1 were at higher risk of relapse (HR=0.75), than were those with low PD-L1 (HR=0.61) or high PD-L1 (HR=0.40) and this was statistically significant (P=0.005).

In conclusion, this systemic review and meta-analysis suggests that 3 cycles of neoadjuvant platinum-based Immune Checkpoint Inhibitors plus chemotherapy for early-stage NSCLC patients leads to meaningful improvements in 2-year Event Free Survival and pathologic Complete Response. It underscores the potential of this treatment approach in enhancing outcomes for NSCLC patients and provides valuable insights into optimizing treatment strategies.

Neoadjuvant Chemo-Immunotherapy for Early-Stage Non–Small Cell Lung Cancer; A Systematic Review and Meta-Analysis. Banna GL, Hassan MA, Signori A, et al. JAMA Netw Open. 2024;7(4):e246837. doi:10.1001/jamanetworkopen.2024.6837.

Cardiovascular Adverse Events Associated with Bispecific T-cell Engager Therapy

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SUMMARY: Bispecific T-cell engager (BTE) therapies are a novel class of targeted immunotherapies with activity against hematologic malignancies. These bispecific antibodies have 2 binding domains, one targeting and binding to CD3 on the T-cell receptor, whereas the other is a modifiable domain designed to bind to specific tumor-associated antigens, which can be CD19, CD20, B-Cell Maturation Antigen (BCMA) or GPRC5D. Blinatumomab (BLINCYTO®) targets the CD19 on B-cells and is approved for the treatment of advanced Acute Lymphoblastic Leukemia (ALL); Mosunetuzumab (LUNSUMIO®), Glofitamab (COLUMVI®), and Epcoritamab (EPKINLY®), target CD20 on B cells and have also been approved for the treatment of Non-Hodgkin lymphoma; Teclistamab (TECVAYLI®), targets BCMA expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma; Talquetamab (TALVEY®) targets GPRC5D expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma.

Adverse events of BTEs include Cytokine Release Syndrome (CRS), hematological toxicities, and neurotoxicity. Serious CardioVascular Adverse Events (CVAEs) have been reported with certain BTEs. However, this has not been clearly defined. Given that CVAEs have not been observed in a previous pharmacovigilance analysis focused on CAR-T therapy, it appears that the pathophysiology of CVAEs associated with novel T-cell modulatory therapies (BTEs) may be different.

The present study was conducted to examine the CardioVascular Adverse Events (CVAEs) associated with Bispecific T-cell Engager therapies (BTEs). The five BTE products considered for analysis were Blinatumomab, Teclistamab, Mosunetuzumab, Glofitamab, and Epcoritamab. Leveraging the vast repository of the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), researchers embarked on a meticulous analysis, investigating the frequency and association of CVAE reporting with BTE, the prognostic implications of CVAEs in patients receiving BTEs, as well as the extent these adverse events overlap with CRS, spanning from October 2014 to March 2023. The primary objective was to delineate the frequency and fatality rates of CVAEs associated with BTEs, encompassing a spectrum of conditions including bleeding, hypotension or shock, thromboembolic disease, heart failure, and conduction abnormalities, myocarditis, pericarditis, sudden death, and vasculitis.

Utilizing multivariable logistic regression models, adjusted for age, sex, and disease status, the researchers calculated adjusted Reporting Odds Ratios (RORs). These RORs served as a metric to gauge the likelihood of reporting a given adverse event with BTEs compared to reporting the same event with all other drugs in the FAERS database.

Their study examined 3,668 cases of reported adverse events, 73.9% of which involved Blinatumomab and 11.2% involved Teclistamab as the primary suspected drug. Mosunetuzumab, Glofitamab and Epcoritamab accounted for a smaller proportion of events. (7.4%, 5.2% and 2.3%, respectively). The median age of patients was 52.0 years, with individuals from 52 countries represented in this analysis, with 43.2% of cases coming from the U.S. The indication for BTE therapy was leukemia/lymphoma in 88.7% of cases, multiple myeloma in 11.2% of cases, and both in 0.1% of cases.

The results of the study unveiled several significant findings:
1) Of the 3668 BTE-related cases reported to FAERS, 20.4% involved CVAEs.
2) BTEs were associated with disproportionately higher rates of fatal CVAEs, an association mainly driven by Teclistamab. Teclistamab was also associated with a disproportionate risk of myocarditis and shock, whereas Blinatumomab was associated with a disproportionate risk of Disseminated Intravascular Coagulation and hypotension.
3) Majority of these fatal CVAEs (96.7%) occurred in individuals without previously documented cardiovascular comorbidities.
4) CVAEs were more likely to be fatal compared with non-CVAEs (31.1% versus 17.4%).
5) CVAEs were not necessarily a consequence of Cytokine Release Syndrome (CRS), as approximately 85% of CVAE reports did not involve concurrent CRS.
6) In general, CVAEs tended to occur sooner following BTE therapy compared with non-CVAEs (median time to onset 6 days versus17 days; p<0.001).
7) No significant associations with CVAEs were observed with the other three BTE products (Glofitamab, Mosunetuzumab, and Epcoritamab).
8) Compared with CVAEs, neurotoxicity and CRS commonly associated with BTEs were associated with lower mortality. The elevated risk of death following CVAEs was especially noted for myocarditis, heart failure, bleeding, and DIC, with which mortality rates were 2-3 times higher than other AEs.

The researchers concluded that in this first postmarketing pharmacovigilance analysis of BTEs, CVAEs were involved in approximately 1 in 5 Adverse Event reports, and carried a significantly high mortality rate. The researchers cautioned that clinicians must be cognizant of the potential of CVAEs when treating patients with BTEs, and consider either stopping or switching therapies when CVAEs are suspected.

Cardiovascular toxicities associated with bispecific T-cell engager therapy. Sayed A, Munir M, Ghazi SM, et al. J Immunother Cancer. 2024 Feb 21;12(2):e008518. doi: 10.1136/jitc-2023-008518.

FDA Approves BREYANZI®, First CAR-T Cell Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

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SUMMARY: The FDA on March 14, 2024 granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel, Liso-cel), a CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy, for the treatment of adults with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have received at least two prior lines of therapy (including a Brutons Tyrosine Kinase-BTK inhibitor and a B-Cell Lymphoma 2-BCL2 inhibitor).

The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitors such as Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®), time limited therapy with BCL2 inhibitor Venetoclax, given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy. Patients have few options and poor outcomes upon progression on these therapies, and there is an unmet need for novel therapies.

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 patients body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® was previously approved by the FDA for treatment of adults with relapsed or refractory Large B-cell lymphoma, who received at least one prior therapy. 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.

TRANSCEND CLL 004 is an open-label, single-arm, multicenter Phase1/2 study, conducted in the United States, to evaluate the efficacy and safety of BREYANZI® in adult patients with relapsed or refractory CLL/SLL. This study included 117 eligible patients who underwent leukapheresis between January 2018 and June 2022, at 27 sites in the United States. Patients received a single intravenous infusion of BREYANZI® at one of two target dose levels: 50×10⁶ (Dose Level 1) or 100×10⁶ (Dose Level 2) Chimeric Antigen Receptor-positive T cells. The median age was 65 years, 68% were men, 44% had bulky lymphadenopathy, and 83% had high-risk cytogenetics. All patients had previously received and failed treatment with a BTK inhibitor and 80% had received prior Venetoclax. Among these patients, 60% had progressed on BTK inhibitors and had Venetoclax failure. Patients had a median of five prior lines of therapy. The Primary endpoint was Complete Response or Remission (including with incomplete marrow recovery), assessed by Independent Review in efficacy-evaluable patients with previous BTK inhibitor progression and Venetoclax failure at Dose Level 2 (100×10⁶). The total efficacy analysis included 89 patients treated at a dose level of 100×10⁶ CAR-positive T cells, with 49 patients evaluable.

In the Primary efficacy analysis set treated at a dose level of 100×10⁶ (N=49), the Complete Response or Remission rate (including with incomplete marrow recovery) was statistically significant at 18% (P=0.0006). The Overall Response Rate was 45%, and the median Duration of Response was 35.3 months. The median Duration of Response in the Complete Responders was Not Reached at the time of data cutoff and Minimal Residual Disease negativity rates were 100% in blood and 92.3% in bone marrow among Complete Responders. The median time to first response was 1.2 months, and for Complete Response or Remission was 3.0 months, respectively.

Among 89 patients in the study treated with BREYANZI®, Cytokine Release Syndrome (CRS) and neurologic events were mostly low-grade. CRS of any grade occurred in 83% of patients, with grade 3 CRS reported in 9% of patients, and with no grade 4 or 5 events reported. Any-grade neurologic events were reported in 46% of patients, with grade 3 neurologic events reported in 20% of patients, and one grade 4 neurologic event reported. No deaths due to either toxicity were reported.

It was concluded that a single infusion of BREYANZI® induced Complete Response or Remission in patients with relapsed or refractory CLL/SLL, including those with previous treatment failure on both BTK inhibitors and Venetoclax. It is the first CAR T-cell therapy approved in this setting and the safety profile was deemed manageable, offering a potential breakthrough in the treatment paradigm for these challenging diseases. Further confirmatory trials will be required to validate these findings and support continued approval of BREYANZI® for this indication.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Siddiqi T, Maloney DG, Kenderian SS, et al. The Lancet. 2023;402:641-654.

FDA Approves TEVIMBRA® for Advanced Esophageal Squamous Cell Carcinoma

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

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

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

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

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

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

Circulating Tumor DNA Can be Used as an Early Marker of Immunotherapy Response

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 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.

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. Immune Checkpoint Inhibitors enhance antitumor immunity by unleashing the T cells. However, this benefit may vary among patients and tumor types. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

First line treatment options for patients with NSCLC include Pembrolizumab as a single agent or a combination Pembrolizumab with Carboplatin and Taxane/Pemetrexed. However, it remains unclear which patients would benefit from Pembrolizumab monotherapy and which group should receive combination immuno/chemotherapy. Further, such therapeutic decisions are not currently supported by either tumor PD-L1 or TMB status. There is therefore an urgent unmet need to implement molecular response-driven approaches to guide therapy selection in the immunotherapy space. Liquid biopsy analyses of circulating cell-free tumor DNA (ctDNA) can capture the tumor burden dynamics during immune checkpoint blockade, and may help guide therapy, to maximize therapeutic benefit and minimize toxicities to patients.

The Canadian Cancer Trials Group (CCTG) BR.36 is an international, multi-center, open-label, biomarker-directed Phase II trial, designed to establish the role of circulating tumor DNA (ctDNA) as a potential early measurement of immunotherapy response, in patients with advanced NSCLC. The trial design consists of two stages. In Stage 1 (observational), the objectives were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. The researchers in this publication reported the findings of the First stage (Stage 1). The Second stage of the trial (Stage 2) will evaluate the potential clinical benefit of tailoring treatment to ctDNA molecular response (whether adding chemotherapy to Pembrolizumab for patients with advanced PD-L1+NSCLC who have persistent ctDNA at 6 weeks will result in better Progression Free Survival (PFS) and Overall Survival (OS) compared to patients who remain on Pembrolizumab therapy until clinical progression).

The first stage (observational stage) of the BR.36 trial enrolled 50 patients with advanced/metastatic NSCLC who did not harbor clinically actionable genomic alterations in EGFR or ALK, and had a PD-L1 expression level of 1% or more. Majority of patients had Stage IV NSCLC (98%) and had no prior systemic therapy (92%), 82% were white, 52% female and 56% were 65 years or older, 76% tumors were adenocarcinomas, and 96% had a PD-L1 Tumor Proportion Score (TPS) of 50% or more.

Patients received Pembrolizumab as per local standard of care, and radiographic response assessments were performed per RECIST criteria every 6 weeks until week 12 and at longer intervals thereafter. Serial liquid biopsies were collected and ctDNA molecular response assessments were performed before treatment administration on C1D1 (baseline), C2D1 (3 weeks) and C3D1 (6 weeks). Molecular response was defined as maximal mutant allele fraction clearance at the third cycle of Pembrolizumab. The Primary endpoint of the trial was to determine the optimal time point of ctDNA molecular response, and validate the concordance of ctDNA molecular response with radiographic response. Secondary endpoints included the evaluation of time to ctDNA response, and correlation with Progression Free and Overall Survival. The median follow up time was 13.5 months, and of the 45 patients evaluable for both radiographic and ctDNA responses, 10 patients had undetectable ctDNA, which is consistent with previously reported ctDNA undetectable rate in patients with metastatic NSCLC.

The trial met its Primary endpoint, and the concordance between ctDNA and radiographic response in terms of sensitivity was 82%, and 75% for specificity. The median time to ctDNA response was 2.1 months, and patients with molecular response attained longer Progression Free Survival (5.03 months versus 2.6 months) and Overall Survival (Not Reached versus 7.23 months). These findings are incorporated into the second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy.

It was concluded from the first stage of the BR.36 trial that ctDNA analyses can be used as an early marker of immunotherapy response and has the potential to determine the early efficacy of investigational agents in clinical trials. The second stage of this study will assess whether outcomes can be improved in those metastatic NSCLC tumors expressing PD-L1 with ctDNA response, by continuation of Pembrolizumab or adding chemotherapy to immunotherapy.

ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results. Anagnostou, V., Ho, C., Nicholas, G. et al. Nat Med 2023;29: 2559–2569. https://doi.org/10.1038/s41591-023-02598-9