Category: Immuno Oncology

Personalized mRNA Cancer Vaccine in Combination with KEYTRUDA® Improves Relapse Free Survival in Resected High Risk Melanoma

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SUMMARY: The American Cancer Society’s estimates that for 2023, about 97,610 new cases of melanoma of the skin will be diagnosed in the United States and 7,990 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.
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 was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab versus 41.2% for ipilimumab. Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. 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 patient’s 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 a randomized Phase IIb trial, which assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, Stages IIIB/IIIC/IIID and IV melanoma, when given in combination with Pembrolizumab, the standard of care adjuvant therapy in this patient population. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157/V940 in combination with Pembrolizumab (107 patients) or Pembrolizumab alone (50 patients). The vaccine was administered 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/V940 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patient 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, and 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. 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. The median follow up was 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. The immunotherapy combination was well tolerated without increased Grade 3-4 immune mediated or serious toxicities. The most common adverse events of any grade attributed to the combination immunotherapy were fatigue, injection site pain and chills.

The researchers concluded that this is the first randomized trial to demonstrate Relapse Free Survival improvement with an individualized neoantigen approach, compared to standard of care treatment with Pembrolizumab, among patients with high-risk resected melanoma.

A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial. Khattak A, Carlino M, Meniawy T, et al. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT001.

FDA Approves Enfortumab vedotin with Pembrolizumab for Advanced Urothelial Carcinoma

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SUMMARY: The FDA on April 3, 2023, granted accelerated approval to Enfortumab vedotin-ejfv (PADCEV®) with Pembrolizumab (KEYTRUDA®) for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for Cisplatin-containing chemotherapy. The American Cancer Society estimates that in the United States for 2023, about 82,290 new cases of bladder cancer will be diagnosed and approximately 16,710 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

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. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. 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 a first-in-class 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 (MMAE), 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 an ongoing multi-cohort, open-label, global, multicenter Phase Ib/II study, investigating Enfortumab vedotin alone or in combination with Pembrolizumab and/or chemotherapy in first or second line settings, in patients with locally advanced or metastatic urothelial cancer, and in patients with muscle-invasive bladder cancer. The present FDA approval was based on Objective Response Rates (ORR) and median Duration of Response (DOR) in combined Dose Escalation/Cohort A and Cohort K of this study, also known as KEYNOTE-869 trial. The Dose Escalation Cohort and Cohort A were single-arm cohorts treating patients with Enfortumab vedotin plus Pembrolizumab, whereas patients in Cohort K were randomized to either Enfortumab vedotin monotherapy or Enfortumab vedotin in combination with Pembrolizumab. Patients had not received prior systemic therapy for locally advanced or metastatic urothelial cancer and were ineligible for Cisplatin-containing chemotherapy. 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. In this analysis, a total of 121 patients (N=121) received Enfortumab vedotin plus Pembrolizumab. Patients received Enfortumab vedotin 1.25 mg/kg IV (up to a maximum of 125 mg for patients 100 kg or more) on days 1 and 8 and Pembrolizumab 200 mg IV on day 1, every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) determined by Blinded Independent Central Review.

Patients treated with a combination of Enfortumab vedotin and Pembrolizumab had an Objective Response Rate of 68%, with 12% of patients experiencing a Complete Response. The median Duration of Response for the Dose Escalation cohort plus Cohort A was 22 months and for Cohort K was Not Reached. The most common Treatment Related Adverse Events (TRAE) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Two thirds of patients had Grade 3 TRAEs, and the most common toxicities were increased lipase, maculopapular rash, and fatigue.

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.

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. Hoimes CJ, Flaig TW, Milowsky M, et al. DOI: 10.1200/JCO.22.01643 Journal of Clinical Oncology 41, no. 1 (January 01, 2023) 22-31.

Tremelimumab in Combination with Durvalumab and Chemotherapy in Metastatic Non Small Cell Lung Cancer: The Phase III POSEIDON Study

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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 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

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 immunoglobulin G1 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® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses. The concurrent addition of chemotherapy to checkpoint inhibitors causes tumor cell death and release of neoantigens, which increases immune priming, important for early disease control.

POSEIDON is a global, randomized, open-label, three-arm, Phase III study, which evaluated the efficacy of Tremelimumab plus Durvalumab along with chemotherapy, and Durvalumab along with chemotherapy, compared to chemotherapy alone, in first-line treatment of metastatic NSCLC. In this trial, 1013 patients (N=1013) with EGFR/ALK wild-type metastatic NSCLC were randomly assigned (1:1:1) to receive either Tremelimumab 75 mg IV plus Durvalumab 1,500 mg IV along with chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, with one additional Tremelimumab dose after chemotherapy at week 16 (fifth dose), Durvalumab 1500 mg IV plus chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, or chemotherapy alone for up to six 21-day cycles. Chemotherapy options for treatment groups included Carboplatin plus nab-Paclitaxel regardless of histology, Cisplatin or Carboplatin plus Gemcitabine for patients with squamous histology, and Cisplatin or Carboplatin plus Pemetrexed for patients with nonsquamous histology. Patients with nonsquamous histology who received Pemetrexed-Platinum doublet could receive Pemetrexed maintenance therapy if eligible. Patients continued treatment until progressive disease or unacceptable toxicity. Patients were stratified by PD-L1 expression (50% or more versus less than 50%), disease Stage (IVA versus IVB), and histology (squamous versus nonsquamous). The median age was 64 yrs, 63% had nonsquamous histology, and approximately a third of the patients had PD-L1 expression less than 1%. The treatment groups were well balanced. The Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) for the Durvalumab plus chemotherapy group, compared to the chemotherapy alone group. Key Secondary end points were PFS and OS for Tremelimumab plus Durvalumab along with chemotherapy, compared to chemotherapy alone.

The coPrimary end point of PFS benefit with Durvalumab plus chemotherapy compared to chemotherapy alone was met (HR=0.74; P=0.0009), and the median PFS was 5.5 versus 4.8 months respectively and the 12-month PFS rates were 24.4% versus 13.1%. However, OS did not reach statistical significance (HR=0.86; P=0.075). When Secondary end points were formally evaluated, Tremelimumab plus Durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to chemotherapy alone (HR=0.77; P=0.003). The median OS was 14 months versus 11.7 months respectively and 2 year OS was 32.9% versus 22.1% respectively. The median PFS was 6.2 months and 4.8 months in the treatment arms, respectively (HR=0.72; P=0.0003) and the 1-year PFS rate was 26.6% and 13.1% respectively. Treatment benefit was seen across all PD-L1 subgroups, particularly in tumors with PD-L1 expression of 50% or more. Patients with tumor PD-L1 expression less than 1% appeared to gain improved survival benefit from the addition of Tremelimumab to Durvalumab and chemotherapy.

Based on this study, the FDA approved Tremelimumab in combination with Durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK genomic tumor aberrations.

It was concluded that Durvalumab plus chemotherapy significantly improved Progression Free Survival when compared to chemotherapy alone. A limited course of Tremelimumab added to Durvalumab and chemotherapy significantly improved Overall Survival and Progression Free Survival when compared to chemotherapy, and the clinical benefit extended to patients who had tumor PD-L1 expression less than 1%.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson ML, Cho BC, Luft A, et al. DOI: 10.1200/JCO.22.01737 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1176-1179.

Real World Experience of Anti-BCMA CAR T-Cell Therapy in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730 new cases will be diagnosed in 2023 and 12,590 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 2023 remains an incurable disease. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median progression-free survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. 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.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR) by transducing with a gene encoding the engineered CAR via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

ABECMA® (Idecabtagene vicleucel) is the first FDA approved cell-based gene therapy for multiple myeloma and was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. The KarMMa trial however had stringent eligibility criteria, which was likely not representative of real-world population.

The researchers conducted this study to evaluate safety and efficacy of Standard of Care ABECMA® for the treatment of Relapsed and Refractory multiple myeloma in a real-world population. This retrospective, multicenter, observational study included 196 patients planned for Standard of Care ABECMA® for Relapsed and Refractory multiple myeloma from 11 US medical centers. Unlike the KarMMa trial which had stringent eligibility criteria, not representative of real-world patient population, the present study included patients with comorbidities that would have made them ineligible for the KarMMa trial. A total of 159 patients successfully received ABECMA®. The median age was 64 years, and 35% of patients had high-risk cytogenetics (del(17p), t(4;14) and t(14;16), the median number of prior lines of therapy was seven and 44% of patients had penta-refractory disease. In this real-world experience study, 21% had prior anti-BCMA therapy, 84% had prior Autologous Stem Cell Transplant and 6% had Allogeneic Stem Cell Transplant. Approximately 75% of patients in this study would not have met KarMMa eligibility criteria. Further, relative to KarMMa trial, this real-world cohort had more patients with extramedullary and penta-refractory disease.

The median time from leukapheresis to ABECMA® infusion was 47 days. The CAR T-cells manufacturing failure rate in real-world patients was higher than that seen in KarMMa trial and this was attributed to poor bone marrow reserve among patients in this study, probably related to prior treatment, including alkylators, which can result in T-cell depletion. Nonetheless, 90% of eligible patients were administered ABECMA®, which is comparable with 91% in the KarMMa trial. The median follow up from infusion was 6.1 months.

Overall, the efficacy of ABECMA® in the real-world population was comparable with that in the KarMMa trial group of patients. The Overall Response and Complete Response rates with Standard of Care ABECMA® were 84% and 42%, which are comparable with 73% and 33% noted in the KarMMa trial. The median DOR was 8.6 months in the present study versus 10.7 months in the KarMMa trial and the median time to response was 1 month. The median PFS in this study was 8.5 months, similar to that observed in the KarMMa trial and the median Overall Survival was 12.5 months. In a multivariable analysis of this study, prior use of BCMA targeted therapy, high-risk cytogenetics, ECOG PS 2 or more, lymphodepletion, and younger age were independent predictors of inferior Progression Free Survival. Any grade and Grade 3 or more Cytokine Release Syndrome and neurotoxicity occurred in 82%/3% and 18%/6%, respectively.

It was concluded from this trial that safety and efficacy of ABECMA® in patients with Relapsed and Refractory multiple myeloma in the Standard of Care setting were comparable with those in the Phase II pivotal KarMMa trial, even though majority of patients in this study did not meet KarMMa trial eligibility criteria. This real-world population study also suggested that if BCMA chimeric antigen receptor-T-cell treatment is planned, prior exposure to BCMA-targeted therapy should be avoided.

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. Hansen DK, Sidana S, Peres LC, et al. DOI: 10.1200/JCO.22.01365 Journal of Clinical Oncology. Published online January 09, 2023.

Zolbetuximab Plus Chemotherapy Improves Survival in CLDN18.2 Positive Metastatic Gastric and Gastroesophageal Junction Cancer

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SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 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 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 6%.

These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6. 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.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with gastric cancer have CLDN18.2 expression.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. In this study, 565 enrolled patients were randomly assigned 1:1 to receive the combination of Zolbetuximab and mFOLFOX6 (N=283) or placebo and mFOLFOX6 (N=282). Zolbetuximab was given at 800 mg/m2 IV on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and days 1 and 22 of subsequent cycles, every 3 weeks. mFOLFOX6 (Oxaliplatin, 5-Fluorouracil and Leucovorin) was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, Zolbetuximab was given at the same dosing schedule in combination with 5-Fluorouracil and Leucovorin IV every 2 weeks. Those in the placebo arm were given placebo at the every 3-week schedule and chemotherapy was administered at the same dosing schedule. Treatment was continued until disease progression or discontinuation criteria were met. Enrolled patients had moderate-to-strong CLDN18 staining intensity in at least 75% of tumor cells based on a validated ImmunoHistoChemistry assay, had HER2-negative disease, and an ECOG performance status of 0 or 1. Patients were stratified by region (Asian versus non-Asian), number of organs with metastases (0-2 versus 3 or more), and prior gastrectomy. The median age was 61 years and 31.4% of patients were from Asia. Majority of patients had 0-2 organs with metastases, 30% had prior gastrectomy. Approximately 13% of patients had tumors with a PD-L1 CPS of at least 5. The primary disease site was stomach in 76% of patients and was GastroEsophageal Junction in 24%. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and Safety.

This study met the Primary endpoint and the median PFS was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The OS was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population. The most common Adverse Events with Zolbetuximab plus mFOLFOX6 were nausea, vomiting and decreased appetite. The incidences of serious Adverse Events were similar between the two treatment groups.

The authors concluded that Zolbetuximab plus mFOLFOX6 is a new potential Standard-of-Care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic Gastric/GE Junction adenocarcinoma. It is unclear if this regimen is superior to chemotherapy plus a checkpoint inhibitor in patients with PD-L1–positive and CLDN18.2-positive disease.

Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Shitara K, Lordick F, Bang Y-J, et al. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292

Five Year Outcomes with KEYTRUDA® Plus Chemotherapy in Metastatic Nonsquamous 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 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-189 is a double-blind, Phase III trial in which 616 patients with untreated Stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin (N=410) or placebo plus the same chemotherapy (N=206). Patients then received either KEYTRUDA® 200 mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR) and Duration of Response (DOR) and Safety. Exploratory end points included PFS2 (time from random assignment to second/subsequent progressive disease on next-line treatment or death from any cause).

In the initial report from the trial, after a median follow-up of 10.5 months, the median PFS was 8.8 months in the KEYTRUDA® combination group and 4.9 months in the placebo combination group (HR=0.52; P<0.001) and the median OS was Not Reached with KEYTRUDA® combination and was 11.3 months in the placebo combination group (HR=0.49; P<0.001).

In this updated analysis, the researchers presented 5-year outcomes from the Phase III KEYNOTE-189 study. The median time from randomization to data cutoff (in March 2022) was 64.6 months. There was continued benefit in the Progression Free Survival and Overall Survival in the KEYTRUDA® group compared to the control group (HR=0.50 versus HR=0.60, respectively). The 5-year Progression Free Survival rates were 7.5% versus 0.6% and 5-year Overall Survival rates were 19.4% versus 11.3% respectively. The Objective Response Rate in the KEYTRUDA® group was 48.3% versus 19.9% in the control group, and the median Duration of Response was 12.7 and 7.1 months, respectively. Similar trends were observed across the PD-L1 subgroups analyzed. Among the 57 patients assigned to KEYTRUDA® combination and completed 35 cycles of KEYTRUDA®, the Objective Response Rate was 86% and the estimated Overall Survival rate 3 years after completion of 35 cycles (approximately 5 years from random assignment) was 71.9%. Sustained improvements in Overall Survival were observed in the KEYTRUDA® combination group, despite a crossover rate of 57% of patients from placebo plus chemotherapy to subsequent anti-PD1 therapy, further supporting the use of KEYTRUDA® plus chemotherapy as first-line treatment.

It was concluded that KEYTRUDA® in combination with Pemetrexed and Platinum chemotherapy continued to demonstrate prolonged survival and durable antitumor activity, compared to chemotherapy alone, regardless of PD-L1 expression. The authors added that these data continue to support the combination of first-line KEYTRUDA® plus a Platinum and Pemetrexed as a standard of care, in patients with previously untreated metastatic nonsquamous NSCLC, without EGFR/ALK alterations.

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. Garassino MC, Gadgeel S, Speranza G, et al. DOI: 10.1200/JCO.22.01989 Journal of Clinical Oncology. Published online February 21, 2023.

Overall Survival Benefit with Pembrolizumab in Advanced Gastric Cancer

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SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 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 Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life. The efficacy of PD-1 inhibitors in combination with chemotherapy has been demonstrated in Gastric and GastroEsophageal cancer.

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

KEYNOTE-859 was a double-blind, placebo-controlled, randomized Phase III trial, conducted to evaluate the benefit of adding Pembrolizumab to Fluoropyrimidine and Platinum-containing doublet chemotherapy in patients with advanced HER2-negative Gastric or GastroEsophageal cancer. In this study, 1,579 patients with locally advanced or metastatic HER2-negative Gastric or GastroEsophageal adenocarcinoma, with known a PD-L1 Combined Positive Score (CPS), were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=790) or placebo (N=789), every 3 weeks for 35 cycles or less, given along with investigator’s choice of 5-FU plus Cisplatin or Capecitabine plus Oxaliplatin (CAPOX). Baseline characteristics were balanced between treatment groups and randomization was stratified by region, PD-L1 CPS (less than 1 versus 1 or more), and choice of chemotherapy. At baseline, 78% of patients had PD-L1 CPS 1 or more, while 35% had tumors with CPS 10 or more.

The Primary end point was Overall Survival (OS) by blinded Independent Central Review. Secondary end points included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and Safety. The researchers provided the data from the interim analysis, at a median follow up of 31.0 months.

The median Overall Survival was 12.9 months with Pembrolizumab plus chemotherapy versus 11.5 months with chemotherapy alone (HR=0.78, P<0.0001). The median PFS was 6.9 months versus 5.6 months, respectively (HR=0.76, P<0.0001). The benefit with Pembrolizumab was consistent across subgroups, including those by PD-L1 CPS. The risk reduction was especially notable among patients with MicroSatellite Instability (MSI)-High status, who had a 66% relative reduction in the risk of death, and patients with PD-L1 CPS 10 or more, whose risk was reduced by 36%. The Objective Response Rate was 51.3% in the Pembrolizumab group and 42.0% in the control group (P=0.00009), and the median Duration of Response was 8.0 months versus 5.7 months, respectively. Immune-related toxicities, especially hypothyroidism, were more common with Pembrolizumab plus chemotherapy and no new safety signals were seen.

It was concluded that treatment with Pembrolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful improvement in Overall Survival, Progression Free Survival and Objective Response Rate, among patients with locally advanced or metastatic, HER2-negative Gastric or GastroEsophageal adenocarcinoma of any PD-L1 expression level, thus providing a new treatment option for this patient group.

Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. Rha SY, Wyrwicz LS, Weber PEY, et al. ESMO Virtual Plenary Session Date: 16-17 February 2023. VP1-2023. Published: February 16, 2023. DOI: https://doi.org/10.1016/j.annonc.2023.01.006.

FDA Approves Adjuvant KEYTRUDA® in NSCLC Irrespective of PD-L1 Expression

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SUMMARY: The FDA on January 26, 2023, approved KEYTRUDA® (Pembrolizumab) for adjuvant treatment following resection and platinum-based chemotherapy for Stage IB (T2a ≥4 cm), II, or IIIA Non-Small Cell Lung Cancer (NSCLC). 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 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. 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.

KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The major efficacy outcome measure was investigator-assessed Disease-Free Survival (DFS). An additional efficacy outcome was Overall Survival (OS).

The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In patients who received adjuvant platinum-based chemotherapy following surgical resection, KEYTRUDA® reduced the risk of disease recurrence or death by 27% (HR=0.73) versus placebo, regardless of PD-L1 expression. For patients who received adjuvant chemotherapy, median DFS regardless of PD-L1 expression was 58.7 months in the KEYTRUDA® group versus 34.9 months in the placebo group. In an exploratory subgroup analysis of the 167 patients who did not receive adjuvant chemotherapy, the DFS Hazard Ratio was 1.25. Overall survival Data were not mature.

It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage NSCLC following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.

EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study of pembrolizumab versus placebo for completely resected early-stage non-small cell lung cancer (NSCLC): Outcomes in subgroups related to surgery, disease burden, and adjuvant chemotherapy use.O’Brien M, Paz-Ares L, Jha N, et al. DOI: 10.1200/JCO.2022.40.16_suppl.8512 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 8512-8512.Published online June 02, 2022.

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