Category: Immuno Oncology

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

FDA Approves Single Agent KEYTRUDA® for Advanced Endometrial Carcinoma

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

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

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

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

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

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. The FDA in 2021 also approved KEYTRUDA® in combination with the multireceptor Tyrosine Kinase Inhibitor LENVIMA® (Lenvatinib) for patients with advanced endometrial carcinoma, irrespective of tumor MSI status based on the KEYNOTE-146 study.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022 Feb 28. doi: 10.1038/s41591-022-01695-5. Online ahead of print.

Platelet-to-Lymphocyte Ratio Predicts the Efficacy of KEYTRUDA® in Patients with Urothelial Carcinoma

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SUMMARY: Immunotherapy with PD-1/PD-L1 (Programmed Death-1/Programmed Death-Ligand 1) inhibitors, also called Immune Checkpoint Inhibitors (ICIs), has dramatically changed the treatment paradigm for patients with solid tumors, with significant improvement in outcomes. However, even among those with tumors expressing high PD-L1 expression and high Tumor Mutation Burden, not all patients benefit from Immunotherapy with ICIs. Therefore identifying biomarkers for patients likely to respond to ICI therapy, and predicting resistance is important and relevant, in selecting the appropriate patients for treatment with ICIs.

There is growing body of evidence on the role of inflammation in cancer biology, and systemic inflammatory response may have prognostic significance in different cancer types. Inflammatory process in various cancers imparts immunoresistance to ICIs, by activating oncogenic signaling pathways, there by promoting cancer growth and dissemination, with resulting poor outcomes.

More recently, attention has been focused on the predictive role of Platelet-Lymphocyte ratio (PLR) as an effective indicator of the severity of systemic inflammatory response. PLR is defined as the ratio of platelets to lymphocytes. Platelets and lymphocytes play multiple roles in the inflammatory response. Increased platelet count accelerates tumor progression by promoting neoangiogenesis and the production of adhesion molecules, whereas lymphocytes activate anti-tumor immunity by releasing a range of cytokines. Elevated PLR has been associated with poor prognosis in multiple solid tumors. In a meta-analysis of data from 12 related studies involving a total of 1340 patients, high PLR in cancer patients was associated with poor efficacy when treated with Immune Checkpoint Inhibitors, and poor prognosis. (https://doi.org/10.1016/j.intimp.2019.105957Get rights and content). Several other studies suggest that using PLR to predict the prognosis of cancer patients treated with immunotherapy remains controversial. The role of PLR in the prognosis of cancer patients treated with immunotherapy has thus remained unclear.

The present study was conducted to determine meaningful predictive factors for selecting patients with advanced Urothelial Carcinoma (UC) who might benefit clinically from treatment with Immune Checkpoint Inhibitor, KEYTRUDA® (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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The researchers retrospectively analyzed 54 patients who received treatment with KEYTRUDA® for Urothelial Carcinoma. Patient’s Hemoglobin, Albumin, Lymphocyte and Platelet (HALP) score, Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR) were calculated as indices of systemic inflammatory response. The relationships between these scores and the initial tumor response or Overall Survival, as well as other clinicopathological factors, were then assessed.

It was noted that a high NLR and PLR were associated with a poor initial tumor response to KEYTRUDA®. A HALP score less than 30.05 and a PLR of 173.73 or more were associated with worse Overall Survival. In the multivariate analysis, a high PLR was a significant independent prognostic factor for unfavorable outcomes.

The authors concluded from this study that a high pretreatment Platelet-to-Lymphocyte Ratio may be a valuable indicator for choosing therapy other than KEYTRUDA® in patients with advanced Urothelial Carcinoma, and may be a potential biomarker for immunotherapy.

Platelet-to-Lymphocyte Ratio Predicts the Efficacy of Pembrolizumab in Patients With Urothelial Carcinoma. Kurashina R, Ando K, Inoue M, et al. Anticancer Research February 2022;42:1131-1136.

OPDIVO® Combination Improves Overall Survival in Advanced Esophageal Carcinoma

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

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

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

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

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

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

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

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

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

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

LAG-3 Inhibitor Relatlimab and OPVIDO® in Advanced Untreated Melanoma

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

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

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

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

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

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

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

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

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

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

KRAS Variant Status and Outcomes with Immune Checkpoint Inhibitor-Based Therapy in Advanced Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

Patients with advanced NSCLC without a driver mutation and with Programmed cell Death Ligand 1 (PD-L1) expression of 50% or greater, are often treated first line with Immune Checkpoint Inhibition (ICI) monotherapy or ICI in combination with chemotherapy. The choice between these two treatment regimens is usually based on tumor burden and patient comorbidities, as there are presently no biomarkers available to predict the risk and benefit of these treatment interventions. The KEYNOTE-042 study demonstrated that single agent Pembrolizumab given as first line therapy demonstrated Overall Survival (OS) benefit over chemotherapy, in patients with previously untreated advanced NSCLC, with PD-L1 expression of 1% or greater. In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants than those without KRAS variants.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. When mutated, KRAS oncogene has the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of NSCLC and in 3-5% of Colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers.

The authors conducted this study to evaluate the association of KRAS status with outcomes following ICI monotherapy versus chemoimmunotherapy in patients with PD-L1 of 50% or greater. The researchers used the Flatiron Health database, comprising 280 cancer clinics across the US and analyzed 1127 patients with advanced non-squamous NSCLC with PD-L1 expression of 50% or greater, known KRAS variant status, and no alteration in EGFR, ALK, or ROS1, who were treated with first line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Of the patients analyzed, 50.8% had KRAS variant status and 49.2% had KRAS wild type status. Patients with KRAS variant status were more likely to be female (58.7% versus 47.1%; P =0.002) and had smoking history (96.4% versus 87.7%; P < .001). Other patient demographics and patient characteristics, including age, race, ethnicity, Performance Status, and stage at diagnosis, were well balanced among the groups analyzed. Patient groups were stratified by treatment type and KRAS status (variant or wild type), and Overall Survival (OS) was compared between the treatment groups. Adjusted Hazard ratios for death associated with KRAS status and treatment regimen was estimated, using Cox proportional hazards models.

It was noted that among patients treated with ICI monotherapy, KRAS variant status was associated with superior median survival compared with KRAS wild type (21.1 months versus 13.6 months; HR=0.77; P=0.03), and this was statistically significant. However, among patients treated with chemoimmunotherapy, there was no significant median survival difference between patients with KRAS variant and KRAS wild type status (20.0 months versus 19.3 months; HR=0.99; P=0.93).

Among patients with KRAS variant status, the median OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (21.1 months versus 20.0 months; P =0.78), whereas among patients with KRAS wild type status, those treated with ICI monotherapy had numerically worse median survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (13.6 months versus 19.3 months; HR=1.19; P =0.06).

In conclusion, this data suggests that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRAS wild type tumors associated with high PD-L1 expression. The authors caution that in this analysis KRAS variant subtype and co-mutation status including TP53 and STK11 was unknown, and further investigation is needed to selection appropriate therapies for patients with PD-L1 High NSCLC.

Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. Sun L, Hsu M, Cohen RB, et al. JAMA Oncol. 2021;7:937-939.

Anti-BCMA CAR T-Cell Therapy for 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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable 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 median survival for patients with myeloma is over 10 years. 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.

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.
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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. In this study, 128 patients with persistent disease after at least three previous regimens including a Proteasome Inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, received ABECMA® target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells, after receiving lymphodepleting chemotherapy. Lymphodepletion therapy consisted of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV given on 3 consecutive days, followed by 2 days of rest before ABECMA® infusion. The median patient age was 61 years and the median time from diagnosis was 6 years. About 51% of patients had a high tumor burden (50% or more bone marrow plasma cells), 39% had extramedullary disease and 35% had a high-risk cytogenetic abnormalities, defined as del(17p), t(4;14), or t(14;16). Patients had received a median of 6 previous antimyeloma regimens and 94% had received previous Autologous Hematopoietic Stem Cell Transplants. The Primary end point was an Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and key Secondary end point was a Complete Response or better (comprising complete and stringent Complete Responses). Other efficacy endpoints include Time to Response, Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Minimal Residual Disease (MRD) evaluated by Next-Generation Sequencing (NGS) assay, and Safety.

At a median follow up of 13.3 months, the ORR was 73%, and 33% had a complete or stringent Complete Response. Of those with a complete or stringent Complete Response, 79% had MRD-negative status at a sensitivity level of 10−5, corresponding to 26% of the treated population. This benefit was consistently observed in most subgroups examined, including older patients, those who received bridging therapy, and those with aggressive disease features, including high-risk cytogenetics, triple or penta-refractory disease, a high tumor burden, and extramedullary disease. The median time to first response was 1.0 month and the median time to a Complete Response or better was 2.8 months. The estimated median Duration of Response was 10.7 months for all patients and 11.3 months among those receiving the highest target dose. The response duration increased with the depth of response. The median PFS was 8.8 months for all patients and 20.2 months in patients having a complete or stringent Complete Response. Data on Overall Survival are immature. Cellular kinetic analysis confirmed CAR+ T cells in 59% at 6 months and 36% at 12 months after infusion. Common toxicities included neutropenia, anemia and thrombocytopenia. Cytokine Release Syndrome was reported in 84% of patients including 5% Grade 3 or higher events. Neurotoxic effects developed in 18% of patients.

It was concluded that ABECMA® induced deep and durable responses in majority of heavily pretreated patients with Refractory and Relapsed myeloma, and fulfills a highly unmet need for this patient group. It should however be noted that although some subsets of patients may have sustained responses for long periods of time, most patients eventually relapse. This has been attributed to the loss of CAR T-cells, loss of antigen expression on the tumor cell surface, or to impaired activity of T cells in an immunosuppressive microenvironment. Studies are underway to overcome these shortcomings by optimizing CAR design, as well as preventing antigen escape and developing combination therapies.

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. Munshi NC, Anderson LD, Shah N, et al. N Engl J Med 2021; 384:705-716