Category: Immuno Oncology

Five-Year Efficacy Outcomes with KEYTRUDA® versus Chemotherapy in Metastatic NSCLC

RR

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.

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. Immune Checkpoint Inhibitors (ICIs) target Programmed cell Death protein-1 (PD-1) receptors on T cells, as well as Programmed cell Death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system, which are upregulated in some tumor types. T-cell proliferation and cytokine production is inhibited upon binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells.

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, releasing PD-1 pathway-mediated inhibition of the immune response. Unleashing the T cells results in T cell proliferation, activation and a therapeutic response. High level of 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-024 is an open-label, randomized, Phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of Platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety. In an updated analysis of the KEYNOTE-024 study, after a median follow up of 25.2 months, the median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). This OS benefit was maintained even after adjusting for crossover.

The authors in this publication reported the 5-year efficacy and safety outcomes from this pivotal Phase III KEYNOTE-024 trial. The median time from randomization to data cutoff was 59.9 months. Among patients initially assigned to chemotherapy, 66% received subsequent anti PD-1 or PD-L1 therapy (66% cross over rate). In the KEYTRUDA® group, 52.9% received additional anticancer therapy.

The median OS was 26.3 months for KEYTRUDA® and 13.4 months for chemotherapy (HR=0.62). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the KEYTRUDA group and 16.3% for the chemotherapy group. The ORR was 46.1% among patients in the KEYTRUDA® group versus 31.1% in the chemotherapy group and the median Duration of Response was 29.1 months in the KEYTRUDA® group and 6.3 months in the chemotherapy group.

The authors concluded that first line KEYTRUDA® provides a durable and clinically meaningful long-term Overall Survival benefit, when compared to chemotherapy, in patients with metastatic NSCLC, with PD-L1 Tumor Proportion Score of at least 50%.They added that this is first 5-year follow up of any first line Phase III immunotherapy trial for Non Small Cell Lung Cancer.

Five-Year Efficacy Outcomes With Pembrolizumab vs Chemotherapy in Metastatic NSCLC With PD-L1 Tumor Proportion Score of at Least 50%: KEYNOTE-024 Trial. Reck M , Rodríguez–Abreu D, Robinson AG, et al. DOI: 10.1200/JCO.21.00174 Journal of Clinical Oncology. Published online April 19, 2021.

FDA Approves LIBTAYO® for Non Small Cell Lung Cancer with High PD-L1 Expression

RR

SUMMARY: The FDA on February 22, 2021, approved LIBTAYO® (Cemiplimab-rwlc) for the first line treatment of patients with advanced Non Small Cell Lung Cancer (NSCLC) (locally advanced who are not candidates for surgical resection or definitive chemoradiation or metastatic), whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] 50% or more), as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations.

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. 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.

Available Immune Checkpoint Inhibitors (ICIs) target Programmed cell Death protein-1 (PD-1) receptors on T cells, as well as Programmed cell Death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system, which are upregulated in some tumor types. T-cell proliferation and cytokine production is inhibited upon binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells.

LIBTAYO® is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. Unleashing the T cells results in T cell proliferation, activation and a therapeutic response. LIBTAYO® is indicated for the treatment of subsets of patients with advanced Basal Cell Carcinoma and advanced cutaneous Squamous Cell Carcinoma.

The present FDA approval of LIBTAYO® is based on EMPOWER-Lung 1, which is a multicentre, open-label, global, Phase III trial, which examined the benefit of LIBTAYO® in the first-line treatment of advanced NSCLC with PD-L1 expression of at least 50%. In this study, 710 (N=710) patients (intent-to-treat) with Squamous or non-Squamous, locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation, or with metastatic NSCLC were randomized (1:1) to receive LIBTAYO® 350 mg IV every 3 weeks for up to 108 weeks (N=356) or 4-6 cycles of investigator’s choice of platinum doublet chemotherapy (N=354). The most common chemotherapy regimens selected were Carboplatin plus Paclitaxel, Carboplatin plus Pemetrexed, and Carboplatin plus Gemcitabine. Crossover from chemotherapy to LIBTAYO® was allowed following disease progression, and never-smokers were not eligible for the trial. The co-Primary end points of the study were Overall Survival (OS) and Progression Free Survival (PFS), per the Blinded Independent Review Committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified population of patients with PD-L1 of at least 50%. Secondary end points included Overall Response Rate (ORR), Duration of Response (DOR), Health-Related Quality of Life (HRQoL), and Safety.

This trial demonstrated statistically significant improvements in OS and PFS for patients receiving LIBTAYO® compared to those treated with platinum-based chemotherapy, despite a high crossover rate (74%). The median OS was 22.1 months with LIBTAYO® versus 14.3 months with chemotherapy (HR=0.68; P=0.0022), demonstrating that LIBTAYO® reduced the risk of death by 32% compared to chemotherapy. An additional analysis of 563 patients with proven PD-L1 expression of 50% or higher found that the median OS was Not Reached with LIBTAYO® (N=283) versus 14.2 months with chemotherapy (N=280). LIBTAYO® reduced the risk of death by 43% compared to chemotherapy HR=0.57; P=0.0002). The median PFS was 6.2 months in the LIBTAYO® group and 5.6 months in the chemotherapy group (HR= 0.59; P<0.0001). Among those with PD-L1 expression of 50% or higher, the median PFS was 8.2 months with LIBTAYO® versus 5•7 months with chemotherapy (HR=0•54; P<0•0001). The confirmed ORR was 37% and 21% in the LIBTAYO® and chemotherapy arms respectively, and the median DOR was 21.0 months in the LIBTAYO® arm versus 6.0 months in the chemotherapy arm.

The authors concluded that LIBTAYO® monotherapy significantly improved Overall Survival and Progression Free Survival compared with chemotherapy, in patients with advanced Non Small Cell Lung Cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population.

Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Sezer A, Kilickap S, Gümüş M, et al. Lancet. 2021;397:592-604. doi: 10.1016/S0140-6736(21)00228-2.

FDA Approves Anti-BCMA CAR T-Cell Therapy for Relapsed or Refractory Multiple Myeloma

RR

SUMMARY: The FDA on March 26, 2021, approved ABECMA® (Idecabtagene vicleucel) for the treatment of adult patients with Relapsed or Refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a Proteasome Inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA approved cell-based gene therapy for multiple myeloma. 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.Chimeric-Antigen-Receptor-T-Cell-Immunotherapy

Anti-BCMA CAR T-Cell Therapy ABECMA® 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.

The FDA approval 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 high unmet need for this patient group.

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

FDA Approves First Line KEYTRUDA® in Combination with Chemotherapy for Esophageal or Gastroesophageal Carcinoma

RR

SUMMARY: The FDA on March 22, 2021, approved KEYTRUDA® (Pembrolizumab) in combination with Platinum and Fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GastroEsophageal Junction (tumors with epicenter 1 to 5 cm above the GastroEsophageal Junction) carcinoma, who are not candidates for surgical resection or definitive chemoradiation. The American Cancer Society estimates that in the US about 19,260 new esophageal cancer cases will be diagnosed in 2021 and about 15,530 people will die of the disease. Esophageal cancer is more common among men than among women. Majority of the patients with Gastric and GastroEsophageal (GE) 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. The prognosis for advanced esophageal cancer is poor, with median survival of less than 12 months.

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.

KEYNOTE-590 is a global, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, in which first line KEYTRUDA® plus chemotherapy was compared with placebo plus chemotherapy, in patients with locally advanced/unresectable or metastatic adenocarcinoma or esophageal Squamous Cell Carcinoma (ESCC) or Siewert type 1 EsophagoGastric Junction adenocarcinoma (EGJ), who were not candidates for surgical resection or definitive chemoradiation. In this study, 749 eligible patients, regardless of PD-L1 expression were randomized 1:1 to KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles (2 years) along with chemotherapy consisting of Cisplatin 80mg/m2 IV given on day 1, plus 5FU 800 mg/m2 IV given on days 1-5, every 3 weeks for 6 cycles, or placebo plus chemotherapy. Treatment was continued until disease progression or unacceptable toxicity, and crossover was not permitted. Approximately 50% of all patients had tumors with a PD-L1 Combined Positive Score (CPS) 10 or more, and half the population was Asian. The dual Primary endpoints of the study were Overall Survival (OS) and Progression Free Survival (PFS). The researchers evaluated outcomes in the overall treatment population, in patients with a PD-L1 CPS 10 or more, and according to histology (Esophageal Squamous Cell Carcinoma versus adenocarcinoma). The Secondary end point was Objective Response Rate (ORR) in all patients. The median follow up was 10.8 months.

There was a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA® with chemotherapy. The median OS among all patients was 12.4 versus 9.8 months (HR=0.73; P<0.0001) and the median PFS among all patients was 6.3 versus 5.8 months, respectively (HR=0.65; P<0.0001). The confirmed ORR in all patients was 45% versus 29.3% (P < 0.0001), with a median Duration of Response of 8.3 versus 6.0 months, respectively. In patients with a PD-L1 CPS 10 or higher, the median OS with the KEYTRUDA® plus chemotherapy was 13.5 months versus 9.4 months with chemotherapy alone (HR=0.62; P<0.0001) and the median PFS was 7.5 months versus 5.5 months, respectively (HR=0.51; P<0.0001). The most common adverse reactions reported in 20% or more of patients who received the KEYTRUDA® combination were nausea, vomiting, constipation, diarrhea stomatitis, fatigue/asthenia, decreased appetite, and weight loss.

It was concluded that treatment with KEYTRUDA® plus chemotherapy combination resulted in superior Overall Survival, Progression Free Survival, and Objective Response Rate, with a manageable safety profile, when compared to chemotherapy alone, in patients with advanced untreated esophageal and EsophagoGastric Junction cancer. These data demonstrate that first line KEYTRUDA® plus chemotherapy is a new standard of care in this patient population.

Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Kato K, Sun J, Shah MA, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.

Advances with First-Line Dual Immunotherapies in Metastatic Non-Small Cell Lung Cancer

RR

By Dr. David Waterhouse | Sponsored by Bristol Myers Squibb
Dr. Waterhouse is a paid consultant for Bristol Myers Squibb and was compensated for his role in drafting this article.

The American Cancer Society estimates that there will be nearly 229,000 new cases of lung cancer in the United States (US) alone in 2020 and nearly 136,000 lung cancer deaths.1 Historically, most patients present with metastatic disease and their long-term outlook is grim.2 However, significant progress has been made in recent years. In August 2020, Howlader et al reported that the population-level mortality from non-small cell lung cancer (NSCLC) in the US fell sharply from 2013 to 2016.3

Based on the results from Checkmate 227 Part 1a, OPDIVO, in combination with YERVOY, is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.4-6 In addition, based on the results from Checkmate 9LA, OPDIVO, in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy (chemo), is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.4,6,7

OPDIVO and YERVOY are associated with the following Warnings and Precautions: severe and fatal immune-mediated reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.4 Please see additional Important Safety Information for OPDIVO and YERVOY at the end of the article and US Full Prescribing Information for OPDIVO and YERVOY at https://packageinserts.bms.com/pi/pi_opdivo.pdf and https://packageinserts.bms.com/pi/pi_yervoy.pdf.

OPDIVO® (nivolumab) is a monoclonal antibody targeting programmed death receptor-1 (PD-1) that has been approved for the treatment of lung cancer.4 YERVOY® (ipilimumab) is another monoclonal antibody that works to activate the immune system by targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4).6,8

Figure 1: OPDIVO and YERVOY mechanisms of action4,6,8-14

OPDIVO+YERVOY-MOAThis graphic is for demonstration purposes only.
The illustrated mechanisms may vary for each patient and may not directly correlate with clinical significance.

The phase 3 Checkmate 227 and Checkmate 9LA trials investigated OPDIVO plus YERVOY-based combinations for first-line treatment of certain NSCLC patients.4 Part 1a of Checkmate 227 investigated the effects of OPDIVO + YERVOY compared with standard chemo* among patients whose tumors expressed ≥1% programmed death ligand 1 (PD-L1)4 (Figure 2).

Figure 2: Checkmate 227 Part 1a study design15
Checkmate-227-Study-Design*In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.4,16,17
ALK=anaplastic lymphoma kinase; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EGFR=epidermal growth factor receptor; NSQ=non-squamous; q2w=every 2 weeks; q6w=every 6 weeks; SQ=squamous.

OPDIVO + YERVOY showed a superior survival benefit compared with chemo*, with the primary analysis at a minimum follow-up of 29.3 months revealing a median overall survival (OS) of 17.1 months vs 14.9 months with chemo*, and a hazard ratio (HR) of 0.79, 95% confidence interval (CI): 0.67–0.94, P=0.0066 (Figure 3).4,16 The median progression-free survival (PFS) was 5.1 months (95% CI: 4.1–6.3) with OPDIVO + YERVOY and 5.6 months (95% CI: 4.6–5.8) with chemo* alone (HR=0.82; 95% CI: 0.69–0.97).4

The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure.4 The most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%).4 Please continue reading for more Important Safety Information for OPDIVO and YERVOY throughout.

Figure 3: Checkmate 227 OS for PD L1 ≥1% (extended 3-year follow-up analysis)4,15

Median-OS-Primary-Analysis-OPDIVO+YERVOY

*In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.4,16,17

At the American Society for Clinical Oncology (ASCO) 2020 Annual Meeting, 3-year follow-up results from this trial were reported. With a median follow-up of more than 3 years (43.1 months), this study represents the longest median follow-up of any dual immuno-oncology (I-O)-based combination in a phase 3 clinical trial in NSCLC.15 This extended follow-up analysis showed 3-year OS rates of 33% for OPDIVO + YERVOY and 22% for chemo* (Figure 3).15

At minimum follow-up of 28.3 months, the objective response rate was 36% (95% CI: 31–41), CR=5.8%, PR=30.1% with OPDIVO + YERVOY and 30% (95% CI: 26–35), CR=1.8%, PR=28.2% with chemo*.4,16,17 The median duration of response from the extended 3-year follow-up analysis was 23.2 months (95% CI: 15.2–32.2) in patients who responded to OPDIVO + YERVOY and 6.7 months (95% CI: 5.6–7.6) with chemo* (Figure 4).15

Figure 4: Checkmate 227 DOR among responders with PD L1 ≥1% (extended 3-year follow-up analysis)15

Median-DOR-OPDIVO+YERVOY

Median follow-up of 43.1 months.15
*In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.4,16,17

The 3-year data from Checkmate 227 Part 1a show the long-term durable survival of a dual immunotherapy approach.15 The FDA approved OPDIVO + YERVOY on May 15, 2020, for first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1(≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. With this approval, these patients with NSCLC can now be offered the option of dual I-O therapy.4,5

Also reported at ASCO 2020 were the results of Checkmate 9LA.18 Patients were randomized to receive either the combination of OPDIVO + YERVOY and 2 cycles of platinum-doublet chemo† or platinum-doublet chemo† for 4 cycles.4 This trial evaluated patients regardless of PD-L1 expression and histology (Figure 5).4

Figure 5: Checkmate 9LA study design18

Checkmate-9LA-Study-Design

†In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm, and up to 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in comparator arm only); SQ: paclitaxel + carboplatin.4
q3w=every three weeks.

The trial showed a superior benefit in OS for patients treated with OPDIVO + YERVOY with limited chemo† compared to those who received chemo† alone.18 At the pre-specified interim analysis at 8.1 months, the median OS was 14.1 months vs 10.7 months (HR=0.69, 96.71% CI: 0.55-0.87, P=0.0006).4 Median PFS per blinded independent central review (BICR) at minimum follow-up of 6.5 months was 6.8 months among patients who received OPDIVO + YERVOY with chemo†, and 5.0 months among patients receiving chemo† (HR=0.70, 97.48% CI: 0.57-0.86).4 Confirmed ORR per BICR at minimum follow-up of 6.5 months was 38% (95% CI: 33-43) and 25% (95% CI: 21-30) respectively.4,18

A follow-up analysis performed at 12.7 months showed median OS of 15.6 months with OPDIVO + YERVOY with chemo† and 10.9 months with chemo† alone with HR of 0.66 (95% CI: 0.55-0.80) (Figure 6).4,18 OS was consistent across PD-L1 expression levels at minimum follow-up of 8.1 months, with median OS of 14.0 months (95% CI:13.2-NR) and 10.0 months (95% CI: 7.7-13.7) in patients treated with OPDIVO + YERVOY with limited chemo† and chemo† respectively in the PD-L1 <1% sub-population (HR=0.65), and median OS of 14.2 months (95% CI:13.1-NR) and 10.6 months (95% CI: 9.4-12.6) respectively (HR=0.67) in the PD-L1 ≥1% sub-population.19

Figure 6: Checkmate 9LA overall survival (extended follow-up)18

Checkmate-9LA-OS
Minimum follow-up of 12.7 months.
†In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm, and up to 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in comparator arm only); SQ: paclitaxel + carboplatin.4

In this study, the most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.4 The most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).4 Please continue reading for more Important Safety Information for OPDIVO and YERVOY throughout. The FDA approved OPDIVO, in combination with YERVOY and 2 cycles of platinum-doublet chemo, for the first-line treatment of adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations in May 2020.4,7

With the approval of both Checkmate 227 and Checkmate 9LA regimens as first-line therapies, I am pleased to be able to offer metastatic NSCLC patients with additional options. Checkmate 227 provides appropriate mNSCLC patients with a chemo-free, dual I-O option with long-term, durable survival. Additionally, the Checkmate 9LA regimen with dual I-O plus limited chemo† has shown superior OS, and consistent OS, regardless of PD-L1 expression in recurrent/metastatic NSCLC patients.4,18

*In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.4,16,17
†In Checkmate 9LA, patients received 2 cycles of platinum-doublet chemo q3w in the experimental arm, and up to 4 cycles in the comparator arm; NSQ: pemetrexed + carboplatin or cisplatin (optional pemetrexed maintenance therapy in comparator arm only); SQ: paclitaxel + carboplatin.4

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-Mediated Hepatitis

OPDIVO and YERVOY can cause immune-mediated hepatitis.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Common Adverse Reactions

In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY:
• https://packageinserts.bms.com/pi/pi_opdivo.pdf
• https://packageinserts.bms.com/pi/pi_yervoy.pdf

References:
1. Key statistics for lung cancer. American Cancer Society. Reviewed October 1, 2019. Revised January 8, 2020. Accessed October 7, 2020. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.
2. Lung and bronchus cancer – cancer stat facts. National Cancer Institute. Accessed October 7, 2020. https://seer.cancer.gov/statfacts/html/lungb.html.
3. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383:640-649.
4. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
5. FDA approval for Checkmate 227. Accessed October 12, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1.
6. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
7. FDA approval for Checkmate 9LA. Accessed October 12, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc.
8. Weber JS, Hamid O, Chasalow SD, et al. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother. 2012;35:89-97.
9. Farber DL, Yudanin NA, and Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014;14(1):24-35.
10. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti–CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non–Hodgkin lymphoma. Clin Cancer Res. 2009;15(20):6446-6453.
11. Felix J, Lambert J, Roelens M, et al. Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response. Oncoimmunology. 2016;5(7):e1136045.
12. Pedicord VA, Montalvo W, Leiner IM, and Allison JP. Single dose of anti–CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA. 2011;108(1):266-271.
13. de Coaña YP, Wolodarski M, Poschke I, et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget. 2017;8(13):21539-21553.
14. Buchbinder EI and Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98-106.
15. Ramalingam S, Ciuleanu T-E, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from Checkmate 227 Part 1. Oral presentation at ASCO 2020. Abstract 9500.
16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.
17. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031. [supplementary appendix].
18. Reck M, Ciuleanu T-E, Cobo M, et al. Nivolumab + ipilimumab + 2 cycles of platinum-doublet chemotherapy vs 4 cycles chemotherapy as first-line treatment for stage IV/recurrent NSCLC: Checkmate 9LA. Oral presentation at ASCO 2020. Abstract 9501.
19. Data on file. NIVO 566. Princeton, NJ: Bristol-Myers Squibb Company.

FDA Approves LIBTAYO® for Advanced Basal Cell Carcinoma

RR

SUMMARY: The FDA on February 9, 2021, granted regular approval to LIBTAYO® (Cemiplimab-rwlc) for patients with locally advanced Basal Cell Carcinoma (laBCC) previously treated with a HedgeHog pathway Inhibitor (HHI) or for whom a HHI is not appropriate, and granted accelerated approval to LIBTAYO® for patients with metastatic BCC (mBCC) previously treated with a HHI or for whom a HHI is not appropriate.

BCC is the most common type of skin cancer in the U.S., with approximately two million new cases diagnosed every year. Exposure to UltraViolet rays is a significant risk factor. Majority of BCCs are diagnosed early and cured with surgery and radiation. However, a small proportion of tumors can become locally advanced or progress to metastatic disease and can be painful and disfiguring. The primary systemic treatment options for these patients with advanced BCC are oral HedgeHog pathway inhibitors such as ERIVEDGE® (Vismodegib) and ODOMZO® (Sonidegib). There are however no FDA-approved treatment options available, for patients who progress on, or are intolerant to HedgeHog Inhibitors (HHIs).

LIBTAYO® is a fully human IgG4, high affinity anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor on tumor-infiltrating T cells and blocks its interaction with tumor derived 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. LIBTAYO® was previously approved by the FDA in 2018 as the first systemic treatment for adults with metastatic Cutaneous Squamous Cell Carcinoma (CSCC) or locally advanced CSCC, who are not candidates for curative surgery or curative radiation.

The present FDA approval of LIBTAYO® was based on results from an interim analysis of an ongoing open-label, multi-center, non-randomized Phase II trial (Study 1620), involving patients with unresectable locally advanced BCC or metastatic BCC (nodal or distant). This was the first and largest prospective clinical trial (N=132) among this patient population, with 112 patients included in the efficacy analysis. Patients in both cohorts (locally advanced and metastatic) had either progressed on HHI therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy. Eligibility required that locally advanced BCC patients were not candidates for curative surgery or curative RT, per multidisciplinary assessment. All patients received LIBTAYO® 350 mg IV over 30 minutes every 3 weeks for up to 93 weeks, until disease progression, unacceptable toxicity, or completion of planned treatment. No PD-L1 or Tumor Mutational Burden (TMB) testing was required before starting treatment with LIBTAYO®. The Primary efficacy endpoint was confirmed Objective Response Rate (ORR) and a key Secondary endpoint was Duration of Response (DOR), as assessed by Independent Central Review.

Among the 84 patients with locally advanced BCC, the confirmed ORR was 29% with a median DOR not reached, and 79% of responders maintained their response for at least 6 months. Among 28 patients with metastatic BCC, the confirmed ORR was 21%, with a median DOR not reached, and all responders maintained their responses for at least 6 months. The most common adverse reactions (incidence 20% or more) were fatigue, musculoskeletal pain, diarrhea, rash, and pruritis.

It was concluded from this study that LIBTAYO® is the first agent to provide clinically meaningful anti-tumor activity including durable responses, in patients with advanced BCC, after progression or intolerance on HHI therapy.

Interim Analysis of Phase 2 Results for Cemiplimab in Patients with Metastatic Basal Cell Carcinoma (mBCC) who Progressed on or are Intolerant to Hedgehog Inhibitors (HHIs). Lewis KD, Peris K, Sekulic A, et al. Presented at the 2021 Winter Clinical Dermatology Conference, January 16–24, Virtual Conference (encore of SITC 2020 poster presentation).

First Line KEYTRUDA® Superior to Chemotherapy in Metastatic MSI-H/dMMR Colorectal Cancer

RR

SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC were diagnosed in the United States in 2020 and about 53,200 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have family histories of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

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 enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR 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.

KEYNOTE-177 is an International, multicenter, randomized open-label, Phase III trial conducted, to evaluate the efficacy and safety of KEYTRUDA® versus Standard-of-Care (SOC) chemotherapy, as first-line therapy for dMMR or MSI-H metastatic ColoRectal Cancer (mCRC). In this study, a total of 307 patients with MSI-H/dMMR mCRC as determined locally, and with ECOG PS of 0 or 1 were randomly assigned 1:1 to first-line treatment with KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=153) or investigator’s choice of mFOLFOX-6 or FOLFIRI every 2 weeks, with or without Bevacizumab or Cetuximab (N=154). Chemotherapy regimens were chosen prior to randomization. Treatment was continued until disease progression, unacceptable toxicity or completion of 35 cycles (for KEYTRUDA® only). The median patient age was 63 years and both treatment groups were well balanced. The co-Primary endpoints of the study were Progression Free Survival (PFS) and Overall Survival (OS). Key Secondary endpoints included Overall Response Rate (ORR) and Safety. Patients with confirmed disease progression on chemotherapy were given the option to crossover, to receive treatment with KEYTRUDA®.

At the second interim analysis, after a median follow up of 32.4 months, it was noted that KEYTRUDA® was superior to chemotherapy with a median PFS of 16.5 months versus 8.2 months for chemotherapy (HR=0.60; P=0.00002). The estimated restricted mean survival time after 24 months of follow up was 13.7 months in the KEYTRUDA® group as compared with 10.8 months in the chemotherapy group. Progression Free Survival was consistently longer with KEYTRUDA® than with chemotherapy across prespecified subgroups. The confirmed ORR was 43.8% with KEYTRUDA® versus 33.1% with chemotherapy, with Complete Responses in 11% and 4%, respectively. Among patients with an Overall Response, 83% in the KEYTRUDA® group had ongoing responses, as compared with 35% in the chemotherapy group at 24 months. The median Duration of Response was not reached in the KEYTRUDA® group and was 10.6 months in the chemotherapy group. Following disease progression, 36% of patients assigned to the chemotherapy group crossed over to the KEYTRUDA® group. This study is being continued to evaluate OS. Grade 3-5 treatment related Adverse Event rates were 22% in the KEYTRUDA® arm and 66% in the chemotherapy group.

The authors concluded that when compared to chemotherapy, first-line therapy with KEYTRUDA® provided a clinically meaningful and statistically significant improvement in Progression Free Survival, among patients with MSI-H/dMMR metastatic colorectal cancer, with fewer treatment-related Adverse Events. The authors added that KEYTRUDA® should be the new standard of care for this patient group.

Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer. Andre T, Shiu K-K, Kim TW, et al. for the KEYNOTE-177 Investigators. N Engl J Med 2020;383:2207-2218.

Salvage YERVOY® and OPDIVO® Combination after Prior Immune Checkpoint Inhibitor Therapy in Advanced RCC

RR

SUMMARY: The American Cancer Society estimates that 73,750 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2020 and about 14,830 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease.

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

The FDA in 2018, approved combination immunotherapy, OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), for the treatment of intermediate or poor-risk, previously untreated advanced Renal Cell Carcinoma (RCC), based on significantly higher Overall Survival (OS) and Objective Response Rates (ORR), compared with Sunitinib, a multikinase inhibitor (CheckMate 214). Subsequently, two studies, a combination of BAVENCIO® (Avelumab), a PD-L1 targeted monoclonal antibody and INLYTA® (Axitinib), a Receptor Tyrosine Kinase inhibitor (JAVELIN Renal-101), and KEYTRUDA® (Pembrolizumab), a PD-1 targeted monoclonal antibody and INLYTA® (KEYNOTE-426), demonstrated superior OS, compared to Sunitinib, and for the first time set the stage for the use of a combination of Immune Checkpoint Inhibitor (ICI) and targeted therapy as first line treatment in this patient population.

The safety and activity of the combination of YERVOY® and OPDIVO® in patients with prior exposure to anti-PD-1 pathway targeted therapy, but no prior exposure to anti-CTLA-4 pathway targeted therapy, remains unknown. The rationale behind combining YERVOY® and OPDIVO® is that these two agents act in different phases of the immune response. Blocking the PD-1/PD-L1 pathway does not induce antitumor immunity if antigen-specific CD8-positive T cells are not present in cancer tissues. However, blocking the CTLA-4 pathway leads to increased activation of CD8-positive cells in the lymph nodes as well as increased infiltration of activated CD8-positive T cells into the tumor. This mechanistic difference between an anti-PD-1 antibody and an anti-CTLA-4 targeted therapy may allow activity of anti-CTLA-4 antibody in combination with anti-PD-1 antibody, upon treatment failure on prior anti-PD-1 targeted therapy.

The authors in this publication evaluated YERVOY® and OPDIVO® combination in patients with metastatic RCC, after prior treatment with anti-PD-1 pathway targeted therapy. This study included 45 patients with metastatic Renal Cell Carcinoma from 5 medical centers in the US and all patients had received prior therapy with Immune Checkpoint Inhibitors (ICIs) targeting the PD-1 pathway. The Primary objective of this study was to estimate the Objective Response Rate (ORR) to salvage YERVOY® and OPDIVO® combination, in patients with metastatic RCC, who received ICI as prior treatment.

The median number of prior lines of therapy was 3 and all patients had received at least one prior therapy targeting the PD-1 pathway. About 76% of patients received an anti-PD-1 antibody, and 24% received an anti-PDL-1 antibody before receiving YERVOY® and OPDIVO® combination. Of the 45 patients included in this study, 60% received monotherapy with prior anti-PD-1 or anti-PDL-1 antibody, 18% received PD-1 pathway targeted Immune Checkpoint Inhibitor (ICI) in combination with a VEGF receptor inhibitor (Axitinib,Sunitinib, or Cabozantinib), 9% received an ICI in combination with Bevacizumab, and 13% received an ICI in combination with another agent . Approximately 71% of the study patients received one line of prior ICI therapy and 29% of the study patients had received more than one prior ICI regimen. The best Objective Response Rate to prior ICI therapy was a Partial Response Rate of 53%, Stable disease in 27%, and Progressive disease in 20%. The median time on prior ICIs was 13 months. The median age at the time of initiation of YERVOY® and OPDIVO® combination was 62 years and all patients had more than one metastatic site, and 38% had brain metastasis. Twenty percent of the patients were favorable risk on the basis of IMDC criteria, 64% were intermediate risk, 7% were poor risk, and 9% were unknown risk.

At a median follow up of 12 months, the Objective Response Rate with the YERVOY® and OPDIVO® combination was 20% and the median Duration of Response was 7 months. An additional 16% of patients had stable disease. The median Progression Free Survival while on YERVOY® and OPDIVO® combination was 4 months. Immune-related Adverse Events of any grade with YERVOY® and OPDIVO® combination were noted in 64% of patients, and Grade 3 Immune-related Adverse Events were noted in 13% of the study patients.

It was concluded from this study that YERVOY® and OPDIVO® combination demonstrated antitumor activity with acceptable toxicity in patients with metastatic Renal Cell Carcinoma, who had prior treatment with Immune Checkpoint Inhibitors, suggesting that responses are possible in a subset of patients with metastatic Renal Cell Carcinoma who are naïve to therapy with anti-CTLA-4 antibody, and had prior exposure to therapy targeting the PD-1 pathway. Salvage YERVOY® and OPDIVO® therapy after single-agent OPDIVO® is currently being evaluated in multiple clinical trials.

Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors. Gul A, Stewart TF, Mantia CM, et al. J Clin Oncol 2020;38:3088-3094

High Tumor Mutational Burden Predicts Response to KEYTRUDA®

RR

SUMMARY: Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High and less than 10 mutations/Megabase as Low. (A megabase is 1,000,000 DNA basepairs). 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.

The authors in this publication prospectively explored the association of high tissue TMB with outcomes, following treatment with KEYTRUDA®, in patients with selected, previously treated, advanced solid tumors. KEYNOTE-158 is a multicenter, multicohort, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. Eligible patients had advanced unresectable or metastatic solid tumors (Anal, Biliary, Cervical, Endometrial, Mesothelioma, Neuroendocrine, Salivary, Small-cell lung, Thyroid, and Vulvar), who had progressed on, or were intolerant to one or more lines of standard therapy, had measurable disease, as well as tumor sample available for biomarker analysis.

This study enrolled 1073 patients of whom 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients, with sufficient tissue for testing. Of these 790 patients, 102 patients (13%) had tumors identified as TMB-High, defined 10 or more mutations /Megabase. TMB status was assessed in Formalin-Fixed Paraffin-Embedded tumor samples using the FoundationOne® CDx assay. Patients received KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety. The median study follow up was 37.1 months.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. The ORR in the non-TMB-High group was 6%. The median duration of response was not reached in the TMB-H group and was 33.1 months in those without high TMB, at the time of data cutoff. There was low correlation between TMB and PD-L1 expression. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

The authors concluded that high Tumor Mutational Burden status identifies a subgroup of patients who could have a robust tumor response to KEYTRUDA® monotherapy . They added that tissue TMB therefore could be a novel and useful predictive biomarker for response to KEYTRUDA® monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Marabelle A, Fakih MG, Lopez J, et al. Lancet Oncol. 2020;21:1353-1365.

FDA Approves KEYTRUDA® Plus Chemotherapy for Triple Negative Breast Cancer

RR

SUMMARY: The FDA on November 13, 2020, granted accelerated approval to KEYTRUDA® (Pembrolizumab) in combination with chemotherapy for the treatment of patients with locally recurrent, unresectable or metastatic, Triple Negative Breast Cancer (TNBC), whose tumors express PD-L1 (Combined Positive Score-CPS 10 or more) as determined by an FDA approved test. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is usually aggressive, and tumors tend to be high grade, and patients with TNBC are at a higher risk of both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates, similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival (PFS) of only 2-3 months.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

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 rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10% to 21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first-line treatment of TNBC.

KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety. The median follow up for patients assigned to receive KEYTRUDA® was 17.5 months and 15.5 months for the placebo group. The authors reported the results from an interim analysis conducted by an Independent Data Monitoring Committee (IDMC).

KEYTRUDA® in combination with chemotherapy, significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. Among patients with CPS of 1 or greater, the median PFS was 7.6 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for the placebo plus chemotherapy arm (HR= 0.74; P=0.0014). This however based on prespecified statistical criteria, was not considered statistically significant. Among the entire Intention-To-Treat (ITT) population, the median PFS was 7.5 months in the KEYTRUDA® plus chemotherapy group, compared with 5.6 months for chemotherapy plus placebo group (HR=0.82). Formal statistical significance was not tested in the ITT population. Overall Survival data are pending. Adverse Events (AEs) were similar in both treatment groups, although immune-related AEs occurred at a higher incidence in the KEYTRUDA® arm.

It was concluded that KEYTRUDA® in combination with several chemotherapy regimens, showed a statistically significant and clinically meaningful improvement in PFS, compared with chemotherapy alone, in patients with previously untreated locally recurrent, inoperable or metastatic TNBC, whose tumors expressed PD-L1 with a Combined Positive Score (CPS) of 10 or more. This data may be particularly relevant for patients who may have received a taxane in the adjuvant setting within a year, and could be more appropriately treated with a non-taxane regimen, in combination with KEYTRUDA®.

KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Cortes J, Cescon DW, Rugo HS. et al. J Clin Oncol 38: 2020 (suppl; abstr 1000)