Tag: Lung Cancer: Non-Small Cell

FDA Approves LUMAKRAS® for KRAS G12C-Mutated Non Small Cell Lung Cancer

RR

SUMMARY: The FDA on May 28, 2021, granted accelerated approval to LUMAKRAS® (Sotorasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C mutated locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy. The FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for LUMAKRAS®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

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.

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. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on, by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have 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 Non Small Cell Lung Cancers (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. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.Inhibiting-KRAS-G12C

LUMAKRAS® is a first-in-class small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that LUMAKRAS® inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors.

The CodeBreaK clinical development program for LUMAKRAS® was designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. This program has enrolled more than 800 patients across 13 tumor types since its inception.

CodeBreaK 100 is a Phase I and II, first-in-human, open-label, single arm, multicenter study, which enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, for their tumor type and stage of disease. The present FDA approval was based on a Phase II trial which enrolled 126 patients with NSCLC, 124 of whom had centrally evaluable lesions by RECIST criteria at baseline. Enrolled patients had locally advanced or metastatic NSCLC with a KRAS G12C mutation, who had progressed on an immune checkpoint inhibitor and/or platinum-based chemotherapy, and those with active brain metastases were excluded. Patient received LUMAKRAS® 960mg orally once daily, until disease progression or unacceptable toxicity. Imaging studies were done every 6 weeks up to week 48 and then once every 12 weeks thereafter. The Primary end point of the trial was Overall Response Rate (ORR) as assessed by blinded Independent Central Review. Secondary end points included Duration of Response (DOR), Disease Control Rate (DCR), time to recovery, Progression Free Survival (PFS), Overall Survival, and Safety. The examination of biomarkers served as an exploratory end point. Patients were followed for a median of 12.2 months.

The ORR was 37.1% and the median Duration of Response was 10 months. Three patients had a Complete Response and the Disease Control Rate was 80.6%. The median Time to response was 1.4 months and 72% of patients had an early rapid response on first CT scan at 6 weeks. Approximately 81% of patients had tumor shrinkage of any magnitude, and the median percentage of best tumor shrinkage among all responders was 60%, and these responses were durable. The median PFS was 6.8 months. In the exploratory biomarker analysis, tumor response to LUMAKRAS® was seen across subgroups, including patients with negative or low expression of PD-L1 and those with STK11 and TP53 mutations. The most common adverse reactions were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities were increase in liver function tests, anemia, hyponatremia and proteinuria.

It was concluded that patients with NSCLC have poor outcomes and limited treatment options following progression on first line treatment. LUMAKRAS® offers a new treatment option for this patient group, and it is the first KRAS-targeted therapy to be approved after nearly four decades of research. A global Phase III study (CodeBreaK 200) is underway, comparing LUMAKRAS® to Docetaxel in patients with KRAS G12C-mutated NSCLC.

CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Li BT, Skoulidis F, Falchook G, et al. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

FDA Approves Bispecific Antibody RYBREVANT® for Metastatic Non Small Cell Lung Cancer

RR

SUMMARY: The FDA on May 21, 2021, granted accelerated approval to RYBREVANT® (Amivantamab-vmjw), a bispecific antibody directed against Epidermal Growth Factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy. FDA also approved the Guardant360® CDx (Guardant Health, Inc.) as a companion diagnostic for RYBREVANT®.

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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions, and occur in about 2-3% patients with NSCLC and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5 year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available and platinum-doublet chemotherapy remains the standard of care for these patients.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors.

RYBREVANT® is a fully-human bispecific antibody directed against EGFR and MET receptors. RYBREVANT® binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, RYBREVANT® downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, RYBREVANT® can bypass primary and secondary TKI resistance at the active site.

The present FDA approval was based on CHRYSALIS, an ongoing multicenter, non-randomized, open label, multicohort, Phase I clinical trial (NCT02609776) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of RYBREVANT® as a monotherapy and in combination with Lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (RYBREVANT® in combination with standard of care Carboplatin and Pemetrexed) in 21 day treatment cycle for participants with advanced NSCLC.

In this analysis of the Phase 1 CHRYSALIS study, researchers assessed the efficacy and safety of RYBREVANT® in patients with NSCLC and EGFR exon 20 insertion mutations, who had progressed on prior Platinum-based chemotherapy, and were treated at the recommended Phase II dose of RYBREVANT® 1050 mg (1400 mg for patients weighting 80 kg or more). The median patient age was 61 years, 51% were female, and median prior lines of therapy was one. The Primary endpoint was Overall Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Clinical Benefit Rate, Progression Free Survival (PFS) and Overall Survival (OS).

It was noted that among this post-platinum cohort of patients (N=81), at a median follow up of 9.7 months, the ORR was 40%, with 4% Complete Reponses and 36% achieving Partial Responses (PR). Responses were durable with median Duration of Response of 11.1 months, with 63 % having responses of at least six months or greater duration. The median PFS was 8.3 months and median OS was 22.8 months. The Clinical Benefit Rate (PR or more, or Stable Disease of 11 weeks or more) was 74%. The most common adverse reactions (20% or more) were rash, infusion-related reactions, paronychia, fatigue, musculoskeletal pain, stomatitis, nausea, vomiting, constipation, edema, cough and dyspnea.

The authors concluded that RYBREVANT® demonstrated robust and durable antitumor activity in patients with EGFR exon 20 insertion mutations, with a manageable safety profile.

Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer. Sabari JK, Shu CA, Park K, et al. Presented at: IASLC 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. Abstract OA04.04

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.

Therapy for Stage IV Non–Small-Cell Lung Cancer with Driver Alterations: ASCO and OH (CCO) Joint Guideline Update

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. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8%, as well as other mutations in BRAF, MET, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.

The ASCO and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated the 2017 ASCO guideline on systemic therapy for patients with Stage IV NSCLC with driver alterations and provided evidence-based recommendations, based on a systematic review of Randomized Controlled Trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020.

This clinical practice guideline addresses three comprehensive clinical questions for patients with Stage IV NSCLC with driver alterations
1) What is the most effective first-line therapy?
2) What is the most effective second-line therapy?
3) Is there a role for a third-line therapy or beyond?

The guideline addresses patients with NSCLC in the following histologic or subgroups: EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK. This update does not apply to patients with Stage IV NSCLC without known driver alterations and those with rarer histologies such as large cell, neuroendocrine, etc.

Summary of Key Recommendations

Recommendation 1.1: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with T790M, L858R, or exon 19 deletion mutations, Osimertinib should be offered.

Recommendations 1.2, 1.3, 1.4, and 1.5: For patients with Stage IV NSCLC and driver alterations in EGFR-if Osimertinib is not available
֍In the first-line setting, if Osimertinib is not available, Gefitinib with chemotherapy may be offered or Dacomitinib may be offered.
֍Other options that may be offered include Afatinib or Erlotinib/Bevacizumab or Erlotinib/Ramucirumab or Gefitinib, Erlotinib, or Icotinib.

Recommendation 1.6: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with a Performance Status (PS) of 3, an EGFR Tyrosine Kinase Inhibitor (TKI) may be offered.

Recommendation 1.7: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with EGFR mutations other than exon 20 insertion mutations, T790M, L858R, or exon 19 deletion alterations, Afatinib may be offered or Osimertinib may be offered or treatments outlined in the ASCO/OH nondriver mutation guideline may be offered.

Recommendation 1.8: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with any activating EGFR mutation (including exon 20 insertion mutations), regardless of Programmed Death Ligand-1 (PD-L1) expression levels, single-agent immunotherapy should not be used.

Recommendation 1.9: For patients with Stage IV NSCLC and driver alterations in EGFR causing resistance to first- and second-generation EGFR TKIs
֍In the first-line setting, for patients with EGFR exon 20 insertion mutation causing resistance to first- and second-generation EGFR TKIs, doublet chemotherapy with or without Bevacizumab or standard treatment outlined in the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 2.1 and 2.2: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the second-line setting, for patients who did not receive Osimertinib and have a T790M mutation at the time of progressive disease, Osimertinib should be offered.
֍In the second-line setting, for patients with any EGFR mutation who have progressed on EGFR TKIs with no T790M mutation OR whose disease has progressed on Osimertinib, treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendation 3.1: For patients with Stage IV NSCLC and driver alterations in ALK
֍In the first-line setting, Alectinib or Brigatinib should be offered.
֍In the first-line setting, if Alectinib and Brigatinib are not available, Ceritinib or Crizotinib should be offered.

Recommendations 4.1, 4.2, and 4.3: For patients with stage IV NSCLC and driver alterations in ALK
֍In the second-line setting, if Alectinib or Brigatinib was given in the first-line setting, Lorlatinib may be offered.
֍In the second-line setting, if Crizotinib was given in the first-line setting, then Alectinib, Brigatinib, or Ceritinib should be offered.
֍In the third-line setting, if Crizotinib was given in the first-line setting and Alectinib, Brigatinib, or Ceritinib in the second-line setting, then Lorlatinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 5.1, 5.2, and 5.3: For patients with Stage IV NSCLC and driver alterations in ROS1
֍In the first-line setting, Crizotinib or Entrectinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered or Ceritinib or Lorlatinib may be offered.

Recommendations 6.1 and 6.2: For patients with Stage IV NSCLC and driver alterations in ROS1
֍In the second-line setting, if ROS1-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.
֍In the second-line setting, if nontargeted therapy was given in the first-line setting, Crizotinib, Ceritinib, or Entrectinib may be offered.

Recommendations 7.1 and 7.2: For patients with Stage IV NSCLC and driver alterations with BRAF V600E mutation
֍In the first-line setting, Dabrafenib/Trametinib may be offered or standard first-line treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 8.1, 8.2 and 8.3: For patients with Stage IV NSCLC and driver alterations with BRAF V600E mutation
֍In the second-line setting, if previous BRAF/MEK-targeted therapy (Dabrafenib/Trametinib) was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.
֍In the second-line setting, if BRAF-targeted therapy was not given in the first-line setting, Dabrafenib/Trametinib may be offered or Dabrafenib or Vemurafenib alone may be offered.
֍If previous chemotherapy, immunotherapy, and/or BRAF-targeted therapy were given in the first- or subsequent-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.

Recommendation 8.4: For patients with Stage IV NSCLC and driver alterations with BRAF mutations other than V600E
֍In the second-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.

Recommendations 9.1 and 9.2: For patients with Stage IV NSCLC and MET exon 14 skipping mutation
֍In the first-line setting, for patients with an MET exon 14 skipping mutation, MET-targeted therapy with Capmatinib or Tepotinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 10.1 and 10.2: For patients with Stage IV NSCLC and MET exon 14 skipping mutation
֍In the second-line setting, for MET abnormalities other than exon 14 skipping mutations or if MET-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.
֍In the second-line setting, patients with an MET exon 14 skipping mutation who previously received or were ineligible for first-line chemotherapy with or without immunotherapy (ie. if MET-targeted therapy was not given in the first-line setting), Capmatinib or Tepotinib may be offered.

Recommendations 11.1, 11.2, and 11.3: For patients with Stage IV NSCLC and driver alterations in RET
֍In the first-line setting, Selpercatinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered or Pralsetinib may be offered.

Recommendations 12.1, 12.2, and 12.3: For patients with Stage IV NSCLC and driver alterations in RET
֍In the second-line setting, if RET-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.
֍In the second-line setting, if RET-targeted therapy was not given in the first-line setting, Selpercatinib may be offered or Pralsetinib may be offered.

Recommendations 13.1 and 13.2: For patients with Stage IV NSCLC and driver alterations in NTRK
֍In the first-line setting, Entrectinib or Larotrectinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 14.1 and 14.2: For patients with Stage IV NSCLC and driver alterations in NTRK
֍In the second-line setting, if NTRK-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.
֍In the second-line setting, if NTRK-targeted therapy was not given in the first-line setting, Entrectinib or Larotrectinib may be offered.

Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Hanna NH, Robinson AG, Temin S, et al. J Clin Oncol. 2021;39: 1040-1091

FDA Approves LORBRENA® for Advanced ALK-Positive Lung Cancer

RR

SUMMARY: The FDA on March 3, 2021, granted regular approval to LORBRENA® (Lorlatinib) for patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose tumors are Anaplastic Lymphoma Kinase (ALK)-positive, as detected by an FDA-approved test. The FDA also approved the Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Inc.) as a companion diagnostic for LORBRENA®. Lung cancer is the leading cause of cancer death in both men and women, and accounts for about 14% of all new cancers and 25% of all cancer deaths. 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.

The discovery of chromosomal rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, and their sensitivity to ALK inhibitors, paved the way to the development of small-molecule ALK Tyrosine Kinase Inhibitors. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8%, as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.

ALK inhibitors include first-generation XALKORI® (Crizotinib) and second-generation ALK inhibitors such as ZYKADIA® (Ceritinib), ALECENSA® (Alectinib) and ALUNBRIG® (Brigatinib). Despite the improved efficacy of second-generation ALK inhibitors, recurrent disease due to drug resistance including CNS disease progression, can still develop.

LORBRENA® is a novel third-generation ALK inhibitor that is more potent than second-generation inhibitors, and has the broadest coverage of ALK resistance mutations that have been identified. LORBRENA® crosses the blood-brain barrier and has marked intracranial activity in previously treated patients with baseline CNS disease, including leptomeningeal disease. LORBRENA® received accelerated approval by the FDA in November 2018 for the second or third-line treatment of ALK-positive metastatic NSCLC. However, the efficacy of LORBRENA®, as compared with that of XALKORI®, as first line treatment for advanced ALK-positive NSCLC, has been unclear.

The CROWN trial is a global, open label, randomized, Phase 3 study, in which LORBRENA® was compared with XALKORI®, in patients with previously untreated ALK-positive advanced NSCLC. In this study, 296 treatment naïve advanced NSCLC patients were randomly assigned 1:1 to receive LORBRENA® 100 mg orally once daily (N=149) or XALKORI® 250 mg orally twice daily (N=147) in cycles of 28 days. Treatment was continued until disease progression or unacceptable toxic effects. Eligible patients were required to have ALK-positive tumors detected by the Ventana ALK (D5F3) CDx assay. Patients with asymptomatic treated or untreated CNS metastases were eligible and had to have at least one extracranial measurable target lesion that had not been previously irradiated. Patients were stratified according to the presence of brain metastases and ethnic group (Asian or non-Asian) and crossover between the treatment groups was not permitted. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included independently assessed Objective Response Rate (ORR) and intracranial response.

At a planned interim analysis, treatment with LORBRENA® resulted in statistically significant and clinically meaningful improvement in PFS as assessed by BICR, with a Hazard Ratio of 0.28 (P<0.001), corresponding to a 72% reduction in the risk of disease progression or death. The median PFS was not estimable in the LORBRENA® arm and was 9.3 months for those treated with XALKORI®. The percentage of patients who were alive without disease progression at 12 months was 78% in the LORBRENA® group and 39% in the XALKORI® group, and the Hazard Ratio favored LORBRENA&reg over XALKORI® across all prespecified patient subgroups. The Overall Survival data were immature at the PFS analysis.

The confirmed ORR was 76% with LORBRENA® and 58% with XALKORI®. About 70% of the patients who received LORBRENA® and 27% of those who received XALKORI® had a response that lasted at least 12 months. Additionally, treatment with LORBRENA® was associated with increased intracranial activity compared with XALKORI®. Among patients presenting with measurable brain metastases, the intracranial ORR was 82% with LORBRENA® and 23% with XALKORI®, with a intracranial Complete Response rate of 71% and 8%, respectively. The duration of intracranial response was 12 months or more in 79% and 0% of patients in the LORBRENA® and XALKORI® groups, respectively. The most common adverse events with LORBRENA® were hyperlipidemia, edema, weight gain, peripheral neuropathy, and cognitive effects.

It was concluded that treatment LORBRENA® resulted in a significantly longer Progression Free Survival and a higher frequency of intracranial response, compared to XALKORI®, among patients with previously untreated advanced ALK-positive NSCLC.

First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. Shaw AT, Bauer TM, de Marinis F, et al. N Engl J Med 2020; 383:2018-2029.

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.