Nivolumab plus Ipilimumab in Non–Small-Cell Lung Cancer

Abstract

Nivolumab and ipilimumab, two therapeutic immune checkpoint inhibitor antibodies that block PD-1 and CTLA-4, respectively, have indications in cancer as single agents and in combination. In this Review, we examine the potential role of dual immune checkpoint inhibition with nivolumab plus ipilimumab in the management of patients with previously untreated advanced non-small-cell lung cancer, based on results from the Phase III CheckMate 227 study. Immunotherapies with indications in the first-line treatment of non-small-cell lung cancer include pembrolizumab alone and combined with chemotherapy, and atezolizumab combined with bevacizumab and chemotherapy. CheckMate 227 is the first Phase III study evaluating first-line chemotherapy-sparing combination immunotherapy and including tumor mutational burden as a biomarker for patient selection.Lung cancer is the most commonly diagnosed cancer and the leading cause of death from cancer worldwide, accounting for an estimated 18.4% of all cancer-related deaths in 2018 [1]. In the USA, lung cancer has the second highest age-adjusted incidence among primary cancer types (after breast cancer) and is associated with by far the highest cancer-related mortality [2]. Global, age-standardized incidence rates for lung cancer are lower among women than men across all regions; however, high rates among women are seen in North America, Northern and Western Europe, and Australia/New Zealand [1]. Of an estimated 222,500 new cases of lung cancer in the USA in 2017, almost half (47%) were diagnosed in women [3]. Non-small-cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases in the USA [4]. Although smoking is the most common cause of NSCLC, approximately 10-15% of patients with NSCLC have never smoked [5].Until a few years ago, the treatment for patients with advanced NSCLC with no known targetable driver mutations was essentially limited to systemic cytotoxic therapy, with platinum doublet chemotherapy as the standard first-line treatment. In randomized controlled trials, platinum-based therapies were associated with a median overall survival (OS) of 10-13 months and 2-year survival rates of 17-24% from the time of treatment initiation [6][7][8][9][10][11]. Patients who experienced disease progression during first-line therapy had few remaining treatment options, including docetaxel, erlotinib, gefitinib or pemetrexed for nonsquamous NSCLC and docetaxel, erlotinib or gefitinib for squamous NSCLC. The recent introduction of immune checkpoint inhibitors [12] has greatly improved outcomes in many cancers, including NSCLC. Therapeutic antibodies that disrupt the interaction between PD-1 and PD-L1, in other words, PD-1 and PD-L1 inhibitors, are now the preferred second-line treatment option after first-line chemotherapy [13,14]. Furthermore, the PD-1 inhibitor pembrolizumab has been approved as monotherapy for the first-line treatment of patients with advanced NSCLC and high PD-L1 expression (tumor proportional score ≥50%) [15,16]. To provide effective first-line treatment optio...

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Phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: adrenocortical carcinoma cohort

“…Across S1609 DART, the combination of low-dose ipilimumab and nivolumab was chosen to maximize the likelihood of immunotherapeutic response relative to monotherapy, and the dose of ipilimumab of 1 mg/kg intravenously every 6 weeks was chosen on the balance of toxicity and efficacy, and based on the results of CheckMate 227. 15 …”