br Keywords Immuno related adverse
Keywords: Immuno-related adverse events, Non-small cell lung cancer, Response, Survival
Lung cancer, including 85% of nonesmall-cell lung cancer (NSCLC),1 remains the most common cause of cancer-related death.2
1Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France 2Aix Marseille University, Inserm U911 CRO2, Marseille, France 3Oncology Department, Centre Hospitalier Departemental de Castellccio, Ajaccio, France 4Chronic Diseases and Quality of Life eResearch Unit, Aix Marseille University, EA 3279 - Public Health, Marseille, France
New treatment options, such as immune checkpoint inhibitors (ICIs), are approved for the treatment of naive and relapsing advanced NSCLC. ICIs target and inhibit programmed cell death protein 1 on T GS-5734 (anti-PD-1) or its ligand (PD-L1) on tumor
Address for correspondence: Dr Pascale Tomasini, Service d’Oncologie Multi- disciplinaire et Innovations Therapeutiques, Hopital Nord, Chemin des Bourrely, 13915 Marseille, France E-mail contact: [email protected]
IRAEs and Immunotherapy Efficacy in NSCLC
cells (anti-PD-L1) or on tumor microenvironment cells to enhance anti-tumor immunity.3
Until recently, ICIs have been primarily used for the second-line treatment of advanced NSCLC. To date, 3 drugs have been approved by the United States Food and Drug Administration based on 4 phase III clinical trials demonstrating the superiority of ICIs over standard docetaxel.4-6 ICIs are now also registered in the first-line setting alone or in combination with chemotherapy as a result of the Keynote024 (phase III trial of pembrolizumab (MK-3475) vs platinum-based chemotherapy as first-line therapy for patients with metastatic non-small cell lung cancer (NSCLC) that expresses programmed cell death ligand 1) and 021G (Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study) trials.5,7
Releasing the brakes of the host-immune system, ICIs may alter the physiologic homeostasis of immune response, thus leading to the development of immune-related adverse events (IRAEs). A meta-analysis of the phase III Checkmate 017 (Nivolumab versus docetaxel in advanced squamous-cell nonesmall-cell lung cancer), Checkmate 057 (Nivolumab versus docetaxel in advanced non-squamous nonesmall-cell lung cancer), and Keynote 010 (Pem-brolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a rando-mised controlled trial) studies was performed to assess the type and frequency of these IRAEs.8 Adverse events of any grades based on the National Cancer Institute Common Terminology Criteria for Adverse Events occurred in 69% of patients, and adverse events grade 3 or higher occurred in 7% to 13% of patients.9-11 The most frequent IRAEs exhibit endocrinopathy (hypothyroidism 4%-8%, hyperthyroidism 0%-5%), skin rashes (5%-11%), and hepatitis (2%-11%). The most severe were pneumonitis (3%-5%), colitis (1%-2%), hypophysitis (2%), and adrenal failure (0%-1%).
The development of new targeted therapies sometimes leads to new adverse events.12,13 In a totally different context, these adverse events have been assessed as markers of treatment outcomes. This is the case for skin rash and tyrosine kinase inhibitors efficacy,14 and we tried to find an analogy with ICIs and IRAEs.
A first trial published in November 2016 suggested a correlation between IRAEs and efficacy of ICIs in melanomas.15 To date, there is mainly 1 retrospective study with 134 patients16 and 2 prospective studies with 3817 and 43 patients,18 all treated with nivolumab only, suggesting an association between the occurrence of IRAEs and the efficacy of ICIs in NSCLC.
The primary endpoint of this study was to assess the association between IRAEs and overall survival (OS) of patients with advanced NSCLC. Our secondary endpoints were to assess the association between IRAEs (type and severity) and progression-free survival (PFS), as well as the objective response rate (ORR) and disease control rate (DCR).
Materials and Methods
In this observational retrospective study, data from all patients older than 18 years of age who were diagnosed with metastatic NSCLC at 2 centers and who received at least 1 cycle of ICI (anti-PD-L1 or anti-PD-1) alone or in combination from April 2, 2013
Table 1 Baseline Characteristics
Median age, y (min-max)
Smoker/former smoker 239