Clinical factors associated with early progression and grade 3–4 toxicity in patients with advanced non-small-cell lung cancers treated with nivolumab

PLOS ONE, Nov 2019

Introduction The prognosis of advanced non-small-cell lung cancer (NSCLC) has been improved by development of immune checkpoint inhibitors (ICIs) such as nivolumab for second-line treatment. As phase III trials include only selected patients, we here investigated the clinical factors associated with efficacy and safety of nivolumab in ‘real life’ patients with advanced NSCLC. Methods Clinical and histological characteristics, therapies and survival data of all consecutive patients with advanced NSCLC included prospectively and treated by nivolumab in two French academic hospitals between February 2015 and December 2016 were examined. Results Sixty-seven patients were included, mostly male (69%), current or former smokers (87%) with PS <2 (73%). Median age was 68.5 years and 42% were aged ≥70 years. According to uni- and multi-variate analyses, only PS 2 (OR = 0.17, 95% CI 0.03–0.99, p = 0.049) and number of previous treatment lines (OR = 0.33, 95% CI 0.13–0.85, p = 0.022) were significantly negatively associated with tumor control. Worse progression-free survival (PFS) was significantly associated with PS 2 (HR = 5.17, 95% CI 1.99–13.43, p = 0.001) and use of steroids (HR = 3.27, 95% CI 1.39–7.69, p = 0.006). Worse overall survival was associated with symptomatic brain metastasis (HR = 3.15, 95% CI 1.23–8.85, p = 0.029). Treatment-related adverse events occurred in 47 patients (70%), symptomatic brain metastasis being significantly associated with Grade ≥3 toxicity (OR = 8.13, 95% CI 1.21–55.56, p = 0.031). Age and nutritional status were not associated with response, PFS, OS or toxicity. Conclusion Our results suggest that nivolumab is not beneficial or safe for patients with PS 2 and symptomatic brain metastases.

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Clinical factors associated with early progression and grade 3–4 toxicity in patients with advanced non-small-cell lung cancers treated with nivolumab

April Clinical factors associated with early progression and grade 3±4 toxicity in patients with advanced non-small-cell lung cancers treated with nivolumab Coraline Dumenil 0 1 Marie-Ange Massiani 1 Jennifer Dumoulin 0 1 Violaine Giraud 0 1 Sylvie Labrune 0 1 Thierry Chinet 0 1 Etienne Giroux Leprieur 0 1 0 Department of Respiratory Diseases and Thoracic Oncology, APHPÐAmbroise Pare Hospital , Boulogne- Billancourt , France , 2 Department of Medical Oncology, Ren e Huguenin Hospital, Curie Institute , Saint- Cloud, France, 3 EA4340 , University of Versailles Saint-Quentin-en-Yvelines, Paris-Saclay University , Boulogne-Billancourt , France 1 Editor: Ramon Andrade De Mello, Universidade do Algarve Departamento de Ciencias Biomedicas e Medicina , PORTUGAL The prognosis of advanced non-small-cell lung cancer (NSCLC) has been improved by development of immune checkpoint inhibitors (ICIs) such as nivolumab for second-line treatment. As phase III trials include only selected patients, we here investigated the clinical factors associated with efficacy and safety of nivolumab in `real life' patients with advanced NSCLC. - Data Availability Statement: All relevant data are within the paper and its Supporting Information file. Funding: The authors received no specific funding for this work. Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MAM: advisory board for Bristol-Myers-Squibb; EGL: research Methods Results Clinical and histological characteristics, therapies and survival data of all consecutive patients with advanced NSCLC included prospectively and treated by nivolumab in two French academic hospitals between February 2015 and December 2016 were examined. Sixty-seven patients were included, mostly male (69%), current or former smokers (87%) with PS <2 (73%). Median age was 68.5 years and 42% were aged 70 years. According to uni- and multi-variate analyses, only PS 2 (OR = 0.17, 95% CI 0.03±0.99, p = 0.049) and number of previous treatment lines (OR = 0.33, 95% CI 0.13±0.85, p = 0.022) were significantly negatively associated with tumor control. Worse progression-free survival (PFS) was significantly associated with PS 2 (HR = 5.17, 95% CI 1.99±13.43, p = 0.001) and use of steroids (HR = 3.27, 95% CI 1.39±7.69, p = 0.006). Worse overall survival was associated with symptomatic brain metastasis (HR = 3.15, 95% CI 1.23±8.85, p = 0.029). Treatment-related adverse events occurred in 47 patients (70%), symptomatic brain metastasis being significantly associated with Grade 3 toxicity (OR = 8.13, 95% CI 1.21±55.56, p = 0.031). Age and nutritional status were not associated with response, PFS, OS or toxicity. grants from Bristol-Myers-Squibb. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors did not have competing interests. Conclusion Our results suggest that nivolumab is not beneficial or safe for patients with PS 2 and symptomatic brain metastases. Introduction Non-small cell lung cancer (NSCLC) is the leading cause of cancer related±death worldwide [1]. The treatment of NSCLC has recently been improved by development of immune checkpoint inhibitors (ICIs), which target inhibitor pathways such as programmed death 1 (PD1)/ programmed death-ligands 1 (PDL1), thus blocking the immune responses of tumor-infiltrating lymphocytes, allowing proliferation of tumor cells [2]. Nivolumab, a fully human IgG4 PD-1 ICI antibody, was the first agent to show efficacy in second-line treatment of patients with NSCLC in two recent phase III trials and had a favorable safety profile compared with docetaxel [3, 4]. A new era of immunotherapy has begun with encouraging results from randomized phase II and III trials, putting into question and extending the potential indications for ICIs for NSCLC [5]. However, patients included in these trials all had performance status (PS) 0±1, did not have active or untreated brain metastases, and were relatively young (only 7% and 11% of 75 years-old patients in Checkmate-057 and Checkmate-017 trials, respectively). Thus, benefit and safety of ICIs for all patients with advanced NSCLC in `real life' is still unanswered. Seventeen percent of patients with Stage IV NSCLC have central nervous system (CNS) metastases at initiation of first-line treatment [6] and around one third of patients with NSCLC have a PS of 2 [7]. The objectives of this study were to determine the clinical factors associated with the efficacy and safety of nivolumab in `real-life' patients with advanced NSCLC, including elderly patients and those with poor PS, brain metastases, or poor nutritional status at the time of nivolumab. Materials and methods Patients Records of all consecutive patients with advanced NSCLC treated by nivolumab (3 mg/ kg every two weeks) between February 2015 and December 2016 were retrieved from a database of prospectively collected information on all p (...truncated)


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Coraline Dumenil, Marie-Ange Massiani, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Etienne Giroux Leprieur. Clinical factors associated with early progression and grade 3–4 toxicity in patients with advanced non-small-cell lung cancers treated with nivolumab, PLOS ONE, 2018, Volume 13, Issue 4, DOI: 10.1371/journal.pone.0195945