A Treatment-Related Deaths Predictive Score for Treatment-Naïve Advanced Non-Small Cell Lung Cancer

Abstract

Background: Combined chemotherapy with nivolumab and ipilimumab (NIC) improves survival outcomes in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC). However, these patients have a higher incidence of treatment-related deaths (TRDs) especially due to NIC. The aim of this study is to devise a risk stratification score for selecting patients with lower or higher TRD-risk. Methods: A dataset from the JCOG2007 study is used, which compared NIC with combined chemotherapy with pembrolizumab (PC). TRD score was built from an adaptive LASSO regression analysis. Results: JCOG2007 study randomly assigned 295 patients to the PC (n=147) and NIC (n=148) arms, respectively. The TRD score was constructed for 124 patients who underwent NIC and had no missing covariates. The dichotomized TRD score was built and stratified all treated 290 (all enrolled 295) patients into 92 high-risk and 198 (203) low-risk patients. No apparent differences in TRD incidence were observed in low-risk patients (2.2% [0/92] with PC and 2.8% [3/106] with NIC); however, this difference was noteworthy in high-risk patients (1.9% [1/52] with PC and 20.0% [8/40] with NIC). Of the 295 patients, the hazard ratios for death were 0.894 (0.553-1.444) in low-risk patients, and that was 1.215 [0.696‐2.122] in high-risk patients. Worse outcomes in the NIC arm were consistently observed for both irAEs and progression-free survival. Conclusions: Although further validation studies with external data inside and outside Japan are required, the TRD score is a valuable tool for identifying patients with comparable toxicity-efficacy profiles among PC and NIC regimens.

Note:
Funding declaration: This study was supported by the National Cancer Center Research and Development Fund (grant numbers 2020-J-3 and 2023-J-03) and the Japan Agency for Medical Research and Development (grant number JP23ck0106669)

Conflict of Interests: Dr. Nomura reported receipt of personal fees and honoraria for lectures (AstraZeneca,Chugai Pharmaceutical, Kyowa Hakko, Byer, Asahi-Kasei Pharma, MSD, Takeda, and Eli Lilly); grants and research funding to institution (AstraZeneca, MSD, Chugai); and consultancy (Asahi-Kasei Pharma, Daiichi Sankyo). Dr. Shiraishi reported receipt of personal fees and honoraria for lectures (Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, and Kyowa Kirin); and grants to institution (Chugai Pharmaceutical). Dr. Toi reported receipt of personal fees and honoraria for lectures (Bristol-Myers Squibb, Ono Pharmaceutical, MSD K.K. AstraZeneca, Chugai Pharmaceutical, and Taiho Pharmaceutical). Dr. Yoshida reported receipt of personal fees and honoraria for lectures (Novartis, Daiichi-Sankyo, AstraZeneca, MSD, Chugai Pharmaceutical, BMS, Ono Pharmaceutical, Takeda, Pfizer, Lilly, and Merck Biopharma); grants and research funding to institution (Novartis, AbbVie, Amgen, Daiichi-Sankyo, AstraZeneca, MSD, Chugai Pharmaceutical, Astellas, Boehringer Ingelheim, BMS, Ono Pharmaceutical, and Merck Biopharma); and participation on advisory boards (Novartis, MSD, Amgen, Chugai Pharmaceutical, Daiichi-Sankyo, Pfizer, and Boehringer Ingelheim). Dr. Tanaka reported receipt of personal fees and honoraria for lectures (Ono Pharmaceutical, Bristol-Myers Squibb). Dr. Suzuki reported receipt of grants to institution (Nippon Boehringer Ingelheim).

Ethical Approval: The JCOG2007 study was performed in accordance with the Declaration of Helsinki and the Clinical Trials Act of Japan. The study protocol was approved by the Japan Clinical Oncology Group (JCOG) Protocol Review Committee in January, 2021, and by the National Cancer Center Hospital East Certified Review Board in March, 2021, before the start of patient accrual. Written informed consent was obtained from each patient before enrollment.

Keywords: Treatment related deaths, immunotherapy, immune-checkpoint inhibitors, immune-related adverse events