Abstract 2052: Tumor mutation burden as a biomarker of relapse free survival of non-squamous non-small cell lung cancer treated with PEM/CDDP in adjuvant setting (the JIPANG-TR)
Authors: Tsuboi Masahiro , Nishio Kazuto , Sakai Kazuko , Kenmotsu Hirotsugu , Yamanaka Takeharu , Takahashi Toshiaki , Goto Koichi , Daga Haruko , Ikeda Norihiko , Seto Takashi , Toyooka Shinichi , Date Hiroshi , Mitsudomi Tetsuya , Okamoto Isamu , Saka Hideo , Okamoto Hiroaki , Takiguchi Yuichi , Yamamoto Nobuyuki 
Published: September 2020

Background: The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine /cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small-cell lung cancer (Ns-NSCLC)(UMIN000006737, jRCTs041180023). This phase III study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. Patients without EGFR mutation detected by IVD kits showed favorable outcome (longer RPF) by Pem/Cis compared with Vnr/Cis. Tumor mutation burden (TMB) is thought to be associated with the amount of tumor neoantigen and to have a predictive value of immune checkpoint inhibitors. However, the relationship between EGFR and other mutation status, and TMB in NSCLC remains unclear and the relevance of TMB to cytotoxic chemotherapy is not yet fully understood.

Purpose: The aim of this exploratory study was to investigate relationship between tumor mutation profiles, including TMB and clinical outcome (RFS), of Pem/Cis vs Vnr/Cis for completely resected stage II-IIIA Ns-NSCLC in the JIPANG study (UMIN000006737, jRCTs041180023).

Materials and Methods: FFPE tumor tissues (n=385) were obtained from the patients in the JIPANG study. Mutation status of tissue DNA was analyzed by targeted deep sequencing (Comprehensive cancer panel, CCP). TMB was evaluated by mutations per megabase (mut/Mb).

Results: Assay success rate of CCP was 99.2% (374/385). EGFR (37.2%, 139/374) mutations were detected frequently in Ns-NSCLC. Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm (median; not reached) compared with Vnr/Cis arm (52.6 mo) as reported previously. Median value of TMB of all tumor samples was 9.4 (2.5-83.8). Tumors with EGFR mutations had lower TMB values than EGFR wild type (TMB median; 8.5 vs 11.0, p&lt;0.0001). Pem/Cis in patients with high TMB (≥12, 14, or 16 mut/Mb) tended to improve survival (HR for RPF; 0.650, 0.554, and 0.541, respectively, by Cox proportional hazard model). In patients with wild type EGFR, TMB≥12 mut/Mb was associated with improved RPF with Pem/Cis vs Vnr/Cis (HR; 0.477 0.237-0.958, p=0.038) with RFS periods of not reached vs 52.5 months (p=0.033).

Conclusions: TMB value was lower in Ns-NSCLC tissues harboring EGFR mutation. TMB was predictive of RPF benefit with Pem/Cis vs Vnr/Cis in Ns-NSCLC. Based on this exploratory analysis, further investigation of TMB combined with EGFR mutation status as a predictive biomarker for chemotherapy as well as immune checkpoint inhibitors is warranted.

Citation Format: Masahiro Tsuboi, Kazuto Nishio, Kazuko Sakai, Hirotsugu Kenmotsu, Takeharu Yamanaka, Toshiaki Takahashi, Koichi Goto, Haruko Daga, Norihiko Ikeda, Takashi Seto, Shinichi Toyooka, Hiroshi Date, Tetsuya Mitsudomi, Isamu Okamoto, Hideo Saka, Hiroaki Okamoto, Yuichi Takiguchi, Nobuyuki Yamamoto. Tumor mutation burden as a biomarker of relapse free survival of non-squamous non-small cell lung cancer treated with PEM/CDDP in adjuvant setting (the JIPANG-TR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2052.