Radiation therapy (RT)-free pembrolizumab plus chemotherapy (P+C) for PD-L1 TPS ≥50% locally advanced non-small cell lung cancer (LA-NSCLC): An early report analyzing depth of response from multicenter single arm phase II study (Evolution trial: WJOG11819L).
Authors: Hata Akito , Ninomaru Taira , Okada Hideaki , Kogure Yoshihito , Oki Masahide , Katakami Nobuyuki , Kijima Takashi , Yokoyama Toshihide , Matsumoto Hirotaka , Sato Yuki , Kato Terufumi , Sugawara Shunichi , Sawada Takeshi , Yoshimura Kenichi , Seto Takashi , Yamamoto Nobuyuki , Nakagawa Kazuhiko 
Published: June 2023

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Background: Standard of care for unresectable LA-NSCLC is chemoradiation therapy (CRT) followed by durvalumab (D). Survival curves of P monotherapy/P+C for PD-L1 TPS ≥50% stage IV NSCLC suggested possible comparable survival to CRT for stage III patients (pts). Moreover, some studies of neoadjuvant C+immunotherapy (I) for stage III pts have demonstrated high pCR and MPR rates, implying potentially outstanding efficacy of C+I for earlier stage. We thus hypothesized P+C without RT in PD-L1 ≥50% LA-NSCLC pts provides a comparable efficacy to CRT followed by D while avoiding CRT-induced severe toxicities. Methods: This early report focuses on depth of response in a phase II study by WJOG. P with platinum plus pemetrexed (PEM) (non-squamous) or P with carboplatin plus nab-paclitaxel (squamous) was administered every 3 weeks without RT. After four cycles of induction P+C, P with PEM (non-squamous) or P alone (squamous) was continued until progression or 2 years. The primary endpoint was PFS rate at 2 years. Results: Between May 2020 and February 2022, 21 pts were enrolled. Median age was 74 (range, 53-89). Stage IIIA/B/C included 12 (57%)/6 (29%)/3 (14%), respectively. Histologic subtypes were 13 (62%) adeno, 5 (24%) squamous, and 3 (14%) others. Investigator-assessed best response: 8 (38%) CR; 10 (48%) PR; 2 (10%) SD; and 1 (5%) NE were confirmed, resulting in response rate (RR) of 86% and disease control rate of 95%. RR of TPS 50-79% and 80-100% were 78% and 92%, respectively. Deep response (DR): defined as tumor shrinkage ≥80% was obtained in 12 (57%) of 21 pts. DR was accomplished in 4 (44%) of 9 TPS 50-79% and 8 (67%) of 12 TPS 80-100%. Median time to response was 43 (range, 41-92) days. Early tumor shrinkage (ETS): PR-in at the time of first CT evaluation (6 weeks) was achieved in 16 (89%) of 18 CR+PR pts. At the time of data cut-off, median follow-up period was 18.5 (range, 0.3-29.0) months, and 14 (67%) of 21 pts were progression-free. All 12 pts achieving DR, including all 8 CR were progression-free, also in 14 (88%) of 16 ETS pts. Three pts after local progression received salvage definitive-CRT. Median number of P administrations was 20 (range, 1-35). AEs ≥grade 3 were observed in 11 (52%) pts, including: 2 (10%) pneumonitis; 2 (10%) pneumonia; 1 (5%) diarrhea; 1 (5%) ALT elevation; and 1 (5%) acute heart failure, excluding hematological AEs. There was one (5%) possible grade 5 AE (pneumonia). Conclusions: RT-free P+C exerted a notably high RR, including some CRs. The deeper/earlier response and higher PD-L1 TPS could be associated with the higher progression-free incidence at the data cut-off. To investigate our hypothesis: RT-free P+C can be a less toxic curative option in selected LA-NSCLC pts with PD-L1 TPS ≥50%, further matured data is warranted. Clinical trial information: NCT04153734 .