Multicenter phase II study of neoadjuvant nivolumab or nivolumab plus relatlimab (anti-LAG3 antibody) plus chemoradiotherapy in stage II/III esophageal/gastroesophageal junction (E/GEJ) carcinoma.
Authors: Ronan Joseph Kelly, Ali Hussainy Zaidi, Jenna VanLiere Canzoniero, Josephine Louella Feliciano, Russell K. Hales, K. Ranh Voong, Richard James Battafarano, Blair Anderson Jobe, Stephen Yang, Stephen Broderick, Jinny Suk Ha, Kellie Nicole Smith, Elizabeth D. Thompson, Fyza Shaikh, Eun Ji Shin, Ali Imran Amjad, Patrizia Guerrieri, Chen Hu, Valsamo Anagnostou, Vincent K. Lam
Journal: Journal of Clinical Oncology (2022)

321 Background: The phase III CheckMate 577 study resulted in adjuvant nivolumab becoming a new standard of care for patients with completely resected E/GEJ cancer with residual pathologic disease post neoadjuvant chemoradiotherapy. We evaluated if neoadjuvant nivolumab (N) or nivolumab/relatlimab (N/R) combined with chemoradiotherapy (CRT) can further improve patient outcomes. Methods: Patients with stage II/III E/GEJ carcinoma eligible for curative resection were treated with standard of care regimen of carboplatin (AUC2), paclitaxel (50mg/m2), RT 41.1Gy in 23 fractions and an Ivor-Lewis esophagectomy (E/MIE) 6-10 weeks after last CRT/IO dose. Patients on arm A (n=16) received 2 cycles of induction N (240mg q2 wks) plus three additional cycles of N on week 1, 3 and 5 of CRT. After safety and feasibility evaluation of arm A, patients on arm B (n=16) received N (240mg q 2 wks) plus R (80mg q 2 wks) following the same schedule. The primary endpoints of the study were safety and feasibility. Secondary endpoints include pCR, MPR (&lt;10% residual cancer cells), DFS and OS. We also evaluated pathologic response and molecular ctDNA responses via longitudinal targeted error correction sequencing. Results: From August 2017 to July 2021, 32 patients were enrolled. Median age 65 (39 to 73), male 81%, adeno/SCC (87.5%, 12.5%). CRT combined with N on arm A was well tolerated with 4/16 (25%, 95% CI: 9.3-52.6%) reporting grade 3 AEs. Dual IO inhibition targeting PD1 and LAG3 combined with CRT on arm B demonstrated unacceptable toxicities as per predefined early stopping rule after 9 patients which resulted in a protocol amendment; 6/9 patients (66%) in arm B developed G3 or higher IO-related toxicities including pericarditis (2/9, 22%) and adrenal insufficiency (2/9, 22%). The amended arm B (n=7) involved induction N + R for 2 cycles prior to standard CRT and was well tolerated. In 31 evaluable patients to date, the pCR rate is 29.0% (95% CI: 14.9-48.2%), (arm A, pCR 6/16 (37.5%, 95% CI: 16.3-64.1%) and MPR 8/16 (50.0%, 95% CI: 28.0-72.0%) (arm B, pCR 3/15 (20.0%, 95% CI: 5.3-48.6% and MPR 8/15 (53.3%, 95% CI: 27.4-77.7%). With a median follow-up time of 30m, the median DFS is 35.4m (95% CI: 24.7-NA) and 1 year DFS rate of 79.1% (95% CI: 65.5-95.6%). For patients in Arm A (arm B data pending), ctDNA clearance was associated with pathologic response, while ctDNA persistence was linked with disease recurrence. Conclusions: The addition of N to preoperative CRT is safe and is associated with a higher MPR rate and pCR in Arm A compared to historical controls. In this study, neoadjuvant anti PD-1/LAG3 combination IO-IO strategies with CRT were challenging due to enhanced IR toxicities. In depth immune correlates and liquid biopsy analyses will be presented. Clinical trial information: NCT03044613.