Chemotherapy (CT) for advanced ESCC offers poor long-term survival. We report the final analysis from the phase III ATTRACTION-3 study of the programmed death (PD)-1 inhibitor nivolumab (NIVO) versus CT in patients (pts) with unresectable advanced or recurrent ESCC refractory or intolerant to 1 prior fluoropyrimidine/platinum-based CT.
Pts were enrolled regardless of PD-ligand 1 (PD-L1) expression and randomized 1:1 to either NIVO (240 mg Q2W) or investigator’s choice of paclitaxel or docetaxel. Primary endpoint was overall survival (OS).
419 pts were randomized (NIVO = 210, CT = 209). At a minimum follow-up of 17.6 months (mo; time from randomization of the last pt to data cutoff), NIVO showed a statistically significant improvement in OS vs CT (HR for death 0.77 [95% CI, 0.62–0.96; P = 0.02]; median OS, 10.9 vs 8.4 mo; Table). The proportion of pts alive at 18 mo was numerically larger with NIVO vs CT (31% vs 21%; Table). HRs for the risk of death favored NIVO over CT across tumor PD-L1 expression levels (PD-L1 ≥1%, HR 0.69 [95% CI, 0.51 to 0.94]; PD-L1 <1%, HR 0.84 [95% CI, 0.62 to 1.14]). The Table shows objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Fewer treatment-related adverse events (TRAEs) were reported with NIVO (any grade, 66%; grade 3–4, 18%) vs CT (any grade, 95%; grade 3–4, 63%; Table). NIVO showed a statistically significant overall improvement in quality of life vs CT through on-treatment week 42 in both the EQ-5D visual analog scale (least square [LS] mean, 6.9; 95% CI, 3.0–10.9; P < 0.001) and EQ-5D utility index (LS mean, 0.076; 95% CI, 0.011–0.142; P = 0.023).Table:
|Efficacy (all randomized pts)||NIVO N = 210||CT N = 209|
|Median OS, mo (95% CI)||10.9 (9.2–13.3)||8.4 (7.2–9.9)|
|HR (95% CI; P-value)||0.77 (0.62–0.96; P = 0.02)|
|12-mo rate, % (95% CI)||47 (40–54)||34 (28–41)|
|18-mo rate, % (95% CI)||31 (24–37)||21 (15–27)|
|ORR, n (%)a||33 (19)||34 (22)|
|Median DOR,b mo (95% CI)||6.9 (5.4–11.1)||3.9 (2.8–4.2)|
|Median PFS, mo (95% CI)||1.7 (1.5–2.7)||3.4 (3.0–4.2)|
|HR (95% CI)||1.08 (0.87–1.34)|
|6-mo rate, % (95% CI)||24 (19–30)||17 (12–23)|
|12-mo rate, % (95% CI)||12 (8–17)||7 (4–12)|
|Safety (all treated pts)||N = 209||N = 208|
|Pts with TRAEs, n (%)||137 (66)||198 (95)|
|Grade 3–4 TRAEs, n (%)||38 (18)||131 (63)|
|Pts with serious TRAEs, n (%)||33c (16)||47 (23)|
|Pts with TRAEs leading to discontinuation, n (%)||18 (9)||19 (9)|
Assessed in randomized pts who had target lesion measurements at baseline: NIVO, N = 171; CT, N = 158.b
Time from date of first response to date of first documented tumor progression or death.c
One grade 4 serious TRAE was not reported before the database lock and is not captured here.
NIVO demonstrated superior OS and a favorable safety profile vs CT in pts with previously treated advanced ESCC, with survival benefit observed regardless of tumor PD-L1 expression. NIVO may represent a new standard second-line treatment option for pts with advanced ESCC.
Clinical trial identification
Professional medical writing assistance and editorial assistance were provided by Jennifer Granit, PhD, and Christine Craig of Parexel, funded by Bristol-Myers Squibb.
Legal entity responsible for the study
Ono Pharmaceutical Co, Bristol-Myers Squibb.
Ono Pharmaceutical Co, Bristol-Myers Squibb.
B.C. Cho: Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD ; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Honoraria (self): Novatis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novatis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takega, MSD; Speaker Bureau / Expert testimony: Novartis. K. Kato: Advisory / Consultancy: Ono Pharmaceutical, BeiGene, MSD, Oncolys BioPharma; Research grant / Funding (institution): Ono Pharmaceutical, Shionogi, MSD, Beigene. M. Takahashi: Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Ono Pharmaceutical, Brystol-Myers Squibb, Daichi-Sankyo. M. Okada: Speaker Bureau / Expert testimony: Tahio Pharmaceutical, Johnson & Johnson, Coviden, Lilly, Chugai Pharma; Research grant / Funding (institution): Taiho Pharmaceutical, Nippon Kayaku, Chugai Pharma, Coviden, Johnson & Johnson, Daiichi Sanko, Yakult Honsha, Lilly Japan, Nihon Medi-Physics, Pfizer, Mochida Pharmaceuticals Co. Ltd, Shionogi. S. Kadowaki: Research grant / Funding (institution): Ono Pharmaceutical, Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb. Y. Doki: Speaker Bureau / Expert testimony: Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Kaken Pharmaceutical, Abbott Japan; Research grant / Funding (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly, MSD, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Kaken Pharmaceutical, Abbott Japan, Eisai, Shionogi . C. Yen: Honoraria (self): Lilly, Merck Sharp & Dohme, Amgen, Eisai; Advisory / Consultancy: Lilly, Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Lilly, Ono Pharmaceutical, Eisai, Effective Pharmaceuticals. S. Kim: Research grant / Funding (institution): Novartis, Genzyme, Dongkook Pharma. C. Hsu: Advisory / Consultancy: Ono Pharmaceutical, Lilly, MSD, Novartis; Honoraria (self): Bristol-Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme; Research grant / Funding (institution): Ono Pharmaceutical, AstraZeneca, MSD, Genentech. I. Xynos: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb. M. Kodani: Shareholder / Stockholder / Stock options: Ono Pharmaceutical Co. Ltd. Y. Kitagawa: Honoraria (self): Ethicon, Olympus, Ono Pharmaceutical, Tahi Pharmaceutical, Chugai Pharma, Nippon Kayaku, Asahi Kasei; Research grant / Funding (institution): Astellas, Otsuka, Kaken Pharmaceutical, Kyowa Hakko Kirin, Kowa, CSL Behring, Shionogi, Saiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharma, Tsumura & Co., Teijin Pharma, Medtronic, Boehringer Ingelheim, Merck Serono, Novartis, Ajinomoto, Asahi Ka. All other authors have declared no conflicts of interest.