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Clinical Trial
. 2024 May;13(9):e7235.
doi: 10.1002/cam4.7235.

Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial

Ken Kato  1 , Yuichiro Doki  2 , Ian Chau  3 , Jianming Xu  4 , Lucjan Wyrwicz  5 , Satoru Motoyama  6 , Takashi Ogata  7 , Hisato Kawakami  8 , Chih-Hung Hsu  9 , Antoine Adenis  10 , Farid El Hajbi  11 , Maria Di Bartolomeo  12 , Maria Ignez Braghiroli  13 , Eva Holtved  14 , Tomoki Makino  2 , Mariela Blum Murphy  15 , Carlos Amaya-Chanaga  16 , Apurva Patel  16 , Nan Hu  16 , Yasuhiro Matsumura  17 , Yuko Kitagawa  18 , Jaffer Ajani  15
Affiliations
Clinical Trial

Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial

Ken Kato et al. Cancer Med. 2024 May.

Erratum in

Abstract

Background: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data.

Methods: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population.

Results: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients.

Conclusions: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Keywords: cancer management; check point control; chemotherapy; clinical cancer research; clinical trials; esophageal squamous cell carcinoma.

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Conflict of interest statement

KK reports receiving personal fees for advisory roles from Ono Pharmaceutical, BeiGene, MSD, Oncolys BioPharma, and Bayer; receiving honoraria (lecture fees) from Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, and MSD; and receiving research funding from Ono Pharmaceutical, Shionogi, MSD Oncology, Chugai Pharma, AstraZeneca, Taiho Pharmaceutical, Bayer, and BeiGene. YD reports receiving personal fees for advisory roles from Ono Pharmaceutical receiving honoraria (lecture fees) from Otsuka, Taiho Pharmaceutical, Chugai Pharma, MSD, Ono Pharmaceutical, Lilly Japan, Daiichi Sankyo; and receiving research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharma, Yakult Honsha, and Daiichi Sankyo. IC reports receiving personal fees for advisory roles from Lilly, Bristol Myers Squibb, MSD Oncology, Merck Serono, Roche/Genentech, AstraZeneca, Boehringer Ingelheim, Incyte, OncXerna Therapeutics, Astellas Pharma, GlaxoSmithKline, Eisai, Sotio, Daiichi Sankyo/AstraZeneca, Taiho Oncology, Servier, Seattle Genetics, and Turning Point Therapeutics; receiving honoraria (lecture fees) from Lilly, Eisai, Servier, and Roche/Genentech; and receiving research funding from Janssen‐Cilag and Lilly. LW reports receiving personal fees for advisory roles from GlaxoSmithKline and Servier; and receiving honoraria (lecture fees) from Bristol Myers Squibb, BeiGene, MSD, and Servier. TO reports receiving honoraria (lecture fees) from Ono Pharmaceutical, MSD, and Bristol Myers Squibb Foundation. HK reports receiving personal fees for advisory roles from Taiho Pharmaceutical, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, and Daiichi Sankyo; receiving honoraria (lecture fees) from Chugai/Roche, Taiho Pharmaceutical, Bristol Myers Squibb Japan, Yakult Pharmaceutical, Takeda, MSD K.K., Merck Serono, Lilly Japan, Daiichi Sankyo, and Bayer; and receiving research funding from Chugai Pharma, Daiichi Sankyo, Eisai, and Kobayashi Pharmaceutical. C‐HH reports receiving personal fees for advisory roles from Ono Pharmaceutical, MSD, Bristol Myers Squibb, Merck Serono, and Roche/Genentech; receiving honoraria (lecture fees) from Bristol Myers Squibb, Ono Pharmaceutical, MSD, Roche, and Eisai; and receiving research funding from Ono Pharmaceutical, AstraZeneca, MSD, Merck Serono, Taiho Pharmaceutical, Bristol Myers Squibb, BeiGene, Nucana, Johnson & Johnson, Roche/Genentech, BeiGene, NGM Biopharmaceuticals, and Eucure Biopharma. AA reports receiving personal fees for advisory roles from Bristol Myers Squibb, Merck, Merck Serono, Astellas Pharma, Arcus Biosciences, and Bayer Health; receiving honoraria (lecture fees) from MSD Oncology, Bristol Myers Squibb, and Novartis; receiving honoraria from Bristol Myers Squibb, MSD, Servier, and Pierre Fabre; and receiving research funding from Sanofi, Bayer, Roche, BeiGene, Bristol Myers Squibb, Merck, and Arcus Ventures. MB reports receiving personal fees for advisory roles from Lilly and MSD Oncology; receiving honoraria (lecture fees) from Lilly, MSD Oncology, Servier, and BMS; receiving honoraria from Daiichi Sankyo/AstraZeneca; and receiving research funding from Lilly. MIB reports receiving personal fees for advisory roles from MSD, Lilly, Roche, Merck, and Servier; receiving honoraria (lecture fees) from MSD, BMS Brazil, Eurofarma, Takeda, and Amgen; and receiving honoraria from MSD. MBM reports receiving research funding from Bristol Myers Squibb and Genentech/Roche. CA‐C is an employee of and received stocks from Bristol Myers Squibb. AP is an employee of and received stocks from Bristol Myers Squibb and received stocks or stock options from Merck. NH reports is an employee of Bristol Myers Squibb. YM reports is an employee of and received stocks from Ono Pharmaceutical. YK reports receiving personal fees for advisory roles from Bristol Myers Squibb and Ono Pharmaceutical; receiving honoraria (lecture fees) from Asaki Kasei, Taiho Pharmaceutical, Chugai Pharma, Otsuka, Ono Pharmaceutical, Kaken Pharmaceutical, AstraZeneca Japan, Ethicon, Olympus, Nippon Covidien, Bristol Myers Squibb, MSD, Smith & Nephew, and Shionogi; and receiving research funding from Chugai Pharma, Taiho Pharmaceutical, Yakult Honsha, Asahi Kasei, Otsuka, Takeda, Ono Pharmaceutical, Tsumura & Co., Kyowa Kirin, EA Pharma, Medicon, Kaken Pharmaceutical, Eisai, Otsuka, Teijin Pharma, Nihon Pharma, and Nippon Covidien. JA reports receiving personal fees for advisory roles from Bristol Myers Squibb, Merck, Astellas, Taiho, More, Zymeworks, BeiGene, Dava, AstraZeneca, Acrotech, Daiichi, Vaccinogen, Innovent, Merck Serono, OncoTherics, Bayer, OncLive, Five Prime, Amgen, GRAIL, Novartis, Geneos, Arcus, Servier, Boehringer Ingelheim, and Gilead; and receiving research funding from Bristol Myers Squibb, Merck, Astellas, Taiho Pharmaceutical, Delta Fly, Roche, Prolinx, Zymeworks, Daiichi, Leap, Gilead, LaNova, and Turning Point.

Figures

FIGURE 1
FIGURE 1
Overall survival, progression‐free survival, and duration of response with nivolumab plus chemotherapy versus chemotherapy. Kaplan–Meier estimates of overall survival in (A) patients with tumor cell PD‐L1 expression ≥1% and (B) overall population, progression‐free survival by BICR in (C) patients with tumor cell PD‐L1 expression ≥1% and (D) overall population, and duration of response by BICR in (E) patients with tumor cell PD‐L1 expression ≥1% and (F) overall population. BICR, blinded independent central review; HR, hazard ratio; PD‐L1, programmed death ligand 1. aNumber of responders. [Correction added on October 4, 2024 after first online publication. The figure 1B has been updated in this version.]
FIGURE 2
FIGURE 2
Overall survival, progression‐free survival, and duration of response with nivolumab plus ipilimumab versus chemotherapy. Kaplan–Meier estimates of overall survival in (A) patients with tumor cell PD‐L1 expression ≥1% and (B) overall population, progression‐free survival by BICR in (C) patients with tumor cell PD‐L1 expression ≥1% and (D) overall population, and duration of response by BICR in (E) patients with tumor cell PD‐L1 expression ≥1% and (F) overall population. BICR, blinded independent central review; HR, hazard ratio; PD‐L1, programmed death ligand 1. aNumber of responders. [Correction added on October 4, 2024 after first online publication. The figure 2 has been updated in this version.]
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