Expert Point of View: Kei Muro, MD, PhD

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The RATIONALE 302 trial1 was discussed by Kei Muro, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan, who found the results promising. However, Dr. Muro questioned the role of PD-1/L1 inhibitors as second-line therapy for advanced esophageal squamous cell carcinoma.

RATIONALE 302 is the third large trial to demonstrate a survival advantage for checkpoint inhibitors as second-line treatment for advanced esophageal squamous cell carcinoma, all showing similar efficacy for three different anti–PD-1 compounds. Median overall survival was 8.6 months (hazard ratio [HR] = 0.70) with teslelizumab in RATIONALE 302, 10.9 months (HR = 0.77) with nivolumab in ATTRACTION-3,2 and 8.2 months (HR = 0.78) with pembrolizumab in KEYNOTE-181.3 Results were even better in PD-L1–positive patients in these trials.

Kei Muro, MD, PhD

Kei Muro, MD, PhD

Despite proven efficacy for immune checkpoint inhibitors as second-line therapy, the role for these drugs in previously treated patients remains questionable, since overall survival benefits have also been shown in the first-line setting, commented Dr. Muro. These studies include KEYNOTE-590,4 CheckMate 648,5 and ESCORT6 (which evaluated the novel agent camrelizumab, also being developed in China). Now, moving even earlier into the treatment algorithm, pembrolizumab and nivolumab are being studied as neoadjuvant therapy.

“It can be said that esophageal cancer treatment has entered the era or the heyday of immune checkpoint inhibitors,” Dr. Muro commented. “Based on the results of these trials, immune checkpoint inhibitors will be administered in the first-line treatment of esophageal cancer, and the position of immune checkpoint inhibitors in second-line treatment is extremely difficult.”

Future studies of immune checkpoint inhibitors for esophageal cancer will focus on perioperative treatment, augmenting radiotherapy efficacy, and various combination strategies, he added. 

DISCLOSURE: Dr. Muro has received honoraria from Bayer, Bristol Myers Squibb, Chugai Pharma, Lilly, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, and Takeda; has received research funding from Amgen Astellas BioPharma, Astellas Pharma, and Taiho Pharmaceutical; and has received institutional research funding from Daiichi Sankyo, Gilead Sciences, Kyowa Hakko Kirin, Mediscience Planning, Merck Serono, MSD, Ono Pharmaceutical, Parexel International, Pfizer, Sanofi, Shionogi, Solasia Pharma, and Sumitomo Dainippon Pharma.


1. Ajani J, El Hajbi F, Cunningham D, et al: Randomized phase III study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302) in the overall population and the Europe/North American subgroup. 2021 ESMO World Congress on Gastrointestinal Cancer. Abstract O-15. Presented July 3, 2021.

2. Kato K, Cho BC, Takahashi M, et al: Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:1506-1517, 2019.

3. Kojima T, Shah MA, Muro K, et al: Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol 38:4138-4148, 2020.

4. Kato K, Sun J, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study. 2020 ESMO Virtual Congress. Abstract LBA8_PR. Presented September 21, 2020.

5. Chau I, Doki Y, Ajani JA, et al: Nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: First results of the CheckMate 648 study. 2021 ASCO Annual Meeting. Abstract LBA4001. Presented June 5, 2021.

6. Xu RH, Luo H, Lu J, et al: ESCORT-1st: A randomized, double-blind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma. 2021 ASCO Annual Meeting. Abstract 4000. Presented June 5, 2021.

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