Expert Point of View: Stefano Cascinu, MD

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Stefano Cascinu, MD, of the Comprehensive Cancer Center, Università Vita-Salute, IRCCS-Ospedale San Raffaele, Milan, Italy, was the invited discussant of KEYNOTE-5901 and CheckMate 649.2 “These landmark studies could change the treatment paradigm of advanced esophageal and gastric cancers. They cleared the way to immunotherapy in the first line, and I think they will lead to a completely different treatment landscape,” he ­commented.

Pembrolizumab is already approved in the United States for all esophageal cancers, and nivolumab is approved for all esophageal, gastric, and gastroesophageal junction cancers (regardless of PD-L1 expression). The European Medicines Agency, on the other hand, has approved the drugs only for patients with combined positive score (CPS) ≥ 10 and ≥ 5, respectively. Dr. Cascinu said the updated findings, based on longer follow-up, provide important information and praised the investigators for continuing with their analyses.

Stefano Cascinu, MD

Stefano Cascinu, MD

Trial Updates

KEYNOTE-590 showed an advantage for pembrolizumab across all subgroups, though particularly impressive was the benefit in patients with adenocarcinoma and a PD-L1 CPS ≥ 10, said Dr. Cascinu. Additional noteworthy findings were that 20% of patients remained in response after 24 months or more and that the addition of the checkpoint inhibitor to chemotherapy did not worsen quality of life, he added.

Similarly, all subgroups benefited from nivolumab in CheckMate 649, but most impressively in the patients with a PD-L1 CPS ≥ 5 (the primary endpoint). The subgroup analysis provided data that may help clinicians select patients for nivolumab plus chemotherapy, he added, since the checkpoint inhibitor was of limited use in patients with hypoalbuminemia and peritoneal metastases. Those younger than age 65 as well as those with a low tumor burden and absence of liver metastases also enjoyed little benefit.

Does CPS Matter?

The updates do call into question the value of singling out potential nonresponders based on CPS, Dr. Cascinu said. However, they did confirm an enriched overall survival benefit for patients with a CPS ≥ 5 in CheckMate 649 (hazard ratio [HR] = 0.71) and ≥ 10 in KEYNOTE-590 (HR = 0.64). These subsets of patients are potentially driving the overall benefit in the trials, he suggested. “I believe CPS does matter.”

The use of CPS as a biomarker is also supported by recent findings from an analysis of CheckMate 649 and KEYNOTE-062, based on data unreported in the primary manuscripts.3 The conclusion was the lack of benefit of checkpoint inhibitors in low PD-L1–expressing gastroesophageal adenocarcinoma tumors, he added.

Remaining Questions

Although Dr. Cascinu is enthusiastic over the positive findings for checkpoint inhibitors plus chemotherapy in advanced esophagogastric cancer, he said their optimal use will be clearer once the following questions are answered:

What is the role of PD-L1 in identifying patients likely to respond or not? PD-L1 may be most informative as a continuous variable, regarding the magnitude of benefit, and may be useful in discussing relative benefits with patients, he said.

How reproducible are the data in some common clinical situations, such as for those with a poor performance status, malnutrition, and peritoneal involvement?

What is the role of checkpoint inhibitors in the first-line treatment of advanced esophageal cancer previously treated with adjuvant nivolumab (now approved for residual disease after neoadjuvant chemotherapy)? 

DISCLOSURE: Dr. Cascinu reported financial relationships with Bristol Myers Squibb, Lilly, MSD Oncology, Sanofi, Servier, and Bayer.


1. Metges JP, Kato K, Sun JM, et al: First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: Longer-term efficacy, safety and quality-of-life results from the phase 3 KEYNOTE-590 study. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 241. Presented January 20, 2022.

2. Shitara K, Janjigian YY, Moehler MH, et al: Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: Expanded efficacy, safety, and subgroup analyses from CheckMate 649. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 240. Presented January 20, 2022.

3. Zhao JJ, Yap DWT, Chan YH, et al: Low programmed death-ligand 1-expressing subgroup outcomes of first-line immune checkpoint inhibitors in gastric or esophageal adenocarcinoma. J Clin Oncol 40:392-402, 2022.

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