Data from the phase 3 KEYNOTE-062 trial have revealed that in patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, first-line pembrolizumab, alone or in combination with chemotherapy, is noninferior but not superior to chemotherapy alone. In patients with a PD-L1 CPS of 10 or greater, pembrolizumab monotherapy showed a possible benefit, but one that cannot be considered definitive owing to the design of the study.
As the third leading cause of cancer death worldwide, G/GEJ cancer is a serious public health concern. For patients with human epidermal growth factor receptor 2 (HER2)-negative disease, the chemotherapy combination regimens recommended as frontline therapy for locally advanced or metastatic G/GEJ cancer result in a median overall survival of one year or less, with significant toxic effects.
"Safe and effective therapies for untreated, advanced G/GEJ cancer remain an unmet need," note the study investigators in their publication in JAMA Oncology, led by first author Kohei Shitara, MD, Chief of the Department of Experimental Therapeutics and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, and principal investigator Josep Tabernaro, MD, PhD, MSc, Director of the Vall d'Hebron Institute of Oncology in Barcelona, Spain.
The partially blinded trial enrolled 763 patients with HER2-negative untreated locally advanced/unresectable or metastatic G/GEJ cancer with a PD-L1 CPS of at least 1. Patients, who were treated at 200 centers in 29 countries, had a median age of 62 years (range 20 to 87), and the study population was 72.6% male. Patients were randomized in a 1:1:1 ratio to receive pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2 on Day 1 plus fluorouracil 800 mg/m2 per day on Days 1 to 5, or capecitabine 1,000 mg/m2 twice daily) or chemotherapy plus placebo every three weeks, for primary end points of overall survival and progression-free survival in patients with a PD-L1 CPS of 1 or greater or with a PD-L1 CPS of 10 or greater.
At a median follow-up of 29.4 months, pembrolizumab was noninferior but not superior to chemotherapy in patients with a PD-L1 CPS of 1 or greater, producing a median overall survival of 10.6 months compared with 11.1 months for chemotherapy, with a hazard ratio of 0.91 (95% confidence interval, 0.69 to 1.18). In patients with a PD-L1 CPS of at least 10, pembrolizumab did prolong median overall survival compared with chemotherapy (17.4 vs 10.8 months, with a hazard ratio of 0.69); however, owing to study design, this difference was not statistically tested.
Pembrolizumab/chemotherapy was not superior to chemotherapy alone, producing a slight difference in median overall survival that did not meet statistical significance in patients with a CPS of at least 1 (12.5 vs 11.1 months) or in patients with a CPS of 10 or greater (12.3 vs 10.8 months).
"The lack of superiority of chemotherapy plus pembrolizumab versus chemotherapy alone is disappointing for many clinical researchers. Previously, results from KEYNOTE-059 had demonstrated high response rates for chemotherapy plus pembrolizumab in treatment-naive, PD-L1–expressing gastric cancers," note Elizabeth C. Smyth, MD, of the Department of Oncology of Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK, and Markus Moehler, MD, of the Department of Internal Medicine at the University Medical Centre of the Johannes Gutenberg University in Mainz, Germany, in an editorial published alongside the study in JAMA Oncology. "Chemotherapy also abrogates the short progression-free survival seen with pembrolizumab monotherapy. While KEYNOTE-062 confirmed these improved responses for combination therapy (49% for pembrolizumab plus chemotherapy vs 37% for chemotherapy alone), this synergy did not translate into a survival benefit in either patients with CPS of 1 or greater or patients with CPS of 10 or greater."
Treatment-related adverse events of grade 3 or higher were substantially lower in the pembrolizumab monotherapy arm compared with the chemotherapy-containing arms, with rates of 17% for pembrolizumab alone, 73% for pembrolizumab/chemotherapy, and 69% for chemotherapy alone.
The investigators note that while Kaplan-Meier overall survival curves for pembrolizumab versus chemotherapy showed an early favorable trend toward chemotherapy in patients with a CPS of at least 1, they later favored pembrolizumab, with a higher two-year overall survival rate (27% vs 19% for chemotherapy). In patients with a PD-L1 CPS of at least 10, the two-year overall survival rate was also higher with pembrolizumab compared with chemotherapy (39% vs 22%). Dr. Shitara and colleagues suggest that "alternative statistical approaches to addressing changes in risk over time will be necessary in future clinical studies evaluating the delayed onset of benefit typically observed with immunotherapies."
Among the 7% of patients in the trial who had microsatellite instability–high (MSI-H) tumors, a survival benefit was seen both for pembrolizumab alone, with a hazard ratio of 0.29, and for pembrolizumab/chemotherapy, with a hazard ratio of 0.37.
"Pembrolizumab was noninferior to chemotherapy, with fewer adverse events in patients with untreated, advanced G/GEJ adenocarcinoma with PD-L1 CPS of 1 or greater," conclude Dr. Shitara and colleagues. "The survival benefit was clinically meaningful in patients with PD-L1 CPS of 10 or greater or with MSI-H tumors. There was no clinically meaningful benefit of pembrolizumab plus chemotherapy versus chemotherapy."
For More Information
Shitara K, Van Cutsem E, Bang YJ, et al (2020). Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2020.3370
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