Select patients with advanced gastric or gastroesophageal junction cancer may benefit from initial therapy with pembrolizumab, according to the KEYNOTE-062 trial.
CHICAGO-Select patients with advanced gastric or gastroesophageal junction (GEJ) cancer may benefit from initial therapy with pembrolizumab, according to new data from the international randomized phase III KEYNOTE-062 clinical trial (abstract LBA4007) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago. Researchers reported that pembrolizumab resulted in clinically meaningful improvements in overall survival (OS) in patients with tumors that had high levels of programmed death ligand 1 (PD-L1) expression.
The researchers found that 39% of patients with high PD-L1 levels who received pembrolizumab alone were alive at 2 years’ of follow-up compared with 22% of patients who received standard chemotherapy. Lead study author Josep Tabernero, MD, PhD, head of the medical oncology department at the Vall d’Hebron University Hospital and Institute of Oncology in Barcelona, said this trial shows that front-line pembrolizumab is effective and could provide a new treatment option for patients with high levels of PD-L1 expression.
The trial included 763 patients (median age, 62 years); 69% had gastric cancer and the remainder had GEJ cancer. In this cohort, 26% of patients had previous gastric tumor resection. Investigators focused only on HER2-negative cancers, which are known to have higher recurrence rates after treatment. In this international trial, 58% of patients were from North America, Europe, and Australia; 25% were from Asia; and 17% were from other regions of the world. Patient randomization was stratified by region, disease status, and fluoropyrimidine treatment.
The researchers assessed PD-L1 expression by combined positive score (CPS), which is based on the number of PD-L1–positive cells derived from biopsied tissue and the number of viable tumor cells. Previous studies of gastric or GEJ cancers have demonstrated that patients with a PD-L1 CPS of 1 or more may benefit from pembrolizumab, and a PD-L1 CPS of 10 or more indicates a higher likelihood of benefit. In the current trial, all patients had a PD-L1 CPS of 1 or greater, and 281 (37%) had a score of 10 or more. The investigators randomly assigned patients to receive one of three initial treatment therapies (intravenous pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy plus placebo).
The researchers found that patients treated with pembrolizumab with a PD-L1 CPS of one or more had a survival comparable to those who were treated with chemotherapy (hazard ratio, 0.91), with a median follow-up of 11.3 months. The median OS was 10.6 months for those receiving pembrolizumab compared with 11.1 months for those who received chemotherapy. The researchers concluded that pembrolizumab was noninferior to chemotherapy in regard to OS in patients with advanced gastric/GEJ cancer with a PD-L1 CPS ≥ 1. In addition, there was an improved safety profile with pembrolizumab vs chemotherapy.
Survival with pembrolizumab among patients with a PD-L1 CPS of 10 or more was superior to chemotherapy (hazard ratio, 0.69), with a median OS of 17.4 months for those receiving pembrolizumab compared with 10.8 months for those receiving chemotherapy.
The rates of serious side effects were lowest in patients treated with pembrolizumab alone. Grade 3 or higher treatment-related adverse events occurred in 17% of patients receiving pembrolizumab, in 73% of patients receiving pembrolizumab plus chemotherapy, and in 69% receiving chemotherapy alone. “No new safety events were seen,” said Tabernero.
He said much better biomarkers than PD-L1 are needed to better determine which patients may be the best responders to pembrolizumab alone or in combination with chemotherapy. Prior population-based studies have shown that people from Asia tend to have better survival rates for gastric and GEJ cancers, have lower amounts of tumor, and slower disease progression. The researchers are currently analyzing the effectiveness of the treatments based on prespecified geographical regions.
Ravi Paluri, MD, an assistant professor in the University of Alabama at Birmingham division of hematology and oncology and an associate scientist at the O’Neal Comprehensive Cancer Center, said cytotoxic chemotherapy has been the treatment of choice for the past few decades for the management of advanced gastric and GEJ cancers and has been associated with significant adverse effects. He said that in the United States immunotherapy is approved in the third-line setting, and PD-L1 expression has emerged as one of the key predictive markers of response to immunotherapy. However, the timing of usage of checkpoint inhibitors is not in global consensus.
“This study has practice-changing implications on managing advanced gastric and GEJ cancers. Pembrolizumab, with its safety and efficacy, has the potential to be considered as recommended first-line treatment for PD-L1 CPS score > 10. For patients with CPS > 1 but < 10, pembrolizumab, because of its favorable side effect profile, is optional in the front-line setting, to defer cytotoxic chemotherapy and related adverse effects,” Paluri told Cancer Network.