CHICAGO-Frontline immunotherapy with pembrolizumab shows promise as an alternative to chemotherapy for patients with advanced gastroesophageal junction (GEJ) and gastric cancers. Initial therapy with pembrolizumab resulted in comparable (non-inferior) overall survival (OS) as standard chemotherapy and showed clinically meaningful improvement in OS among patients with tumors that had high levels of PD-L1 expression.
Current recommended gastric cancer treatment options include first-line platinum plus fluoropyrimidine and second-line docetaxel, paclitaxel, irinotecan, and ramucirumab with or without paclitaxel. Pembrolizumab has shown antitumor activity and manageable safety in patients with advanced gastric cancer.
"The trial met its primary endpoint and shows that frontline pembrolizumab is effective and could provide a new opportunity for people newly diagnosed with advanced gastric or gastroesophageal junction cancers. There remains a significant unmet need for treatments for these cancers and our results reinforce the importance of continued research in this field," said lead author Josep Tabernero, MD, PhD, Head of the Medical Oncology Department at the Vall d'Hebron Barcelona Hospital and Director of the Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Tabernero discussed the results of the study at a press briefing before the 2019 ASCO Annual Meeting (Abstract LBA4007).
Approximately 27,510 new gastric cancers and 11,140 deaths from the disease are expected to occur in the U.S. this year. GEJ, a less common cancer, has seen increasing incidence rates during this decade, particularly in Western nations, but the reasons for this increase are not entirely clear.
Pembrolizumab received accelerated approval by the FDA in September 2017 for patients with recurrent, locally advanced or metastatic, gastric or GEJ cancer with tumors that express PD-L1 with a combined positive score (CPS) of one or more. The CPS is calculated based on the number of PD-L1 positive cells derived from biopsied tissue and the number of viable tumor cells.
Trial Details
The KEYNOTE-062 phase III randomized clinical trial enrolled 763 patients, median age 62 years. One-quarter had had previous gastric surgery to remove a tumor. In total, 69 percent had gastric cancer and 30 percent had GEJ cancer, which are typically very similar types of tumors despite their adjacent locations, said Tabernero. The researchers focused only on HER2-negative cancers, which studies have shown have a higher chance of recurrence after treatment, to limit factors that could affect outcomes.
Previous studies have demonstrated that gastric cancer patients with a PD-L1 CPS of one or more may benefit from pembrolizumab, while 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 one or greater, and more than one-third had a score of 10 or more.
The patients were randomly assigned in equal numbers to receive one of three treatment options as initial therapy: intravenous pembrolizumab, pembrolizumab and chemotherapy, or chemotherapy plus placebo. The patients were followed for a median of 11.3 months.
Key Findings
The trial reached its primary endpoint, demonstrating that OS for pembrolizumab was non-inferior (comparable) to standard chemotherapy. A favorable survival outcome was seen among enrolled patients with PD-L1 CPS of 10 or more.
For patients with PD-L1 CPS of one or more, survival was non-inferior to chemotherapy. Median OS was 10.6 months for those receiving pembrolizumab compared with 11.1 months for those who received chemotherapy. For patients with PD-L1 CPS 10 or more, survival with pembrolizumab was superior to chemotherapy, with median OS of 17.4 months for those receiving pembrolizumab compared with 10.8 months for those receiving chemotherapy. After 2 years, 39 percent of those taking pembrolizumab were alive compared with 22 percent of those taking chemotherapy. "This is more proof of the benefit of pembrolizumab over chemotherapy," Tabernero noted.
For patients treated with pembrolizumab plus chemotherapy, both OS and progression-free survival , regardless of CPS score, were comparable to that of chemotherapy alone.
Serious side effects were lowest among patients treated with pembrolizumab alone. Grade 3 or higher toxic treatment-related adverse events were found in 17 percent of those receiving pembrolizumab, 73 percent of those receiving pembrolizumab and chemotherapy, and 69 percent receiving chemotherapy alone. The most common adverse events were nausea and fatigue. The safety profile of pembrolizumab was consistent with prior experiences of patients, Tabernero explained.
Next Steps
The researchers plan to analyze subsets of the data to determine who benefitted the most. Tabernero noted that better biomarkers than PD-L1 are needed to truly determine who the best responders might be to pembrolizumab alone, as well as to combination chemotherapy.
The trial enrolled 58 percent of patients from North America, Europe, and Australia, 25 percent from Asia, and 17 percent from other regions of the world. Prior population-based studies have shown that people from Asia usually have better survival rates for gastric and GEJ cancers, and have lower amounts of tumor and slower disease progression. Tabernero noted that, among Asians, pembrolizumab led to a slight improvement in survival over chemotherapy. The researchers are currently analyzing the effectiveness of the medicines based on pre-specified geographical regions.
Richard L. Schilsky, MD, Senior Vice President and Chief Medical Officer of ASCO, commented: "This study demonstrates that using immunotherapy can improve survival with a substantially improved safety profile. It is quite clear that pembrolizumab is superior to chemotherapy in the high biomarker-positive population. For patients with advanced gastric and gastroesophageal junction cancer, pembrolizumab should really replace chemotherapy as first-line treatment."
Mark L. Fuerst is a contributing writer.