Frontline pembrolizumab noninferior to chemo with less toxicity in gastric cancer
Pembrolizumab is noninferior to standard chemotherapy for overall survival (OS) in advanced gastric or gastroesophageal junction (G/GEJ) cancer in the first-line setting, thus providing a potential alternative treatment option for patients with G/GEJ, according to the KEYNOTE-062 study presented at ASCO 2019.
Furthermore, the clinical benefit with pembrolizumab was greater over chemotherapy in the patient population with high PD-L1 expression.
“Chemotherapy has been our only option for many years. These results introduce a potential alternative in pembrolizumab that comes with fewer side effects, and importantly, for some it can greatly extend survival. This opens the door to helping patients live longer and better lives,” said Dr Richard L. Schilsky, senior vice president and chief medical officer of ASCO, who was not affiliated with the study.
The phase III active-controlled trial enrolled 763 patients (median age 62 years, ≥70 percent male) with locally advanced, unresectable or metastatic gastric or gastroesophageal adenocarcinoma (69 percent with gastric cancer, 30 percent with GEJ cancer) who were HER2/neu-negative and PD-L1-positve (with a combined positive score [CPS] of ≥1). They were randomized 1:1:1 to receive pembrolizumab 200 mg Q3W or chemotherapy alone or pembrolizumab + chemotherapy. [ASCO 2019, abstract LBA4007]
The study met its primary endpoint by showing that pembrolizumab was noninferior to chemotherapy for OS among patients with CPS ≥1 (median, 10.6 vs 11.1 months, hazard ratio [HR], 0.91, 91 percent confidence interval [CI], 0.69–1.18).
The survival benefit with pembrolizumab became superior over chemotherapy when the researchers analysed patients with high PD-L1 expression CPS ≥10 (median, 17.4 vs 10.8 months, HR, 0.69, 95 percent CI, 0.49–0.97). At 2 years, 39 percent of patients in the pembrolizumab arm were still alive compared with 22 percent of those in the chemotherapy arm.
On the other hand, there was no additional benefit by combining pembrolizumab with chemotherapy vs chemotherapy alone. Both the median OS and progression-free survival were comparable between the combination group and the chemotherapy group, as per the prespecified boundaries regardless of CPS status, although there was a trend in favour of the combination group.
The tolerability profile with pembrolizumab vs chemotherapy was also better than pembrolizumab + chemotherapy vs chemotherapy. The rate of grade ≥3 toxic treatment-related adverse events (TRAEs) was the lowest in the pembrolizumab group (17 percent), followed by the chemotherapy group (69 percent) and the pembrolizumab + chemotherapy (73 percent). Nausea and fatigue were the most commonly reported AEs.
“Patients who received pembrolizumab had fewer AEs and grade 3–5 events … and fewer patients discontinued therapy due to AEs,” said lead author Dr Josep Tabernero from the Vall d’Hebron Barcelona Hospital University Hospital and Institute of Oncology, Barcelona, Spain.
“This trial shows that frontline pembrolizumab is effective and could provide a new opportunity for people newly diagnosed with advanced G/GEJ cancers,” he concluded. “There remains a significant unmet need for treatments for these cancers and our results reinforce the importance of continued research in this field.”
Better biomarkers, other than PD-L1, are needed to select patients mostly likely to respond to and benefit from the treatment, Tabernero noted. He also said analysis of treatment efficacy based on prespecified geographical regions is under way, noting that Asians have been shown to have better survival for G/GEJ cancer and slower disease progression in previous population-based studies.