Pembrolizumab-trastuzumab-chemo a new treatment alternative for gastric cancer?
In a prespecified interim analysis of the phase III KEYNOTE-811 study presented at ESMO GI 2021, the addition of pembrolizumab to standard of care (SoC) first-line therapy comprising trastuzumab and chemotherapy led to a significant improvement in overall response rate (ORR) in previously untreated individuals with HER2-positive, metastatic gastric or gastroesophageal junction (G/GEJ) cancer.
A total of 264 participants with unresectable or metastatic HER2-positive G/GEJ cancer and ECOG PS* 0/1 comprised the efficacy cohort. Participants were randomized 1:1 to receive either IV pembrolizumab 200 mg or placebo Q3W (day 1) for up to 2 years or until disease progression or intolerable toxicity. This was administered on top of IV trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) and a chemotherapeutic regimen comprising either capecitabine and oxaliplatin or 5-fluorouracil and cisplatin at standard doses**. [ESMO GI 2021, abstract LBA-4]
After a median follow-up of 12 months, confirmed ORR was significantly greater in the pembrolizumab vs the placebo arm (74.4 percent vs 51.9 percent; difference, 22.7 percent, 95 percent confidence interval, 11.2–33.7, p=0.00006).
The pembrolizumab arm also demonstrated greater complete response rate (11.3 percent vs 3.1 percent) as opposed to placebo. Median duration of response was slightly longer in the pembrolizumab arm vs the placebo arm (10.6 vs 9.5 months).
In the safety cohort (n=217 and 216 in the pembrolizumab and placebo arms, respectively), the incidence of grade 3–5 adverse events (AEs) was similar between arms (57.1 percent vs 57.4 percent), as were the rates of discontinuation of any study drug (24.4 percent vs 25.9 percent).
Taken together, the current findings support those observed in phase II studies reflecting the promising efficacy and manageable safety of pembrolizumab plus SoC in HER2-positive, metastatic G/GEJ cancer.
The results have also paved the way for an accelerated FDA approval for this combination therapy in this patient setting. [www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer, accessed September 1, 2021] “This was based on clinical rationale suggesting [a] synergy between a combination of anti-HER2 and anti-PD-1 therapy,” said study author Dr Yelena Janjigian from the Memorial Sloan Kettering Cancer Center, New York, New York, US, in an interview.
While data on progression-free and overall survival have yet to mature, the durable responses and manageable safety profile support pembrolizumab plus trastuzumab and chemotherapy as a possible new treatment option for HER2-positive, metastatic G/GEJ cancer for which treatment options are limited and prognosis is poor. [Future Oncol 2021;17:491-501]. “This is really an important breakthrough for our patients,” said Janjigian.