Lenvatinib-pembrolizumab combination shows promise in advanced gastric cancer

Last Updated: 2020-07-24

By Will Boggs MD

NEW YORK (Reuters Health) - The combination of the anti-PD-1 antibody pembrolizumab and the multikinase inhibitor lenvatinib provides objective response rates in many patients with advanced gastric cancer, according to results from an early single-arm trial.

"Based on these results, we feel this combination warrants further evaluation in a larger cohort in first-line treatment," Dr. Kohei Shitara of National Cancer Center Hospital East, in Chiba, Japan, told Reuters Health by email.

In earlier trials, pembrolizumab provided response rates of around 15% in patients with advanced gastric cancer but failed to demonstrate a survival benefit compared with standard chemotherapies.

Lenvatinib monotherapy was associated with durably stable disease in a phase-1 study of patients with solid tumors, and the combination of lenvatinib plus pembrolizumab has shown promising antitumor activity with manageable safety profiles for several malignancies.

Dr. Shitara and colleagues in the phase-2 EPOC1706 trial evaluated the antitumor activity and safety of daily oral lenvatinib plus intravenous pembrolizumab every three weeks in 29 patients with advanced gastric cancer (14 receiving treatment as first-line and 15 receiving treatment as second-line).

After a median follow-up of 12.6 months, eight patients were still undergoing treatment and 21 had discontinued treatment mostly due to disease progression.

Twenty patients (69%) achieved an objective response, including one patient who was mismatch repair (MMR)-deficient, the researchers report in the Lancet Oncology.

Objective-response rates were similar in patients receiving the study treatment as first-line and in those receiving it as second-line.

An immune-related objective response was achieved by 20 patients (69%), disease control was observed in all 29 patients, and eight of nine patients with stable disease showed initial tumor shrinkage from baseline.

The median progression-free survival was 7.1 months, and median overall survival was not reached. At the data cutoff, 20 patients were still alive and nine had died.

In exploratory analyses, objective response rates were higher in patients with at least 1% PD-L1-positive tumor cells (84%) than in patients with fewer PD-L1-positive cells (40%).

Higher tumor mutational burden was also associated with higher objective-response rates.

All 29 patients experienced treatment-related adverse events, and 14 patients (48%) experienced grade-3 treatment-related adverse events. There were no treatment-related deaths.

There were no study discontinuations resulting from treatment-related adverse events, but such events led to dose interruptions in 28 patients and at least one dose reduction of lenvatinib in all 29 patients.

"Although small sample size is a major limitation of this study, the combination of lenvatinib plus pembrolizumab had promising antitumor activity and a manageable safety profile," Dr. Shitara said. "We are now planning the next study to confirm these results."

Dr. Stefano Cascinu of Universita Vita-Salute, IRCCS-San Raffaele Hospital, in Milan, Italy, who wrote an accompanying editorial, told Reuters Health by email, "This trial brings new opportunities in the treatment of patients with advanced gastric cancer and potentially also for treatment of other tumor types. This trial is relevant because it shows how immune microenvironment may play a crucial role in the response to immunotherapy and how this may be modified."

"These results should be confirmed in a trial enrolling Western patients since there could be some differences in terms of results between Asian and non-Asian patients due to different immunity signatures," he said. "If these results are confirmed, this combination may become a standard of care in gastric cancer in first and second line."

Merck Sharp and Dohme funded the study. Dr. Shitara and two of his coauthors report financial ties to the company.

SOURCE: https://bit.ly/2BvOJUR and https://bit.ly/2NLRpQT Lancet Oncology, online June 23, 2020.