ESMO: In newly diagnosed stomach cancer, 2 Opdivo-Yervoy flops show immunotherapy alone might not be the answer

Bristol Myers Squibb
Compared with chemotherapy, Bristol Myers Squibb's Opdivo and Yervoy failed to significantly extend the lives of patients with newly diagnosed advanced stomach cancer. (Bristol Myers Squibb)

Bristol Myers Squibb boasts a historic go-ahead for Opdivo plus chemotherapy as the first immunotherapy regimen for previously untreated stomach cancer. But the PD-1 inhibitor didn't repeat that success in combination with Yervoy.

Compared with chemo, Opdivo and Yervoy failed to significantly extend the lives of patients with newly diagnosed advanced gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma that expressed PD-L1 at a combined positive score of 5 or above, according to data presented at the European Society for Medical Oncology annual meeting.

The data came from the same CheckMate-649 trial that gave Opdivo’s chemo combo bragging rights in front-line stomach cancer. The trial now showed that patients on the dual immunotherapy regimen lived a median 11.7 months, versus 11.8 months for chemotherapy.

Still, Jonathan Cheng, M.D., BMS' head of oncology development, noted that Opdivo-Yervoy showed “encouraging results” in terms of duration of response and in some patient subgroups, such as those with MSI-high tumors.

“I do think it's important to be able to investigate where checkpoint inhibitor combinations or even monotherapy have potential clinical benefit, as well as places where you have to be more selective in finding that patient benefit,” he said in an interview.

RELATED: With 'evolved' treatment landscape, Merck pulls Keytruda's FDA nod in third-line stomach cancer

CheckMate-649 only included patients with HER2-negative disease. In an investigator-initiated phase 2 trial dubbed Intega, a group of researchers in Germany tested Opdivo alongside Roche’s Herceptin in previously untreated HER2-positive esophagogastric cancer. Patients in the trial also received either Yervoy or the chemotherapy FOLFOX.

The goal was to increase the 12-month overall survival rate to 70% from the 55% historically seen in Herceptin-chemo’s phase 3 ToGA trial in gastric cancer. Turns out, only the Opdivo-Herceptin-chemo group hit the goal, while Opdivo-Herceptin-Yervoy managed just 57%.

Stomach cancer has proven a tough nut to crack for immuno-oncology agents, especially by themselves. Merck & Co.’s Keytruda, as a monotherapy, has failed to show a survival advantage over chemo in both newly diagnosed and second-line stomach cancer patients in the Keynote-602 and Keynote-601 trials, respectively. Those flops, coupled with Opdivo’s chemo-combo victory, recently cost Keytruda its conditional nod in third-line stomach cancer.

RELATED: ASCO: Merck details Keytruda's Herceptin combo stomach cancer win as its single-agent nod's in danger

By contrast, Keytruda has shown early success in front-line, HER2-positive stomach cancer when used alongside Herceptin and chemotherapy and has won an FDA nod based on tumor shrinkage data.

The Opdivo-chemo arm of CheckMate-649 continued to show a survival benefit after another 12 months’ follow-up, according to an update at ESMO 2021. The combo cut the risk of death by 21% over solo chemo as patients, regardless of their PD-L1 status, lived a median 13.8 months and 11.6 months, respectively. The magnitude of improvement was greater in patients with PD-L1 expression of at least CPS 5 as the risk reduction widened to 30%.