Bristol Myers' Opdivo fights Keytruda again with dual FDA nods in esophageal cancer

Bristol Myers Squibb’s Opdivo and Merck & Co.’s Keyturda have been duking it out for years across various tumor types. Now, BMS has scored a duo of FDA nods to level the playing field in esophageal cancer.

The FDA has cleared Opdivo combinations with chemotherapy or Bristol Myers’ Yervoy for newly diagnosed, advanced esophageal squamous cell carcinoma (ESCC), the New York pharma said Friday.

The simultaneous FDA approvals cover patients regardless of their tumors’ PD-L1 expression levels. That gives the Opdivo pairings a broader application in the U.S, than in Europe. Last month, the European Commission approved the two combo regimens only for patients with PD-L1 expression of at least 1%.

BMS used the same phase 3 CheckMate-648 trial for the two approvals. In newly diagnosed ESCC patients with PD-L1 expression of at least 1%, the combination of Opdivo and Yervoy cut the risk of death by 36% compared with chemotherapy alone, and the Opdivo-chemo cocktail slashed that risk by 46%.

The BMS therapies’ power appeared weaker in PD-L1-negative patients. When those patients are also counted in analyses of all randomized trial participants, the death risk reduction was 22% for the Opdivo-Yervoy combo and 26% for Opdivo plus chemo. In all patients, those who took Opdivo and Yervoy lived a median 12.8 months, and those who were on Opdivo and chemo lived a median 13.2 months, versus 10.7 months for chemo alone.

As for the measurement of the time to disease progression or death, the Opdivo-chemo combo failed to show statistically significant benefit over chemo alone in the overall population, and Opdivo-Yervoy didn’t even move the needle in PD-L1 expressers.

Still, BMS has argued that an ESCC patient doesn’t have to be PD-L1-positive to benefit from either of the two Opdivo combos. But in limiting the drugs’ usage, the European Medicines Agency clearly thinks the effects in PD-L1-negative patients weren’t enough.

Before the advanced ESCC nods, Opdivo a year ago became the first FDA-approved immunotherapy for patients whose esophageal or gastroesophageal junction tumors had been surgically removed, but showed residual pathologic disease, provided those patients had received chemoradiotherapy before surgery. The new FDA nods give BMS an opportunity to challenge Keytruda in previously untreated patients with advanced ESCC.

Keytruda, used in combo with chemo, obtained an FDA go-ahead last March for a broad patient population with advanced esophageal or gastroesophageal junction carcinoma. Keytruda also posted better responses in patients with higher PD-L1 expression levels.

Among patients with PD-L1 expression at a combined positive score of at least 10, Keytruda and chemo cut the risk of death by 38% over chemo alone in the phase 3 Keynote590 trial. But in all enrolled patients, which also included PD-L1 nonexpressers, the death-risk reduction dropped to 27%.

Keytruda’s label covers both ESCC and esophageal adenocarcinoma. While the current Opdivo nods cover ESCC only, BMS had already secured an approval for previously untreated esophageal adenocarcinoma in a landmark nod that also covers stomach cancer. 

In the U.S., about two-thirds of newly diagnosed esophageal cancer cases were adenocarcinoma, and a third were squamous cell carcinoma, according to Merck. An estimated 20,640 new cases of esophageal cancer will be diagnosed in the U.S. in 2022, and typically about 39% of the diagnoses are in the advanced stage, BMS said.