It was a decent idea: Team Tecentriq, the Roche checkpoint inhibitor, with its Exelixis-partnered drug Cotellic to treat melanoma. After all, Roche’s PD1-L1 rivals are approved for melanoma, and Cotellic itself boasts its own nod in the disease.
Sure, Cotellic’s approval in melanoma is for BRAF-mutated disease. But the drug is a MEK inhibitor, and as trial investigators noted, “emerging data” suggest that interfering in the MAPK pathway, as MEK inhibitors do, could act on tumors without BRAF mutations.
Unfortunately, the idea didn’t work out as planned—at least not when it came to beating the foe it chose to challenge: Merck & Co.’s megablockbuster PD-1 immunotherapy, Keytruda. A logical choice, because it's the current standard of care.
In the phase 3 IMspire170 trial, the duo failed to beat their comparator at fending off melanoma’s advance on almost every measure. Overall response rate, progression-free survival, side effects—the combo fell short of Keytruda, if only slightly, in each instance.
"The thought was that Cotellic, by inhibiting the MEK pathway, could offer a immunostimulatory component and enhance atezo," said Alan Sandler, M.D., Roche's senior vice president of oncology product development, referring to Tecentriq's generic name. "It was a nice scientific hypothesis and a well designed study to address it. It doesn't always work, unfortunately."
On the response rate side, Tecentriq plus Cotellic spurred a response in 26%; Keytruda’s response rate hit 32%. The combo patients went a median 5.5 months without their disease progressing; the median in the Keytruda arm was 5.7 months.
And on the safety side, 67% of patients taking the combo suffered serious side effects—grade 3 or higher—compared with 33% of those on Keytruda. Twelve percent of the combo patients quit the trial because of those side effects, and 6% of Keytruda patients did.
In sum? “IMspire170 did not meet its primary endpoint,” the investigators stated.
It’s not the first time this particular duo has failed to beat an already entrenched drug. When pitted against Bayer’s Stivarga in heavily pretreated colorectal cancer—the IMblaze370 trial—the two meds fell short.
Again, the pair were taking on not only a tough comparator, but a tough patient group: All but 5% of patients in that study were microsatellite instability (MSI) stable, a tougher group than the MSI-high patients known to respond to PD-1 therapy.
When the top-line IMspire170 data were released earlier this year, Stifel analyst Stephen Willey said it wasn’t unexpected, given the similar failure against Bayer in colorectal cancer. The news wasn’t “thesis-changing,” the analyst said, and his team “continue to view the displacement of first-line immunotherapy in this setting as unlikely.”
Roche has other plans for Cotellic, of course. Cotellic and Zelboraf, Roche’s BRAF-targeted med, are together approved for previously untreated melanoma patients with BRAF mutations, and a three-drug cocktail—Cotellic, Zelboraf and Tecentriq—are in phase 3 testing against melanoma. That trial, IMspire150 Trilogy, pits the trio against Cotellic-plus-Zelboraf, and it's expected to read out by the end of this year, Sandler said.
"The negative impact of IMspire 170 doesn't change our enthusiasm for 150," Sandler emphasized.
That trial, if positive, might not lead to much in the way of additional sales for the meds, though, Willey figures. It’s "more of a ‘check the box’ vs. an ‘expand the market’ exercise,” he wrote.