Merck & Co., Incyte say late-stage study of Keytruda, epacadostat combination in melanoma misses main goal

Merck & Co. and Incyte announced Friday that a Phase III study investigating the combination of Keytruda (pembrolizumab) with the IDO1 inhibitor epacadostat in patients with unresectable or metastatic melanoma failed to meet its primary endpoint of progression-free survival (PFS). The drugmakers indicated that the ECHO-301/KEYNOTE-252 trial will be halted, with shares in Incyte falling as much as 20 percent on the news. 

The study randomised more than 700 patients with unresectable or metastatic melanoma who were stratified by tumour PD-L1 expression and BRAF mutation status. The trial's dual primary endpoints are PFS and overall survival, while key secondary goals include objective response rate, safety and tolerability. 

The companies noted that an external Data Monitoring Committee review of the study determined that the combination of Keytruda and epacadostat did not improve PFS in the overall population compared to Keytruda monotherapy. Merck and Incyte added that the trial's second main goal of overall survival "is not expected to reach statistical significance."  

FirstWord reports in this therapy area - KOL Insight Malignant Melanoma: Find out how KOLs expect the market to evolve, which pipeline treatments are most promising, and which clinical trials will shape treatment decisions. Learn more.

Incyte CEO Herve Hoppenot said the result "is obviously disappointing and it has a negative impact on the probability of success of the other studies combining epacadostat" with anti-PD-1 drugs, such as Keytruda. In addition to melanoma, Merck and Incyte are examining the combination of Keytruda and epacadostat in other tumour types, including lung and bladder cancers. Hoppenot indicated that the company will discuss with Merck whether to alter these studies in light of the ECHO-301/KEYNOTE-252 trial.

Last year, Merck and Incyte reported updated results from the Phase I/II ECHO-202 trial, with results showing that the combination of Keytruda and epacadostat in patients with advanced melanoma, including treatment-naïve and treatment-experienced patients, led to an overall response rate of 56 percent. Further data indicated median PFS of 12.4 months in these patients. Incyte is also investigating epacadostat in combination with Bristol-Myers Squibb's PD-1 inhibitor Opdivo (nivolumab).

Commenting on the latest results, Guggenheim analyst Tony Butler said the data suggest epacadostat provided no additional benefit above Keytruda alone, adding "we assume the probability of success of other studies with epacadostat is zero." William Blair analyst Katherine Xu called the data surprising, noting that the failure will make things difficult for the cause of IDO inhibitors.

Meanwhile, Bernstein analyst Tim Anderson suggested that the combination of an IDO inhibitor with an anti-PD-1 drug is unlikely to work in other tumour types, since melanoma is considered one of the more susceptible tumours to immunotherapy. It may be "too early to fully pronounce IDO as 'dead' yet, but it is not looking promising," Anderson cautioned.

Shares in NewLink Genetics, whose lead therapies indoximod and NLG802 target the IDO pathway, plummeted as much as nearly 45 percent in response to the ECHO-301/KEYNOTE-252 trial failure. The company said that it will review its clinical programmes in light of the results, though it stressed that indoximod has a "differentiated mechanism of action which may demonstrate clinical benefit for patients where direct enzymatic inhibitors have not."

Last year, Bristol-Myers Squibb released Phase I/IIa study data indicating that the combination of Opdivo (nivolumab) plus its experimental IDO1 inhibitor BMS-986205 led to an "encouraging response" among heavily pre-treated patients with advanced bladder and cervical cancers.

For related analysis, see ViewPoints: ECHO-301 failure will reverberate throughout I/O universe.

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