Lessons from the ECHO chamber

What ECHO-301 can teach us about designing future combo studies

Lessons from the failure of ECHO-301 go beyond the prospects of combining IDO1 and PD-1 inhibition to treat cancer. The broader concern is for the gamut of Phase I/II trials testing PD-1 combinations, many of which will see companies and patients punished for sticking with traditional trial designs rather than adopting novel formats with better chances of predicting Phase III success.

The goal should be to move away from large scale Phase III programs that test combinations in many indications in parallel. Instead, companies should conduct smaller, more focused Phase III programs, only enrolling the patient populations most likely to respond. Early stage trials that use adaptive study designs and include a control arm will likely be key to finding those patients, and finding them quickly.

Incyte Corp. isn’t alone in scaling up to multiple Phase III trials on the back of a single Phase I study with a traditional design. But it was among the first testing a dual checkpoint combo, and its failure will likely reverberate throughout the field.

ECHO-301 tested Incyte’s indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor epacadostat with Merck & Co. Inc.’s Keytruda pembrolizumab in first-line metastatic melanoma. A Phase I/II trial of the combo was started in 2014, and last year produced an overall response rate (ORR) that was 75% greater than the historical rate of Keytruda in the same setting.

Those results didn’t bear out in ECHO-301. On April 6, the partners announced they were terminating the trial after a DSM review showed the combo missed the primary endpoint of improving progression-free survival (PFS) vs Keytruda alone.

Incyte and Merck have eight other Phase III trials testing the two compounds in different tumor types. Both companies declined to be interviewed for this story.

At least two other companies also have IDO1 inhibitors combined with anti-PD-1/PD-L1 mAbs in one or more Phase III trials, bringing the total of at-risk Phase III trials of the combos to 11.

Across all clinical stages, at least 30 trials are testing IDO and PD-1 or PD-L1 inhibition. None of the Phase I studies use control arms (see “IDO Uh Oh”).

Figure: IDO Uh Oh

At least 30 combination studies testing IDO inhibitors plus anti-PD-1/PD-L1 mAbs have been launched, but the recent failure of Incyte Corp. (NASDAQ:INCY) and Merck & Co. Inc. (NYSE:MRK)’s ECHO-301 trial suggests many of them are at risk of failure.

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