4:45 PM
Apr 20, 2018
 |  BioCentury  |  Product Development

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. Among the companies testing indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, Incyte is running the largest number, with 19 trials for epacadostat in combination with PD-1 or PD-L1 inhibitors, including eight in Phase II/III or Phase III. Bristol-Myers Squibb Co. (NYSE: BMY) has eight studies testing its BMS-986205 plus its PD-1 inhibitor Opdivo nivolumab, two of which are in Phase III or Phase II/III. The graph below shows combination studies enrolling or ongoing across four different IDO1 inhibitors, including NewLink Genetics Corp. (NASDAQ:NLNK)’s Indoximod and LY3381916 from Eli Lilly and Co. (NYSE:LLY). Source: ClinicalTrials.gov

Beyond IDO1, a December report from the Cancer Research Institute (CRI) found that there are 1,105 ongoing combination trials in oncology that include an anti-PD-1/PD-L1 therapy, of which 465 started in 2017.

Positive early findings that fail to be confirmed in Phase III have long confounded drug development in cancer. But the sheer number of combination studies for PD-1/PD-L1-targeted therapies not only risks wasting larger amounts of money than ever sorting out the best regimens, but also spreads patients thin.

For example, since the start of the year, Bristol-Myers Squibb Co. and Merck have committed over $2 billion to gain rights to combination agents for their respective PD-1 inhibitors, with plans to launch multiple Phase III trials.

And open Phase III trials testing IDO1/PD-1 or PD-L1 combinations alone are set to enroll more than 7,000 patients, according to ClinicalTrials.gov.

The question is whether the ECHO-301 data can be a wake-up call to rethink the rush to go too big too fast, launching multiple Phase III trials on shaky Phase I data.

Investigators, statisticians and biotech executives contacted by BioCentury think it’s time companies embrace alternative study designs in their Phase I/II trials, in particular the use of adaptive, controlled trials.

Moreover, they argue companies need to focus combo studies on populations where PD-1 alone has little benefit, and look to immuno-oncology pathways that are complementary to PD-1 blockade (see “Pathway to Success”).

The bar has been further raised in first-line lung cancer following this week’s data from Merck at the American Association for Cancer Research (AACR) meeting, which showed Keytruda plus chemotherapy produced a 51% reduction in the risk of death in the first year for all patients regardless of PD-L1 expression.

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