Incyte/Merck's ECHO-301 Failure Casts More Shadow On IDO Space

Following failure of Incyte/Merck's epacadostat/Keytruda study, NewLink Genetics says it is reviewing its IDO clinical programs.

The Phase III failure of the combination of Incyte Corp.'s IDO inhibitor epacadostat and Merck & Co. Inc.'s Keytruda in melanoma represents another knock on the new immuno-oncology class, raising uncertainty about prospects for other IDO candidates in development.

Epacadostat is the most advanced inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme on the tumor microenvironment that plays an important role in immune response. Bristol-Myers Squibb Co. and Merck moved fast into Phase III studies with combinations of epacadostat with their PD-1 inhibitors –  Opdivo (nivolumab) and Keytruda (pembrolizumab), respectively – in multiple tumor types, while developing their own earlier-stage IDO inhibitors.

However, Incyte and Merck announced April 6 that the combination of Keytruda and epacadostat failed to improve the primary endpoint of progression-free survival (PFS) and was unlikely to meet the coprimary endpoint of overall survival (OS) against Keytruda monotherapy in the Phase III ECHO-201/KEYNOTE-252 study of 700 patients with metastatic melanoma, according to an external data monitoring committee. 

The announcement casts doubt on the space generally, including other epacadostat/PD-1 combination studies and in-house assets. It is the latest in a string of setbacks for the IDO class, which analysts have started to write off. Roche walked out on a development deal for the IDO inhibitor navoximod (GDC-0919) with NewLink Genetics Corp. in June 2017.  (Also see "NewLink Absorbs Big Blow As Roche Exits IDO Inhibitor Partnership" - Scrip, 8 Jun, 2017.) This January, Pfizer Inc. handed back worldwide rights to EOS200271, an IDO1 inhibitor licensed from iTeos Therapeutics SA, after the candidate failed as a monotherapy in glioblastoma.  (Also see "Pfizer Pulls Plug But iTeos Has High Hopes For IDO1 Inhibitor" - Scrip, 4 Jan, 2018.)

Other big tests are coming up. Bristol started a Phase III study of their IDO inhibitor BMS-986205, an asset gained through its buyout of Flexus Biosciences Inc. in 2015, with Opdivo in previously untreated metastatic melanoma in late November 2017. And NewLink started a Phase III study of its IDO pathway inhibitor indoximod with Keytruda or Opdivo at the end of December. (Also see "IDO Emerges As Clean Combo Partner, Rising Star At AACR" - Scrip, 4 Apr, 2017.)

NewLink said in an April 6 statement that it is reviewing development plans for its IDO pathway inhibitor indoximod and NLG802, which is in Phase I.

"This morning’s announcement by Incyte and Merck on the ECHO-301 trial for patients with advanced melanoma is a disappointing result for the IDO field. Indoximod, NewLink Genetics’ IDO pathway inhibitor, has a differentiated mechanism of action (MOA) which may demonstrate clinical benefit for patients where direct enzymatic inhibitors have not. In light of Incyte’s announcement, however, NewLink is undertaking a review of its clinical programs and will provide an update when it is completed," the company said. 

Seeking Answers In Subgroups

In the ECHO-301 study, the hazard ratio for the PFS result was 1.00 with a confidence interval of 0.83 to 1. In the survival analysis, which was less mature, the hazard ratio was 1.13 with a confidence interval of 0.86 to 1.49. Safety was consistent with previously reported data for the combination. Based on these findings, and at the recommendation of the external data monitoring committee, the study will be stopped, the partners said. 

The study included an extensive biomarker panel and an analyses of biomarkers will be released between now and the end of the year, including the impact of tumor mutation burden and PD-L1-expression status.

"For epacadostat in melanoma, the next step is to analyze the data in detail to understand if there are any differences in the benefits observed within subgroups," Incyte CEO Hervé Hoppenot said during an April 6 investor call. The results will be presented at an upcoming medical meeting.

Hoppenot said that that the ECHO-301 results are obviously disappointing and have negative implications for the probability of success of other studies combining epacadostat with PD-1 inhibitors. Aside from the melanoma study just reported, eight other industry sponsored Phase III studies are ongoing with Merck's Keytruda or Bristol's Opdivo with epacadostat in metastatic lung cancer, renal cancer, bladder and head and neck cancer.

The biomarker analyses from the melanoma study will inform Merck and Incyte as to whether changes need to be made to ongoing studies, Hoppenot said.

"Whether the results from ECHO-301 have any readthrough to other IDO1-based combinations beyond PD-1 remains an open question. We do intend to continue to investigate the potential of epacadostat in these settings, where preclinical or translational data are compelling," Hoppenot said.

Most of the combination studies have enrolled between 30 and 50 patients so there is "more than adequate time to do any modifications as may be needed," Incyte Chief Medical Officer Steven Stein said.

However, "even with reduced or no expectation for epacadostat, we are on a great trajectory toward becoming a fast-growing, innovative and profitable biopharmaceutical company," Hoppenot maintained. The CEO said that the strength of Incyte in 2018 will come from revenue growth of existing commercial products Jakafi (ruxolitinib) and Iclusig (ponatinib), plus royalties from Jakafi and Olumiant (baricitinib), a portfolio of near-term launches, and optionality in its early-stage portfolio.

Rise And Fall Of IDO

Excitement around IDO as a mechanism to enhance performance of PD-1/L1 inhibitors safety reached a peak around the time of the American Society of Clinical Oncology annual meeting in June 2017 – when Incyte's stock was trading in the $130 range. 

On Feb. 21, Incyte stock was trading at about $86 and on April 6 it closed down 22.93% to $64.02.

BMO Capital Markets analyst Alex Arfaei commented in an April 6 note that many investors were becoming skeptical about the melanoma study of epacadostat. "Our conversation with [Pfizer] management also indicated that it was not particularly bullish about the incremental benefit of IDO. Even the recent tone from [Merck]’s management was not particularly bullish about IDO," Arfaei said.

Keytruda monotherapy is likely to remain an attractive option in melanoma, which is expected to account for 15% of the $7bn forecast for Keytruda in 2018, Arfaei said.

Bernstein analyst Tim Anderson said in an April 6 note that "the writing seemed to be on the wall that this combination would not work, and that IDO in general remains a questionable target." 

IDO has not shown compelling single-agent activity, which is usually a red flag in development, Anderson explained. Additionally, Roche, which he noted is arguably one of the smartest oncology companies, pulled out the IDO space and Merck had been sounding appropriately cautious about the study's prospects over the past several months, Anderson said.

"It is unclear what the fate of these different programs will be, but if the combination didn't work in malignant melanoma – commonly felt to be one of the most immunogenic cancers – then it would seem unlikely to work in other settings as well.  It may to too early to fully pronounce IDO as 'dead' yet, but it is not looking promising," Anderson added. 

The analyst pointed out that as many second-generation IO drugs have failed, PD-1/L1 monotherapy and PD-1/L1 plus CTLA-4 combinations may end up continuing to be the dominant regimens.

Bristol is set to present results from the CheckMate 227 study of Opdivo with its CTLA-4 inhibitor Yervoy (ipilimumab) in first-line non-small cell lung cancer at the American Association of Cancer Research meeting on April 16. During the same session, Merck will present Phase III data for Keytruda in combination with chemo in first-line NSCLC, which already holds accelerated approval from FDA.

Credit Suisse analyst Vamil Divan said that the perceived lack of competition from IDO "increases the importance of CTLA-4 (Yervoy) and opens up more of a runway for their Opdivo + Yervoy combinations." 

Bristol's new tie-up with Nektar Therapeutics for the IL-2 stimulating NKTR-214 may also now have more value with IDO failing to show a benefit, in Divan's view.  (Also see "Nektar's NKTR-214 IO Deal With Bristol Looks Even Sweeter With More Data" - Scrip, 2 Mar, 2018.)

The epacadostat failure may drag on the entire immuno-oncology space, the analyst said, but investors should not make broad assumptions regarding the viability of other platforms.