Incyte dramatically ups the immuno-oncology combo ante

Incyte has propelled itself into the immuno-oncology premier league by revealing plans to initiate eight new phase III studies with its IDO1 inhibitor epacadostat and an anti-PD-1 antibody, bringing the total of such registration trials to nine. The plan covers six new studies with Merck & Co’s Keytruda and two new trials with Bristol-Myers Squibb’s Opdivo, and represents the most ambitious registrational expansion for any novel IO agent.

Although only the indications and settings have been disclosed at this point, it is possible that in two cases Incyte could find itself with parallel registration studies of Merck’s and Bristol’s agents. And, in a third case, it could end up conducting the first study that compares a combination with one anti-PD-1/PD-L1 agent with single-agent use of another (see tables below).

The ambitious move clearly cements epacadostat as the go-to IDO inhibitor for combining with checkpoint blockers, which has implications for companies with competing agents. Bristol even seems to have passed over its own early clinical-stage IDO inhibitor, BMS-986205, in favour of epacadostat.

Merck collaboration

Incyte and Merck are to initiate two studies of their combo in first-line NSCLC – in PD-L1-high and unselected patients; two in urothelial bladder cancer, and one each in renal cell carcinoma (RCC) and squamous cell carcinoma of the head and neck (SCCHN). The two companies already have one phase III under way (Keynote-202) in metastatic melanoma, as well as the large phase I/II study Keynote-037 in solid tumours.

Meanwhile, Incyte and Bristol are starting studies with Opdivo in first-line NSCLC and first-line SCCHN. In addition, an existing phase I/II study (Echo-204) in solid tumours will be expanded to include an anti-PD-1/PD-L1-relapsed/refractory melanoma cohort. All of the new studies will be 50/50 co-funded and run with the big pharma partner.

Phase III combination trials with epacadostat*
Indication Combined with Comparator** n
1L metastatic melanoma*** Keytruda Keytruda 600
1L NSCLC, high PD-L1 expression Keytruda Keytruda n/a
1L NSCLC, non-selected Keytruda Keytruda (PD-L1 high)/ chemo (low) n/a
1L bladder cancer Keytruda chemo n/a
2L bladder cancer Keytruda Tecentriq or Keytruda n/a
1L RCC Keytruda Sutent n/a
1L SCCHN Keytruda chemo + 5FU and cetuximab n/a
1L NSCLC, high/low PD-L1 expression Opdivo Keytruda or chemo n/a
1L SCCHN Opdivo chemo + 5FU and cetuximab n/a
Note: *no study design details have yet been disclosed; **assumed comparators are shown in italics, and are based on current standards of care; ***Keynote-202 (NCT02752074).

In NSCLC it seems logical that the study in PDL-1-high patients will test the combo against Keytruda monotherapy, which is indicated for first-line use at PD-L1 expression >50%. For Opdivo in this indication the new study will recruit “across the spectrum of PD-L1 expression”, suggesting that at least at high levels the comparison will also be made with Merck’s agent, although chemo could be appropriate for those with lower expression levels.

The design of the NSCLC studies, once revealed, will be particularly closely examined, given the pending readout of high profile IO-IO combo trials like AstraZeneca’s Mystic, and IO-chemo combos, such as Roche’s Impower-150.

Both Merck and Bristol have selected first-line SCCHN for new trials, so it is possible for similar trials with the two PD-1 agents to be conducted in parallel, testing perhaps against chemo plus Erbitux.

Meanwhile, the study in second-line bladder cancer might provide an opportunity to test the Keytruda combo directly against Roche’s Tecentriq, which is now a new standard of care in this setting. Of course, Merck might shortly obtain approval for Keytruda as monotherapy here on the basis of Keynote-045, so it could chose not to do this.

Leerink analysts said the expanded collaboration with Bristol was surprising since Merck had an exclusivity period as a result of its earlier phase III initiation in melanoma. However, they said this might have been circumvented by agreeing to examine different clinical questions in the two companies’ studies, which would be achieved through differences in the comparator arms.

One of the key factors that Merck and Bristol alike will have considered is potential changes in standards of care that could occur while the trials are under way. In all five indications targeted by the new studies there are many competing trials with anti-PD-1/PD-L1s, including Keytruda and Opdivo.

Incyte has several earlier phase I/II trials under way with epadocastat and other checkpoint inhibitors, including Astrazeneca’s durvalumab and Roche’s Tecentriq. It will be interesting to see if it can extend its portfolio of phase III partnerships to accommodate future phase III trials with other anti-PDL-1 companies.

Phase I/II combination studies with IO agents and epacadostat
Acronym Indication Combined with Enrolment Trial ID Data
None Unresectable or metastatic melanoma Yervoy 136 NCT01604889 Jan 2017
Keynote-037 Various cancers Keytruda 403 NCT02178722 May 2017
Echo-203 Advanced solid tumours Durvalumab 185 NCT02318277 Mar 2017
Echo-204 Melanoma, NSCLC, colorectal cancer, SCCHN, ovarian cancer & lymphoma Opdivo 291 NCT02327078 Apr 2019
Echo-206 Advanced solid tumours Azacitidine + Keytruda 142 NCT02959437 Sep 2021
Echo-207 Advanced/metastatic solid tumours Opdivo or Keytruda 332 NCT03085914 Apr 2021
Echo-110 Previously treated NSCLC and urothelial carcinoma Tecentriq 118 NCT02298153 Oct 2020
Note: all are single-arm phase I/II studies.

To contact the writer of this story email Robin Davison in London at robind@epvantage.com or follow @RobinDavison2 on Twitter

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