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Saturday, 7 April 2018

IDO a no-go: what’s up next in immuno-oncology combination therapy?

IDO inhibitors: only stalled or
now off-road?
Earlier this year, I mused on the prospects for inhibitors of IDO (indoleamine-2,3-dioxygenase-1),then considered among the most promising of small molecule drugs that might safely enhance the effectiveness of immune checkpoint inhibitors [Are IDO inhibitors still the next big thing in immuno-oncology? ]. 

While attracting big pharma interest (and partnering dollars), IDO inhibitor clinical development progress has been mixed, with both Roche and Pfizer abandoning early-stage clinical collaborations, leaving Incyte Pharma’s epacadostat in the spotlight and all eyes on the outcome of ECHO-301, a Phase III clinical study designed to establish whether combination treatment with epacadostat and Merck’s anti-PD-1 immune checkpoint inhibitor, pembrolizumab (Keytruda®), first approved as a melanoma treatment in 2014 might further benefit patients with advanced melanoma. 

According to a joint release from Merck and Incyte, data analysis indicates that, in contrast to Phase II study findings, combination treatment did not result in an improvement in progression-free survival over Keytruda® alone, nor is a meaningful increase in overall survival anticipated. 

The ECHO-301 study is to be halted and it’s likely that that a raft of other studies involving epacadostat- pembrolizumab combination treatment in colorectal, gastric, non-small cell lung, bladder cancer and other solid tumours will be put on hold or terminated. AstraZeneca may be having second thoughts over planned combination studies with their anti-PD-L1 inhibitor.

NewLink Genetics, a pioneer of IDO inhibitor development which has also experienced development setbacks, has been hit by the fallout, suffering a hefty dent in share price and prompting a review of its planned clinical programmes. Bristol Myers Squibb may face the same dilemma with respect to continuing patient recruitment for a Phase III study of its own IDO inhibitor, BMS-986205, in combination with its anti-PD1 drug, nivolumab (Opdivo®). 

Tryptophan metabolism plays a key role in tumour immunosuppression and while epacadostat’s failure will prompt a major rethink of drug development strategy, the door may remain open for those developers focused on different targets within the IDO pathway. Success with epacdostat would have handed Merck a significant advantage over its rivals in the immune checkpoint inhibitor field, but with hundreds of pembrolizumab clinical studies ongoing or in the process of recruiting subjects, Merck remains a strong player in the long game.

The demise of IDO inhibitors (at least for the time being) will move expectation to other “second wave” immuno-oncology drugs, although all are in relatively early stage clinical development. Those catching the interest of oncologists and industry analysts include BMS’s relatlimab, which targets LAG3 (Lymphocyte activation gene 3), a promising immune checkpoint inhibitor expressed on tumour-infiltrating T cells: early studies in melanoma patients have hinted at responses in patients failing to benefit from Opdivo® alone. Recruitment is underway for studies in patients with renal, gastric, lung or colorectal cancers. 

BMS is also evaluating combination with NKTR-214 (Nektar Therapeutics), a protein drug which targets a receptor (CD122) expressed by tumour-infiltrating T cells, in patients with a variety of advanced solid cancers. Pfizer has hopes that utomilumab, an antibody directed against CD137 (4-1BB), a receptor present on a variety of immune cells and also expressed by some tumours, will synergise with anti-PD1 and other immuno-oncology treatments.

There are a variety of possible permutations of established immune checkpoint inhibitors and investigational agents waiting to be explored. Combination therapy has its drawbacks with respect to balancing efficacy and safety and of course cost. In the longer term, it can only be hoped that the current generation of IO drugs will be replaced by next-generation agents able to safely achieve meaningful clinical responses in their own right. 

Photo credit: Pujanak from Wikimedia Commons