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

Are IDO inhibitors still the next big thing in immuno-oncology?

Metastatic melanoma cells

It's a safe prediction that immuno-oncology (IO) drug development activity is unlikely to diminish in 2018, with a major objective being the validation and approval of agents that synergise with the established anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors.

Much has been written on the broad utility of inhibitors of indoleamine-2,3-dioxygenase-1 (IDO), an intracellular enzyme present in both immune cells and cancer cells and  which regulates tryptophan levels in the tumour microenvironment (TME). 

Depletion of tryptophan by upregulated IDO expression starves cancer-antigen specific T cells, while a rise in the concentration of tryptophan metabolites triggers the development of immunosuppressive Treg cells.

This central role in local immunosuppresion and the prospect of synergy with immune checkpoint inhibitor treatment and other immunotherapies has made IDO (along with a similar enzyme, tryptophan-2,3-dioxygenase 2- TDO)  an attractive target for IO drug development, and a variety of  orally available small molecule inhibitors have entered clinical evaluation as both monotherapy and in combination with immunotherapies or cytotoxic cancer drugs.

Big pharma interest in  IDO and TDO inhibitors has fuelled several “big headline” partnering deals, including  BMS and Flexus Biosciences ($1.25 billon); Roche and CuraDev Pharma ($555m); Roche and NewLink Genetics ($1 billion), and Incyte Pharma and Roche, AstraZeneca, Merck and BMS (undisclosed terms).

 

IDO inhibitor progress has been mixed. In June last year, Roche returned the rights to NewLink's navoximod (GDC-0919), the latter failing to meet any of the primary study objectives (overall survival, progression-free survival or objective response rate) when combined with taxane chemotherapy in breast cancer patients.  Combination with Roche's ant-PD-L1 immune checkpoint inhibitor, Tecentriq® did not achieve an overall response rate better than Tecentriq® alone in patients with advanced solid tumours. Absence of efficacy was cited by iTeos Therapeutics today as the reason for termination of an IDO development partnership with Pfizer following analysis of interim trial data from a Phase I monotherapy study in patients with malignant glioma.

Failure in cancer drug development is, unfortunately, the norm rather than the exception, and it's possible that other IDO inhibitors with different chemistries and better bioavailability may prove capable of either upping the response to immune checkpoint inhibitors or being valuable treatments in their own right. Phase II data from a study of Incyte's epacadostat in combination with anti-PD-1 (Keytruda®) hinted that the combination might prove superior to, and safer than, combined anti-CTLA-4 (Yervoy®) and anti-PD-1 therapy in patients with advanced melanoma. A Phase III study (NCT02752074) is underway in collaboration with Merck, with primary data anticipated around the middle of 2018.

AstraZeneca, a company which could stand some good IO related news, recently expanded its collaboration with  Incyte to include lung cancer studies in combination with the anti-PD-L1 checkpoint inhibitor, Imfinzi®; other companies, including Kyowa Kirin, Jubilant Biosys, Kyn Therapeutics and e-Therapeutics have recently entered the IDO/TDO inhibitor game.

The apparent failure of ITeos's  candidate might not give immediate cause for concern (glioma is a very hard target), but it's reasonable to suppose that there are many fingers crossed in pharma management meetings in the hope that Incyte's Phase III study leads to registration and paves the way for the first small molecule IO treatments.

Photo credit: National Cancer Institute