The search to expand on progress made by the checkpoint inhibitors Keytruda and Opdivo and others has put the spotlight on several novel mechanisms. IDO inhibition appears poised to be the next advance after release of data at Asco showing a benefit when used in combination with the Merck & Co and Bristol-Myers Squibb drugs.
Leading the pack is Incyte’s epacadostat, which had detailed phase I/II Keytruda combo data that support pivotal trials in three types of cancer. Incyte’s combination-agnostic approach has also enabled it to confirm clinical benefit with Opdivo, showing responses in melanoma and head and neck cancers.
Epacadostat is not the only IDO inhibitor in the clinic. Newlink Genetics’ two assets, indoximod and the Roche-partnered RG6078, had data at Asco, along with the Danish group IO Biotech’s IO102.
But Incyte’s project so far has generated the richest body of evidence. Thanks to the adaptive design of the Echo-202/Keynote-037 trial with Keytruda, Incyte was able to present efficacy data in head and neck, non-small cell lung, renal cell, triple-negative breast and ovarian cancers, along with pooled safety data.
Breast and ovarian cancers do not look promising – in the former, 30 of 37 patients had progressed or died at a median follow-up of 20.8 weeks, while in ovarian cancer 26 of 34 patients had progressed or died at a median follow-up of 23 weeks. Objective response rates of 10% in breast cancer and 8% in ovarian, with no complete responses, are not very persuasive.
On the other hand, the signs have been strong enough in numerous other diseases to proceed into phase III (Incyte dramatically ups the immuno-oncology combo ante, April 3, 2017).
At Asco, Incyte also featured lung, urothelial, head and neck and kidney cancer (see table).
|Response data from Echo-202/Keynote-037|
|Non-small cell lung||5%||30%|
|Squamous cell head and neck||8%||26%|
|Renal cell carcinoma||3%||30%|
|Triple negative breast||0%||10%|
With the other leading PD-1, Opdivo, also reporting disappointing data in ovarian cancer in combination with epacadostat, it is safe to say that in the absence of a signal in subgroups this indication might not be one where the IDO inhibitors will be used.
On the other hand, the Opdivo-epacadostat pairing also had data in head and neck cancer – cross-trial comparisons are tricky with small patient numbers, but Opdivo and Keytruda look pretty similar at this early stage of development (see table).
|Response data from Echo-204|
|Squamous cell head and neck||3%||19%|
Moreover, the 58% partial response rate in a melanoma cohort in the Echo-204 trial yielded the best objective response rate seen at Asco – not surprising since the skin cancer is the most responsive to immunotherapy. And Incyte has announced plans to advance the Keytruda-epacadostat combination into phase III in melanoma.
Amid the advances for epacadostat, Newlink’s two IDO inhibitors were trying to remain relevant. RG6078 was tested in a phase I dose escalation trial with Tecentriq in solid tumours in which 9% of patient showed a partial response and 24% had stable disease.
Indoximod was tested following treatment with Valeant’s Provenge in metastatic castrate-resistant prostate cancer – patients taking the IDO inhibitor had a median progression free survival of 10.3 months compared with 4.1 months for patients taking placebo.
IO Biotech, meanwhile, had a poster on its planned phase II trial of IO102 in combination with checkpoint inhibitors in advanced, metastatic non-small cell lung cancer.
IDO inhibition shows promise, but the onrush of combination trials with PD-1 inhibitors means that it has to fight for attention (Immuno-oncology combinations surge as sector seeks the fairy dust, June 1, 2017).
Nonetheless, combining two checkpoint inhibitors remains an attractive choice, and medical meetings next year may very well show whether that attraction was worthwhile.