the Incyte drug that Merck was combining with pembrolizumab didn’t fully block the metabolic pathway it was supposed to. It wasn’t clear the drug was really having its intended effect.
Second, the bullish early results from IDO inhibitors came from relatively small trials, in cancers already proven to respond to checkpoint blockers. “I was always skeptical about IDO,” he says. “People need to look at what the red flags were.”
MD Anderson’s Sharma thinks IDO blockers may not have been combined with the right drugs or tested in the right patients. They’ve been paired with checkpoint blockers known as PD-1 inhibitors, like pembrolizumab and nivolumab. But Sharma believes it makes more sense to combine an IDO blocker with a drug like ipilimumab, which impacts a different target, CTLA-4. She also thinks melanoma is “oversaturated” with treatments; perhaps the Merck/Incyte combo would’ve succeeded elsewhere, where the bar might be lower.
“It may have been a blockbuster if it had gone ahead in bladder cancer,” says Ajjai Alva, a medical oncologist at the University of Michigan Rogel Cancer Center who specializes in genitourinary cancers. “We’ll never know. A road not taken.”
Merck and Bristol say they haven’t abandoned IDO completely. Bristol’s Namouni calls it “a good target,” and the firm continues to study a combination in various metastatic cancers.
Merck says it is continuing pembrolizumab and Incyte’s epacadostat in two smaller, mid-stage lung cancer studies to “explore” whether the combination is more effective than pembrolizumab alone. The smaller scale “is a responsible way to definitely answer this question,” Merck spokesperson Eisele says via email.
Looking ahead, Pardoll advises caution testing the next wave of combinations without control arms, and in cancers where the first wave of immunotherapy has had some success. Synthetic cytokine drugs, recently the target of two major deals, could fit this description, he says.
Khushalani of the Moffitt Cancer Center says the IDO failure is “a sobering reminder that we need to truly understand the scientific rationale of combining Drug A with Drug B.” He’d like to see companies test the combinations “sequentially and smartly,” gathering more Phase 2 data before jumping from small, early stage trials straight to big Phase 3 tests.
The backlash against the glut of immunotherapy combinations hasn’t hit yet. But Michigan’s Alva believes advances in targeted therapies—drugs designed to hit specific mutations, like HER2 in breast cancer or ALK in lung cancer—could gain more prevalence as immunotherapy combinations scuffle. (Immunotherapy generally isn’t targeted toward genetic subtypes of tumors.)
“I would rather treat that way and have more certainty of benefit to the patient than a ‘hope for the best’ kind of thing,’” Alva says.
The clinical setbacks are opening cracks for other companies. Regeneron Pharmaceuticals (NASDAQ: [[ticker:REGN]]) is behind Merck, Bristol, and others, yet in January, Regeneron and partner Sanofi boosted investment in their first immunotherapy, cemiplimab, which is still experimental.
Regeneron’s head of oncology Israel Lowy says the company is trying to be precise, not “carpet bomb the universe with trials.” Regeneron has just over 20 studies underway starting where other immunotherapy firms haven’t ventured, such as cervical cancer and the skin cancers cutaneous squamous cell carcinoma and basal cell carcinoma. That will get Regeneron’s foot in the door, then it still plans to distinguish itself through combinations, Lowy says. (But it has stayed away from IDO.)
Regeneron is using PET scans and other technology to measure the impact of its cemiplimab in various patients. It’s important, Lowy says, to find out early who will and won’t respond.
“It’s impossible to test all the future combinations out there by enrolling hundreds of patients for each combination. We have to get smarter,” he says. “Look what happened with IDO.”
Image of malignant melanoma cells by Ed Uthman via a Creative Commons 2.0 license.
