One year ago, on the eve of the yearly American Society of Clinical Oncology conference, a new class of drugs called IDO inhibitors seemed poised to become the next big thing in cancer care. They were a top choice to combine with the powerful but limited immunotherapies that have emerged this decade to fight many types of cancer. IDO inhibitors would broaden immunotherapy’s reach, the thinking went.
“Everything is starting to come together for these IDO inhibitors,” a University of California, San Francisco oncologist said at the time.
Now everything is coming apart. After immunotherapy leader Merck (NYSE: [[ticker:MRK]]) reported in April a failed Phase 3 melanoma study of its pembrolizumab (Keytruda) paired with an IDO inhibitor from Incyte (NASDAQ: [[ticker:INCY]]), several companies with billions of dollars invested have scaled back IDO-immunotherapy regimens or stopped them altogether. Merck, for example, canceled four more late-stage trials and downsized two others. Merck’s chief rival Bristol-Myers Squibb (NYSE: [[ticker:BMY]]) shuttered three Phase 3 studies.
There were warnings ahead of time. Speaking with Xconomy last year, Drew Pardoll, the director of the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, called the IDO excitement “irrational exuberance.”
As buzz about the next promising drug combinations circulates this weekend at ASCO, the IDO story looms large. Cancer experts say the episode is a prime example of drug developers moving too fast and, at times, without scientific rationale or biological insights that might better predict success.
There’s pressure from many sides. Patients facing grim prognoses are now well aware of the hope that cancer immunotherapy brings. The first wave of these drugs, known as checkpoint inhibitors, can provide stunning long-lasting benefits but only in a minority of patients, which creates more pressure to help more people.
“We are facing a really devastating disease,” adds Fouad Namouni, Bristol’s head of oncology. “As drug developers, our obligation is to move with a sense of urgency.”
Drug makers are in fierce competition, and investors are clamoring for more successes like Merck’s pembrolizumab ($3.81 billion in sales in 2017) and Bristol’s nivolumab (Opdivo, $4.95 billion); smaller companies like Incyte have dreams of their drugs breaking through as the right combination partner for the current blockbusters.
“It’s all economics and hope and people dying, and drugs that don’t just give you remission, they give you a very long-term benefit,” says David Nanus, the chief of hematology and oncology at Weill Cornell Medicine and New York-Presbyterian. “There’s a lot of tension there.”
Many in the field, however, say the IDO failure is a sign to slow down. First step comes this weekend at ASCO: Examine what happened with IDO. Merck and Incyte will present details from their failed melanoma study, ECHO301.
Next, do more basic research that builds a case for different combinations, and test those combinations in more precise groups of people. Make sure there are markers to judge the drug’s effects. ECH0301 didn’t measure levels of IDO expression, for instance, to help predict who might best respond to treatment. Bristol hasn’t been measuring IDO levels either, according to spokesperson Audrey Abernathy. Should that change going forward? Some tumors “are screaming with IDO,” Pardoll says. “Will IDO inhibitors work better in those tumors? I don’t know. But the reality is [ECHO301] did not incorporate [those] biomarkers.”
Additionally, experts interviewed by Xconomy also agreed: Don’t completely scrap IDO. “Too many people took that failure as, ‘Let’s just all drop IDO.’ The biology and the science say it’s an important target,” says Padmanee Sharma, co-director of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center in Houston. “Just go back to the drawing board and think about” running a different study, she says. “In oncology we’re used to failures.”
Immunotherapy has already come a long way. Four years ago at ASCO, there was only one FDA-approved agent, a so-called checkpoint inhibitor called ipilimumab (Yervoy) from Bristol. Since that time, the FDA has approved several other checkpoint inhibitors for cancers of the skin, lung, bladder, kidney, and more. For some cancers, these drugs have worked their way forward from last-ditch options to frontline treatments. When it works, immunotherapy can save a patient on death’s door with a longer-lasting response than previously thought possible—years, in some cases.
The problem is typically some 20 percent of people respond to immunotherapy. Combinations are seen as key to boosting those numbers, and biopharma companies have spent billions in acquisitions, alliances and more to find the best mix. That’s led to more than 1,000 combination trials. Merck is running more than 750 trials with its immunotherapy pembrolizumab, and over 400 of them are combination studies, according to spokesperson Pamela Eisele. Bristol has 150 combination studies underway, says spokesperson Abernathy.
As Xconomy reported in May 2017, cancer experts have been concerned that a glut of trials, many redundant, was bound to lead to failures and possible safety problems and provoke backlash.
Since then, the field has seen highs and lows. The highs have come recently in lung and kidney cancer, for which “these combinations are going to be practice-changing,” says Pardoll.
Another good sign is mild side effects for some immunotherapy agents, opening the possibility of combining not just two, but three or four drugs together. “That’s the direction we need to move in order to have better responses for our patients,” Sharma says.
But several combinations have flopped. Patients in two Phase 3 multiple myeloma studies died. Trying to catch up in the immunotherapy race, Johnson & Johnson (NYSE: [[ticker:JNJ]]) had to halt and dial back several studies. Roche and Exelixis (NASDAQ: [[ticker:EXEL]]) had bad news in colorectal cancer, and two AstraZeneca immunotherapies failed a big lung cancer test.
The IDO collapse is the biggest, and notwithstanding the early naysayers, the most surprising of the failures. IDO is an enzyme produced by tumors that suppresses the body’s immune cells, enabling cancer cells to evade detection. Early results combining IDO and checkpoint inhibitors were encouraging. In advanced melanoma, in fact, the effects on tumors were “unprecedented” without adding noticeably more side effects, says Nikhil Khushalani, a melanoma specialist and vice chair for the Department of Cutaneous Oncology at Moffitt Cancer Center in Tampa, FL.
Merck and Bristol extended their long-running immunotherapy battle to IDO combinations. Merck pivoted last year into seven late-stage trials, the first in melanoma. Bristol followed fast in November with its own studies, among them a 700-patient melanoma trial.
Despite the excitement, Pardoll of Johns Hopkins saw two particularly worrisome factors. One is that
