When thousands of cancer researchers from around the world gather in Chicago this weekend for the American Society of Clinical Oncology’s annual meeting, drugs that fight tumors by boosting a patient’s immune system will take center stage, as they have in previous years. But the stage is more crowded, as researchers have begun in earnest combining these immunotherapies into experimental cocktails, hoping to push quickly past the limits of the drugs currently in use as single agents.
With the frenzy to test combinations, some of immunotherapy’s biggest champions now worry that the field is moving too fast; that studies are not being designed with enough care; and that the glut of combination trials—some estimates put the number north of 1,000 at the moment—is bound to provoke a backlash.
Companies are committing huge sums of money to big clinical studies “based literally on [earlier] 20-patient results, because the field is so competitive,” says Drew Pardoll, the director of the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy. With such flimsy foundations, says Pardoll, “my concern is that the ratio of trials that fail to the ratio of trials that succeed is going to be too high, and there will be a lot of pullback in investment. And that will result in the baby being thrown out with the bathwater.”
This concern comes from a true believer. In the same interview, Pardoll says, “I’m convinced that overall we can at least double the number of cancer patients that immunotherapy can capture” with combinations.
Others are sounding similar alarms. “Cancer immunotherapy has its own rules that are different from the rules of normal physics,” says James Sabry, Genentech’s senior vice president of partnering. Genentech and its parent Roche are deeply invested in immunotherapy. Their drug atezolizumab (Tecentriq) has already been approved for certain bladder and lung cancers and is currently part of at least 50 combination trials, according to clinicaltrials.gov. Immunotherapy “is going to come back down to reality,” Sabry says.
To be sure, any new promising biomedical field will attract over-speculation by investors and a rush to capitalize by researchers and developers. And immunotherapy is promising, by any measure. Drugs called checkpoint inhibitors, which disrupt “checkpoint” proteins that tumors use to hide from the immune system, are changing the way a few cancers are treated. Six of these drugs have been approved for skin, lung, bladder, and other cancers, and in some cases they’ve produced uncharacteristically long-lasting results for patients at death’s door. They’ve already produced billions of dollars in revenue—the two leaders, nivolumab (Opdivo, from Bristol-Myers Squibb (NYSE: [[ticker:BMY]])) and pembrolizumab (Keytruda, from Merck (NYSE: [[ticker:MRK]])) generated about $2.7 billion combined in 2016—with billions more at stake.
But a majority of patients still don’t respond to them. In the rush to solve those puzzles, some see familiar patterns. At last year’s ASCO meeting, Anthony Tolcher, the director of clinical research at South Texas Accelerated Research Therapeutics, wondered about “a worrisome bubble.” He compared immunotherapy’s early success to that of cisplatin chemotherapy in the 1970s, which after an initial breakthrough was followed by “incremental improvements” over many years.
Independent investor Brad Loncar is so bullish on immunotherapy he created the world’s first index fund for the field: the Loncar Cancer Immunotherapy ETF (NASDAQ: [[ticker:CNCR]]). He isn’t fazed by the bubble talk. There will be high profile failures, just as there have been with single-agent programs, but he doesn’t think “bad results will chill future investment,” he says. With several kinds of immunotherapy making progress, such as live T cells and vaccines, “the underlying science is too promising to not get funded.”
Promising science has a way of smacking into unexpected obstacles of biology, however. Despite recent advances, researchers are only scratching the surface of the complexity of the human immune system—and how it interacts with tumors that have their own genetic complexities and survival mechanisms.
While large companies can afford to run a massive number of trials and deal with a few failures along the way, smaller biotechs vying for their attention have to think more strategically. Take Cambridge, MA, biotech Checkmate Pharmaceuticals, which is testing a drug, CMP-001, in combination with pembrolizumab. Mike Powell, a general partner at Sofinnova Partners and a Checkmate investor, says the company is trying CMP-001 in melanoma patients who are failing treatment with pembrolizumab because that trial is a “really tough test” and turning these patients’ disease around isn’t easy. “But when you see it, you know it is your drug doing it,” Powell says.
The only FDA-approved immunotherapy combination so far—two Bristol drugs, ipiliumab (Yervoy, which blocks the protein CTLA-4) and nivolumab (which inhibits PD-1)—provided a modest survival benefit for melanoma patients over nivolumab alone with significantly more safety problems, including side effects that were unexpected—such as the onset of diabetes.
There are other examples: Patients developed
