lung scarring after receiving combination of AstraZeneca’s PD-1 blocker durvalumab (Imfinzi) and EGFR inhibitor osimertinib. A tandem of ipilimumab and vemurafenib, a so-called MEK inhibitor, led to a spike in liver enzymes, indicative of potential liver damage.
“We learned from the [ipiliumab/nivolumab combination] that the frequency of adverse events increased” with combination immunotherapy, says Padmanee Sharma, the co-director of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center in Houston. “We have to make sure that we’re aware that these therapies do have some issues regarding safety,” she says, and warn patients to contact their clinicians immediately when problems occur.
Cost is another concern. Single checkpoint blockers alone cost north of $100,000 per patient, per year. What will combinations cost, and will they be good enough to justify the cost? For the ipiliumab/nivolumab combination for melanoma patients, the answer is no, according to a paper published last week in the peer-reviewed Journal of Managed Care & Specialty Pharmacy.
Yet with billions of dollars at stake, time is of the essence for pharma companies beholden to shareholders. PD-1 blockers look promising in a variety of cancers and multiple companies have them. “It’s become this big race to be first to market, and more importantly, trying to have a unique hook,” says ISI Evercore analyst Umer Raffat. That means having the best drug to pair with a PD-1 blocker that others don’t, and running as many tests as quickly as possible. As Genentech vice president of cancer immunology, Ira Mellman, reportedly said at the Society for Immunotherapy of Cancer’s annual meeting last November, the industry is throwing “plates of pasta against the wall, and hoping something is going to stick.”
That’s a concern, says MD Anderson’s Sharma: “I want to make sure that the combinations are really being thought about rationally, that we’re not just throwing Drug A and Drug B together because the companies own Drug A and Drug B.”
Researchers need to unearth more biomarkers—molecular and genetic signatures that may predict a drug response—to help design smarter trials. Trouble is, it’s very difficult to find immunotherapy biomarkers. One breakthrough came last week when the FDA approved pembrolizumab for tumors that have specific genetic alterations, regardless of what organ they originated in—the first approval of its kind in the agency’s history. But that was based on years of work starting at Johns Hopkins University. Right now these insights are the exceptions.
“We really don’t understand the mechanisms” of why these drugs are or aren’t working, says Jill O’Donnell-Tormey, CEO of the nonprofit Cancer Research Institute. “How do you prioritize [drug combinations] without getting that biomarker or that mechanism and really understanding, ‘Will this work?’”
One thing that would help, says Dana-Farber Cancer Institute president and CEO Laurie Glimcher: more funding for studies at academic centers (like Dana-Farber, it should be said) to analyze what’s happening with patients’ immune systems in and around a tumor when they receive an immunotherapy. This would help researchers understand the differences between those who respond to treatment and don’t.
Insurance companies won’t cover those tests, Glimcher says, so the money has to come from philanthropic sources or the drug industry. “If pharma companies are really interested in figuring out new drug targets and new combinations, then we have to make the case that they should be putting more funding into these trials,” she says.
Pardoll of Johns Hopkins says new biopsy technologies are providing better looks at the proteins tumors produce at high levels, like PD-L1. Better methods to analyze a patient’s T cells, the foot soldiers of the immune system, from blood samples are also emerging.
O’Donnell-Tormey would like to cut down on the glut of clinical studies by fostering a collaborative approach. The CRI, for instance, has what it calls a “clinical accelerator.” Scientists around the world work together to identify high-upside combinations; CRI and those drugs’ owners then work together to design studies funded by the venture philanthropy fund that backs CRI. The non-profit has funded over $60 million in clinical trials through this approach.
“Instead of having 50 different companies work on the same thing, it’d be nice if there was some kind of ecosystem where everybody kind of works together,” O’Donnell-Tormey says, before adding: “I guess this is my not-for-profit naiveté.”
More than likely, the frothiness will continue. This weekend at ASCO, the spotlight will shine on a class of treatments called IDO-1 inhibitors. These drugs are being closely watched because they may lead the coming wave of combination therapies. A drug from Incyte (NASDAQ: [[ticker:INCY]]) is being tested with either Merck’s pembrolizumab or Bristol’s nivolumab in a slew of studies, and leads the pack. Pardoll calls the data it’s achieved so far, all from early-stage trials, encouraging, but by no means a guarantee of future success. Yet the drug, Loncar notes, is being valued “somewhere in the range of $10 billion to $15 billion.”
With a laugh, Pardoll says: “You might call that irrational exuberance.”
