[Corrected 6/4/18, 1:53 a.m. ET. See below.] One year ago, the FDA made biomedical history. A cancer drug, pembrolizumab (Keytruda), was approved to treat tumors with a specific genetic fingerprint regardless of their location in the body.
It was the first tissue-agnostic approval of a cancer drug, and it was a big shift for the world’s most powerful drug regulator. “There’s now a precedent that the FDA will do this,” says Jill O’Donnell-Tormey, CEO and director of scientific affairs at the Cancer Research Institute in New York. “The agency has changed a lot.”
Drugs targeted to a cancer with a specific genetic variation date back to imatinib (Gleevec), which was approved in 2001 for the roughly 90 percent of chronic myelogenous leukemia cases with the Philadelphia chromosome. But there have been no other tissue-agnostic approvals since pembrolizumab, owned by Merck (NYSE: [[ticker:MRK]]), got the nod in 2017 to treat tumors with two related genetic problems that propagate a higher amount of mutations within a cancer cell’s DNA. (The two defects, called high microsatellite instability, or MSI-h, and DNA mismatch repair, or dMMR, are found in many cancers, most often colon cancer.)
[Updated with correct FDA deadline.] Loxo Oncology (NASDAQ: [[ticker:LOXO]]) could be next on the approval list. The FDA promised a speedy review, with a Nov. 26 deadline, of larotrectinib, Loxo’s treatment for a range of cancers driven by an abnormal fusion of one gene, TRK (tyrosine receptor kinase), to another. Loxo is also studying a second drug to fight a range of cancers with a different mutation called RET.
But only one other tissue-agnostic drug, from San Diego-based Ignyta (NASDAQ: [[ticker:RXDX]]), is in a so-called registrational trial—that is, the final clinical step before an FDA approval decision. Even with the FDA opening the door, there are big questions how fast it will herald a new era of genomic-first medicine.
First, the pembrolizumab approval wasn’t a great test case of a genetic fingerprint spread more evenly across a variety of cancers, says Keith Flaherty, director of clinical research at Massachusetts General Hospital Cancer Center. Half the patients in the data that triggered FDA approval had colon cancer, “not exactly tissue-agnostic,” he says. What’s more, pembrolizumab was already an established treatment with a strong safety record. Other drugs will likely have a higher safety bar to clear. (Flaherty is also founding director of Loxo and chairs its scientific advisory board, and is one of the leaders of the sprawling, government-funded NCI-Match study.)
Doctors on the ground, especially outside the richly-funded major cancer centers, will be tough to convince, says Edison Liu, a cancer genetics specialist. He is also president and CEO of The Jackson Laboratory in Bar Harbor, ME, which is helping doctors in Maine’s rural and community clinics better understand and use genomic information to guide patient care.
“They’ve heard a lot of promises that don’t always hold true,” says Liu. (A recent instance of results not matching hype is the fall of the IDO inhibitor class of drugs, as Ben Fidler reports here.)
For genomic-first cancer drugs to truly take hold, clinical trial structures will have to change. But shifting the paradigm is a massive undertaking, says Liu: “The process of testing the same drug against the same mutation across many tumors requires a different type of trial.”
That trial is called a basket study, and it is designed to test a drug across many cancer types with common genetic profile. Each cancer type gets its own “arm,” typically designed to recruit small numbers of patients and return results faster than the traditional randomized controlled trial. This new format has made some doctors and watchdogs uneasy. As a way to explore a drug’s effect across a broad range of related cancers, basket studies are “a useful first step” that should point drug developers toward “larger anatomical site-specific phase 3 trials,” wrote David Hunter of the Harvard T.H. Chan School of Public Health and Ralph D’Agostino of Boston University back in 2015, in a New England Journal of Medicine essay called “Let’s Not Put All Our Eggs in One Basket.” The authors worried about too much emphasis placed upon small sample sizes in each arm—“the potential for over-interpretation,” they wrote.
The Loxo review should be a fascinating test case. The FDA is considering its larotrectinib for approval based on data from 55 patients with 17 different types of cancer, including kidney, bladder, and lung; Loxo says larotrectinib shrank tumors consistently across the different types.
Loxo’s fate could send a signal to many other companies. Consulting firm Trinity Partners recently found 37 cancer basket studies in process, not including NCI-Match. Loxo and Ignyta have the only two that are registrational. However, nine of the 37 basket studies, while not explicitly touted as registrational, might provide enough data for an approval, according to Trinity’s report.
There is precedent for exploratory basket data leading straight to approval. In 2017, the FDA green-lighted the Roche drug vemurafinib (Zelboraf) for Erdheim-Chester disease, a rare blood cancer, based on 22 patients who took part in a basket study funded by Roche. No additional evidence was necessary.
But the rest of that study had mixed results, which were published in 2015. Vemurafinib was one of a few drugs already approved to treat the skin cancer melanoma that carried a mutation called BRAF V600 (pronounced BEE-raf). But the basket study, testing vemurafinib against 17 cancer types, held little evidence for a broad anti-BRAF approval, especially with a disappointing result in colon cancer, of which seven percent of cases are BRAF-related.
One lesson: Basket studies can detect early signals of a drug’s potential effectiveness in cancers that would otherwise fly under the radar. But a drug’s effectiveness against a mutation in one cancer won’t necessarily translate across other cancers. The study’s leaders, including David Hyman of Memorial Sloan-Kettering Cancer Center in New York, wrote at the time, “The histologic context is an important determinant of response in BRAF V600–mutated cancers.”
In other words, a cancer’s tissue of origin still matters. Insurers still think so, too, according to the Trinity report: “It appears likely that in the near term, payers will continue to evaluate therapies based on tumor-site-specific data within the tissue-agnostic clinical data package.”
Express Scripts is the largest drug-price negotiator in the U.S. When asked if it is paying for pembrolizumab prescribed for a patient with a high MSI readout, spokesman Brian Henry gives this answer: “For drugs that are developed based on
