The success of precision medicine rests upon the ability of cancer drugs to block specific genetic mutations. Several targeted therapies have shown promise against multiple cancers sharing the same mutation, but their effectiveness has generally varied greatly depending on where the cancer started. People with lung cancer, for example, may respond to a targeted treatment that has little effect for people with colorectal cancer, even if the tumors have the same genetic alteration.
Now landmark results show that a drug called larotrectinib has a dramatic antitumor effect in all cancers harboring a mutation called a TRK fusion. Data from three clinical trials demonstrate that larotrectinib works in the vast majority of both adults and children whose tumors have this mutation. Furthermore, its effects appear to be lasting in most cases.
“We are seeing the true potential of precision medicine come to life,” says David Hyman, Chief of the Early Drug Development Service at Memorial Sloan Kettering. “It’s groundbreaking to have such a consistent response across multiple cancer types. In addition to these results being potentially practice changing, they are also historic in another important way. This is the first cancer therapy of any kind to be developed simultaneously in adults and children.”
Dr. Hyman shared the data from these multisite clinical trials at the annual meeting of the American Society of Clinical Oncology.
The three studies involved a total of 55 people with TRK fusion cancers, ranging in age from four months to 76 years. Larotrectinib was used to treat 17 different tumor types. The overall response rate was 76%, with the longest recipient still on the treatment after 25 months. Among those who responded, 89% remained progression-free at the time the data were analyzed, meaning that the cancer had not gotten worse since starting larotrectinib.
An Inviting Target
TRK fusions occur when one of the NTRK genes (NTRK1, NTRK2, or NTRK3) becomes mistakenly connected to an unrelated gene. This can lead to relentless TRK signaling and uncontrolled growth. “Basically, these fusions act as an ignition switch for cancer,” Dr. Hyman explains.
Although the fusions are rare within most individual cancers, in aggregate they affect thousands of people with cancer each year, many of whom have limited treatment options. Dr. Hyman says that TRK fusions are an especially enticing drug target because they appear to arise early in the development of the cancer and remain even when the disease spreads to other sites.
“In a patient with a cancer that has a TRK fusion, it’s found in every cancer cell in that patient,” he says.
In addition, tumors with TRK fusions rarely have other well-known cancer-promoting mutations. That means a single drug could do the trick, without the cancer cells avoiding its effect by using a different growth pathway.
Larotrectinib was granted a Breakthrough Therapy Designation by the FDA in 2016 based on encouraging early results treating people with these fusions. The FDA applies this label when early clinical data indicate that a drug may demonstrate substantial improvement over existing therapies. The designation is intended to speed up the review process of these drugs.Back to top
Another Step Forward
The study represents progress for basket trials, a concept pioneered by Dr. Hyman and MSK colleagues in which participants are selected by mutation rather than tumor type. The team, including José Baselga, MSK’s Physician-in-Chief, published the data from the first basket trial in 2015. The results then were mixed: The drug was effective in some cancers but not others.
That’s what makes these new findings such a milestone.
“TRK fusion–positive cancers may be the first type that is more appropriate to define on the basis of a shared genetic mutation than by the organ in which it arises,” Dr. Hyman explains.
Because TRK fusions are present from the onset of cancer, detecting this mutation soon after a diagnosis will be especially important for larotrectinib to provide the most benefit. One way to do this is through a genetic-sequencing test, such as MSK-IMPACT™, which looks for alterations in more than 450 genes and can detect TRK fusions.
At present, many people lack access to this kind of sequencing, which is offered mainly at large cancer centers, so other methods could also play an important role. For example, special stains can easily be applied to tumor tissue to indicate mutations.
“I think it is incumbent upon us as a medical community to provide patients with as many options as possible to detect TRK fusions,” Dr. Hyman says.Back to top
The Next Step: Foiling Resistance
While many of the trial’s participants had long-lasting responses to larotrectinib, a few developed resistance over time. Researchers already have a jump on addressing this obstacle.
“When we studied the first six patients with acquired resistance, we found a new TRK mutation that was shared in nearly all cases, suggesting a common mechanism of escape — a way for the cancer to outsmart the pill,” says medical oncologist Alexander Drilon, who was MSK’s principal investigator for the trial.
After reaching this conclusion, the investigators worked with LOXO Oncology, which had already developed a second drug called LOXO-195 to target this mutation. They used LOXO-195 to treat one adult and one child whose tumors had developed the TRK resistance mutation to larotrectinib. Both responded to this new treatment, which brought their cancers back under control. The researchers are reporting these results today in the journal Cancer Discovery.
A clinical trial testing this next-generation drug is about to open. “This is a very uncommon, if not unique, approach in the drug development world — treating the same people who helped establish activity that could lead to the approval of a first-generation inhibitor with a second-generation inhibitor that addresses resistance to the first drug,” Dr. Drilon says.
Dr. Hyman points out that the concept of precision medicine seemed “wildly futuristic” just two decades ago. “Through a combination of advances in basic science, clinical practice, and genetic sequencing, and an evolving design of clinical trials, it’s becoming a reality.”Back to top