Drug Targeting Genetic Mutation Works across All Tumor Types

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Three syringes stuck into an orange and white bull’s-eye

Targeted cancer therapies aim at shutting down tumor growth by blocking a specific genetic mutation.

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.”

It's groundbreaking to have such a consistent response across multiple cancer types.
David Hyman medical oncologist

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.

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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.

VIDEO00:00:40
Dr. David Hyman explains how basket studies are playing an increasingly important role in targeted therapy.
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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.

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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.”

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Comments

Commenting is disabled for this blog post.

Dear Tammy, the TRK fusion is part of the Foundation One test, so that information should already be available in your son’s records. If it’s not, you can contact our Patient Access Service to make an appointment where you can discuss additional testing. You can go to https://www.mskcc.org/experience/become-patient/appointment for more information.

Has this larotrectinib been used on ovarian clear cell cancer or gastric cancer? When do you expect FDA approval? Will it have an indication for previously chemotherapy treated tumors?Thank you

Dear Laura, there were some patients with a form of gastric cancer (GIST) in the trial that has reported data, but none with ovarian clear cell cancer. We can’t say exactly when the FDA approval will happen, but we expect it to be sometime next year. Thank you for your comment.

Thank you for this info. I have and represent a group of patients that have stage IV NSCLC, EGFR, exon 20 insertions. I read that with EGFR, it could still be that one could also have a TRK fusion mutation and therefore still be eligible. Can that be seen through a Guardant 360 testing?

Dear Araldo, the NTRK mutation may be detectable with some versions of the test. We recommend that the patients check with the doctor who ordered the test to find out which genes were included. Thank you for your comment.

What does the “FDA breakthrough status” mean in real world Childrens cancer? I have a son fighting Ewing’s.

Dear Danielle, we are sorry to hear about your son’s diagnosis. FDA breakthrough status means that the agency can grant priority review to a new drug if early clinical trials indicate that it may offer advantages over existing treatments. So in theory it means that the drug could receive approval more quickly, although this can vary on a case-by-case basis. Thank you for your comment, and best wishes to you and your family.

My daughter has gbm. We have stopped the Keytruda immunotherapy about a month ago at MSKCC because another tumor has appeared and is aggressively getting bigger. We did the Msk-impact and Sophie has ntrk1 and ntrk3 mutation. Please advise. She does meet all the criteria’s for this treatment.

Dear Nelson, we’re sorry to hear about your daughter. Please speak with her MSK team about this. They’ll be able advise you on next steps. Thank you for your comment, and best wishes to you and your family.