Drug Targeting Genetic Mutation Works across All Tumor Types

By Jim Stallard,

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

Previous therapies targeting specific genetic mutations have had mixed results across different cancer types. A new drug, larotrectinib, appears to work in all cancers with a mutation called a TRK fusion. These results are potentially practice changing.

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
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.

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

Should patients who have done tumor testing (i.e. FoundationOne, GPS Cancer, MSK-Impact, etc) check to see if they have mutations in NTRK1, NTRK12, NTRK3 or does this TRK fusion require a different diagnostic test?

Dear John, all of the tests you mentioned look for this fusion gene. Thank you for your comment.

Is this drug already FDA approved, or is it still in clinical trial? Has it shown to be effective with colon cancer?

Dear Deirdre, this drug is still available only through clinical trials. Colon cancer was one of the cancers included in the studies mentioned in this article. Thank you for your comment, and best wishes to you.

Is there a list of cancers that exhibit the TRK mutation? Is this seen in solid tumors only, or are they present in blood cancers as well?

Dear Jim, we sent your question to Dr. Hyman, who responded that almost every solid tumor has had at least one case of a TRK fusion reported. TRK fusions have been reported in blood cancers as well, but they are much more rare. Among the 17 types of tumors that were included in these studies were colon, lung, pancreatic, thyroid, salivary, and gastrointestinal cancers, as well as melanoma and sarcoma. Thank you for your comment.

Was metastatic breast cancer included in the studies?

Dear Stephanie, the TRK fusion mutation can occur in almost every solid tumor, including breast cancer. Thank you for your comment.

My dad has Stage 4 NSCLC Adenocarcinoma, both PD-L1 and EGFR came out as negative, with bone mets to the sternum and left scapula, recently discovered brain mets to his right lobe. Was diagnosed in Feb of 2016. Has had three lines of chemotherapy. We are from the Philippines and will the new drug be good for him? I am desperate, please help. Thank you.

Dear Nikko, we're sorry to hear that your father is going through this. If his cancer has a mutation called a TRK fusion, then he could be a candidate for this drug. At this time, however, the drug is only available as part of a clinical trial. If your father would like to find out if there is a clinical trial in the Philippines, you can go to www.clinicaltrials.gov or contact the drug company, Loxo Oncology, to find out. If he is interested in coming to MSK in New York as an international patient, you can email international@mskcc.org or go to https://www.mskcc.org/experience/become-patient/international-patients for more information. Thank you for your comment, and best wishes to you and your family.

Would breast cancer ( primary tumor, invasive carcinoma, E+ P+ Braca neg) which metastasis to right ovary and possible bone possibly have the TRK fusion mutation and be a candidate for this drug?

Dear Ed, yes, it is possible for breast cancer to have a TRK fusion, and if it did, the patient could be a candidate for this drug. Thank you for your comment.

If your already a patient at MSKCC would your Dr. inform you of this trial?

Is prostate cancer among those with TRK fusion?
Does the genetic sequencing test require tumor samples or blood?

Dear Ronald, there were no prostate cancer patients in the studies discussed in this article, but it is possible for a prostate tumor to have one of these mutations.

While it is possible a liquid tumor biopsy (a blood test) could detect a TRK fusion, testing based on next-generation sequencing of tumor samples is currently the best approach to test for TRK fusions.

Thank you for your comment.

I'm a patient at Sloan Hospital and I have pancreatic cancer and I was wondering is this medicine works for pancreas to as well as the liver because they have found some noise in the liver I'm on a treatment Now call the peg 20 on the Dr Kenneth Yu and his staff and they're doing a remarkable job keeping me still alive and I just thank them and God everyday for the great work they do but anyway back to the question can you give me an answer on this

Dear Raymond, if your cancer carries a mutation called a TRK fusion, then this drug may work for you. We recommend you discuss this with Dr. Yu. Please note that the drug is not yet approved by the FDA and is only available as part of a clinical trial. Dr. Yu should be able to tell you if you the trial is right for you. Thank you for your comment, and best wishes to you.

Is the drug effective for kidney cancer?

Dear Andrea, this drug may be effective against kidney cancer if the tumor carries a TKR fusion mutation. Thank you for your comment.

Has this new drug been used with any prostate cancer patients?

Dear Tom, there were no prostate cancer patients involved in the studies discussed in this article. Thank you for your comment.

Has this new drug been used with any brain cancer patients? Specifically, those with astrocytomas?

Dear John, the data from the studies that have been presented so far did not include any patients with primary brain tumors, including astrocytomas. Thank you for your comment, and best wishes to you.

when expect FDA approved ?

How does one get tested for a TSK Mutation? Are there several methods?
Is this post tumor growth or can it be done on a healthy person to predetermine if he/she will develop the cancer later in life?

Dear Philip, the TRK fusion is included in the panel for MSK's tumor sequencing test (called MSK-IMPACT) as well as tests offered at other cancer centers. Its presence in tumors that have already been detected indicates that patients may benefit from drugs that target it. Thank you for your comment.

Congratulations on your breakthrough.
How bout working on other equally challenging conditions like migraines, neuropathic pain, and osteoarthritis.

Dear Dave, as a cancer center, MSK's efforts are focused on cancer, but there are many other research institutions working on these diseases. Thank you for your comment.

My 17 year old son has ewing sarcoma. First diagnosed in 2014 with a tumor on his heart that metastasize to the lungs. After chemo he was cancer-free for a year it returned and was on the backside of his heart and metastasize to his toe. 31 rounds of radiation to the chest and he was cancer-free from October 2016 two October 10th 2017. He was just diagnosed last week again. It has returned to his chest he has a tumor next to his trachea it has not metastasize. Does this new drug work on Ewing's sarcoma? If so how do you get in a clinical trial.

Dear Tammy, we're very sorry to hear about your son's recurrence. The drug that's discussed in this story works on tumors that have a mutation called a TRK fusion, so if your son's tumor carries this mutation the drug may be right for him. MSK has a number of other trials for Ewing sarcoma as well. If you would like to bring your son here for a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you and your family.

Dear Dr. David Hyman, I just saw a news about the new drug targeting genetic mutation. My 15 year old nephew John has an acute myloid luekemia and all treatments have failed and his doctor told us that there is treatment option left. Will you please review his medical record to see if he can get this new drug? I believe John's doctor has done the gene analysis. He was being treated at the Fairfax, VA Children's hospital and also National Children's hospital in Washington D.C. I will look forward to your reply. Thank you!

Dear Yun, we're very sorry to hear about your nephew's diagnosis. To learn more about bringing him to MSK for a consultation, you can go to https://www.mskcc.org/experience/become-patient/appointment. The number to call for an appointment is 800-525-2225. Thank you for your comment, and best wishes to you and your family.

My mother has been diagnosed with small cell lung cancer. Is there any chance the larotrectinib would be effective if she has the TRK fusion?

Dear Mike, we're sorry to hear about your mother's diagnosis. If her tumor carries the TRK fusion mutation, she may qualify for treatment with this drug. If she would like to come to MSK for a consultation to learn more, the number to call is 800-525-2225. You can go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you and your family.

My husband was diagnosed with esophageal cancer in June, 2016. He underwent 6 weeks of chemotherapy and radiation and then had surgery. In January, 2017 they discovered that the cancer had spread to his lung, liver, brain, and back. Would this MSK-IMPACT testing be a routine test performed on a biopsy they took from his lung? He is currently being treated at the University of Cincinnati in Cincinnati. We are looking for anything possible at this point. Do you think this clinical trial might work for him? Should we ask his oncologist if this genetic test has been performed? Thank you for any information you can share with me.

Dear Sandy, we're very sorry to hear about your husband's diagnosis. MSK-IMPACT is a test that is done exclusively at Memorial Sloan Kettering, but it's possible that his doctors in Cincinnati may have done a similar analysis of his tumor sample. We recommend that you ask his healthcare team about this. Thank you for your comment, and best wishes to both of you.

I have lograde lyomyosarcoma...caused by morcellation..hysterectomy.....have had chemo..all it did was make my hair fall out...the tumors came back after they were removed....two more surgeries..tumors removed, except two on my bladder..what would I need to do, in order to see if this might be helpful for me.

Dear Molly, we're very sorry to hear about your diagnosis. If your tumor carries the TRK fusion mutation, then it's possible that you could benefit from this drug. We recommend that you discuss with your healthcare team whether genetic analysis was done on your tumors that have already been removed. If you would like to come to MSK for a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.

Is this drug applicable to Gastrointestinal Stromal Tumor (GIST) of the esophagus or, if a patient is currently responding well to imatinib, is that drug (i.e. Gleevec) considered to be the best drug currently available? If and when the GIST develops resistance to imatinib, but surgery is considered to be too risky, are there any clinical trials for alternate drug treatment?

You mentioned on June 27 that the drug has rarely been effective for blood cancers. I am in semi remission with multiply myeloma since 2010. Has the drug been used in this instance?

Dear Louise, multiple myeloma was not included in the data that have been reported so far. However, Memorial Sloan Kettering does have a number of trials for multiple myeloma with different drugs. If you would like to make an appointment to learn more, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment, and best wishes to you.

My mother is currently a patient at Sloan Kettering, stage 4 Pancreatic cancer and she is enrolled in a clinical trial and has had genetic evaluation done, how will this effect her?

Dear Jackie, we recommend that your mother discuss this with her healthcare team at MSK. Thank you for your comment, and best wishes to both of you.

My fiancé has been diagnosed with a rare form of cancer called Adenoid Cystic Carcinoma, it is resistant to Chemotherapy and there are very little treatments for this type of cancer. Were any people with this rare form of cancer in this clinical trial? Can we ask our doctors here for this TRK test?

Dear Lana, we're sorry to hear about your fiance's diagnosis. MSK researchers are looking at the genetic causes of ACC, and may be able to offer trials, depending on the mutations found in his tumors. If your fiance would like to come here for a consultation, he can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. If you are not in the New York City area and he is not able to travel here, you may want to consult the National Cancer Institute's list of designated cancer centers to find one closer to you. You can find it at https://www.cancer.gov/research/nci-role/cancer-centers/find.

You may also want to reach out to the ACC Research Foundation. You can find them at https://www.accrf.org/.

Thank you for your comment, and best wishes to you both.

Can this test for the mutation be done by my son's oncologists or does it have to be done at MSK?

Dear Tammy, there are a number of genomic sequencing tests that include the TRK fusion. This is something that you could discuss with your son's oncologist. Thank you for your comment, and best wishes to you and your family.

Thank you for answering my questions. I have one more. If my sons oncologists can test for that fusion, do they need to take a piece of the tumor out to do so. Also, they have sent a piece of tumor to Foundation One last year. Should they send this one to test for that fusion or does MSK accept tumors and test for it.

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