NTRK Gene Fusions: Finding the "Golden Ticket" in Oncology

Benjamin P. Levy, MD

Understanding the molecular mechanisms that drive each patient’s cancer is becoming increasingly important to better tailor care as more highly effective agents targeting specific actionable biomarkers are developed and brought to market. These emerging precision agents include tropomyosin receptor kinase (TRK) inhibitors, a class that has been shown to be highly effective in patients with NTRK gene fusions.

However, NTRK gene fusions are rare, observed in <1% of patients with solid tumor malignancies.¹ That makes locating them akin to finding a golden ticket to Willy Wonka’s chocolate factory—an analogy referenced during an OncologyLive Peer Exchange^® discussion by precision medicine experts who specialize in diverse tumor types.

“The chocolate bars [ie, malignant tumors] kind of look alike, and you have to keep opening them up until you find one that has it [ie, NTRK gene fusion],” John L. Marshall, MD, said. “When you look across the whole spectrum, it’s rare, to the point that many physicians out there may never find one—they may never find the golden ticket. But there are enough of them out there [that] over the course of your career,... you probably will [find one] if you start looking and looking correctly.”

During the program, the panelists discussed some of the challenges they face when conducting molecular testing, including determining which patients to test, when to test, and how to test to ensure that no golden tickets, such as NTRK gene fusions, are missed. They also discussed the data surrounding TRK inhibitors and their experiences using these agents.

NTRK Gene Fusions

The TRK receptor kinase family plays an essential role in the development and function of the human nervous system. Binding of neurotrophins activates these 3 transmembrane proteins, which are encoded by 3 NTRK genes: TRKA by NTRK1, TRKB by NTRK2, and TRKC by NTRK3.² Dysregulation of the TRK pathway can lead to neural developmental disorders and various central nervous system (CNS) diseases but has also been associated with cancer when an NTRK gene fuses with an unrelated gene. The resulting altered NTRK fusion protein acts as an oncogenic driver, promoting cancer cell growth and survival. This finding has resulted in NTRK gene fusions emerging as novel targets for cancer therapy.

“The whole NTRK story starts in 1982, with the identification of the mutation in colon cancer,” Benjamin P. Levy, MD, said. However, the physiology of NTRK gene fusions took several decades to work out.

“Fusions are the ones we really are interested in. There are point mutations you see, usually in the kinase domain of the protein, but those don’t really appear to be affecting the biology and don’t seem to be affected by the treatment,” Philip Agop Philip, MD, PhD, FRCP, said. “The amplification, which is, again, very rare—there’s no evidence for that to really make it a target for treatment.”

The panelists emphasized that TRK inhibitors should be considered only for patients with NTRK gene fusions and not those with point mutations or amplifications, despite what patients’ molecular profiling reports might indicate.

NTRK fusion cancers can occur anywhere in the body, although the panelists noted that they are more commonly observed in some cancer types. A 2015 study that included 408 colorectal cancer (CRC) specimens reported a prevalence of about 0.5% for NTRK1 gene fusions.³ Marshall noted that in the CRC setting, almost all NTRK gene fusions have been found in patients with microsatellite instability (MSI).

“If you have an MSS [microsatellite-stable] colon cancer, it’s even rarer,” he said. The panelists noted that NTRK gene fusions have also been observed at elevated frequency in salivary gland tumors, bile duct tumors, sarcomas, and thyroid cancer, particularly metastatic thyroid disease. They have also been found to be almost ubiquitous in certain rare cancers, including infantile fibrosarcoma and mammary analog secretory carcinoma.¹ “There are certain cancers for which it is more common, but no cancer yet where we just decide not to check for it,” Marshall said.

Molecular Testing: Who, When, How

The panelists agreed that all patients with stage IV disease should receive broad profiling to determine which actionable biomarkers they may have. “The timing is important,” Philip said. “I believe it has to be done at the time of the diagnosis or whenever you find that the patient has recurrent or stage IV disease.” He noted that he manages a lot of patients with upper gastrointestinal (GI) and neuroendocrine tumors.

Marshall agreed and explained that patients’ tumor profiles change over time, particularly as they go through different rounds of treatment; thus, an actionable mutation that was not observed may be discovered upon retesting. “We have a case report right now of a patient who’s actually got small bowel cancer and has lived long enough for 4 different biopsies and resections. We’ve profiled each one of those, mostly through research. Each is different,” he said.

The panelists acknowledged that most mutations and other findings are unlikely to be actionable. “Many of the mutations we’re finding now are passenger mutations and mean nothing,” Marcia S. Brose, MD, PhD, said, indicating that better gene databases are needed to better identify links between specific molecular findings and disease.

Although performing a new biopsy each time there is a recurrence is ideal, the panelists noted that it is not always possible. “For metastatic [thyroid] disease, if we don’t know [the patient’s] profile, we get it. If we can, we try to get it on a new biopsy. It’s not uncommon for a thyroid cancer patient to have disease that cannot be biopsied, in which case we would run it on the original [biopsy specimen],” Brose said. She explained, however, that these patients typically do not receive a lot of chemotherapy or other treatments that are likely to cause major changes to their tumor’s molecular profile.

For tumors that cannot be biopsied and are likely to have major changes to their molecular profile, liquid biopsy may be considered. Marshall described one such case in a patient with a pancreatic mass that could not be biopsied despite 3 attempts. The decision was made to proceed with a liquid biopsy, which revealed a RAS mutation in the patient’s blood.

Levy described a similar experience in an elderly woman who was found to have an EGFR mutation that was then acted on. “I’m not advocating for liquid biopsies, but I think there’s an increasing role for them,” he said, indicating that it is yet unclear which alterations can be picked up in plasma compared with tissue.

Unlike Marshall and Levy, Edward S. Kim, MD, said he did not have success finding an actionable mutation when he used a liquid biopsy on a patient whose tumor could not be biopsied. “We still get more information out of the tissue testing, and I think we have to be very mindful and really stubborn about wanting to get that,” Kim said. As part of that, he indicated that, because of the heterogeneity with tumors, it is essential to ensure the biopsy specimen is large enough. Levy concurred and said that he asks his interventional radiologists and surgeons to supply him with “a boatload of tissue” for testing.

Once the tissue specimen is obtained, it can take weeks to obtain molecular profiling results, which can be challenging for patients and physicians. “I think [patients with lung cancer] get impatient, especially when you have a very nice I/O [immune oncology] triplet that you can give to anyone without testing. What we do at our center is a reflex testing on an [Ion] AmpliSeq profile,” Kim said. The Ion AmpliSeq technology consists of targeted next-generation sequencing (NGS) panels that can be designed to interrogate all bases across a gene or be focused on specific mutation hotspots.⁴ “We get that back in 3 to 4 days, and so we have everything we need quickly. Eventually, everyone does get a large genomic test,” he said.

TRK Inhibitors

The clinical efficacy of TRK inhibition in patients with NTRK gene fusions has been demonstrated in phase I and II trials, with larotrectinib (Vitrakvi) becoming the first agent approved by the FDA and entrectinib (Rozlytrek) receiving FDA breakthrough therapy designation and recent approval in Japan.^1,5-7 TRK inhibitors in earlier stages of clinical development include repotrectinib, LOXO-195, DS-6051b, and ONO-5390556.⁷

Larotrectinib

Table. Larotrectinib Efficacy in CNS Metastases With NTRK Fusions⁹

Larotrectinib is a highly selective TRK inhibitor approved by the FDA for adult and pediatric patients with advanced solid tumors (metastatic or surgery not feasible) that have an NTRK gene fusion and no known acquired resistance mutation and who have no satisfactory alternative treatment options or have progression following treatment.^1,8 Approval was based on data from 3 multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).^1,8 Collectively, larotrectinib had a 75% objective response rate (ORR), as determined by independent review committee, with 22% complete responses (CRs) and 53% partial responses (PRs).^1,8

The treatment was well tolerated by adult and pediatric patients, with the most common adverse effects (AEs; ≥20%) being fatigue, dizziness, GI effects (ie, nausea, vomiting, constipation, diarrhea), increased liver enzymes (ie, aspartate aminotransferase, alanine aminotransferase), and cough.⁸

“A third of [patients in these trials] had 3 or more lines of therapy.…Imagine if you’ve gone through the discouragement. When I trained, there was always that misconception that if you didn’t do well with the first [treatment], you were going to have less likelihood of doing well with the second and less likelihood with the third,” Mark Agulnik, MD, said. “To have a response rate this high for someone who potentially could have had 4 lines of other therapy is really encouraging for patients.”

The panelists noted another encouraging finding: Some PRs turned into CRs over time. “There’s a continued sort of efficacy that’s ongoing. You’re not just getting your first hit out. With chemotherapy, we’re used to that. If you’re treating a small cell, if you don’t see that response after the first 2 cycles, it’s not a good sign. Here, it’s quite the opposite. It’s just sort of ramping up and getting a little steam ahead of it,” Kim said.

Of note, larotrectinib also demonstrated efficacy in a subset of patients from the above pivotal trials who had NTRK fusion—positive cancers that involved the CNS, according to findings presented at the 2019 American Society of Clinical Oncology Annual Meeting. In 24 patients with intracranial disease, treatment with larotrectinib at 100 mg or 100 mg/m² twice daily induced responses in 3 of 5 (60%) evaluable patients with NTRK fusion—positive solid tumors with brain metastases and 5 of 14 (36%) evaluable patients with NTRK fusion—positive primary CNS tumors (Table).⁹

Entrectinib

Entrectinib is a potent inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK proteins that has been shown to penetrate the CNS to reach tumors in the brain and spine.⁵ Although not yet approved in the United States, entrectinib was approved in Japan on June 18, 2019, as a treatment for adult and pediatric patients with NTRK fusion-positive, advanced recurrent solid tumors.⁶

Approval was based mainly on data from the pivotal phase II STARTRK-2 study.⁶ In the study, entrectinib had an ORR of 56.9%, with a median duration of response of 10.4 months. It also had a high ORR of 50.0% in patients whose tumors had spread to the brain.⁶

The most commonly observed AEs included GI effects (ie, constipation, diarrhea, nausea), dysgeusia, dizziness, fatigue, edema, weight gain, anemia, blood creatinine increase, and dyspnea.⁶ Entrectinib is undergoing review in Japan as a potential treatment for ROS1 fusion—positive non-small cell lung cancer.⁶

“We found the STARTRK data to be a little more attractive because it had both ROS1 as well as ALK coverage. That might compromise some of the activity that we’re seeing with TRK, but it’s still early. Fifty-five patients— if you put 10 more on it could change to 80%,” Kim said. Levy pointed out that entrectinib does not work in the crizotinib (Xalkori)— refractory setting for ROS1. “It’s more for the crizotinib-naïve,” he said.

If the FDA ultimately approves entrectinib, it is unclear where this drug will fit in the arsenal of TRK inhibitors. “If we don’t have data for what happens for refractory patients or patients who acquire resistance, then there could be a harm done if you’re going to sequence them if they really shouldn’t be sequenced. And that would be my worry,” Agulnik said. “Until we have more data about sequencing, I do worry that people will end up using both, which may not be the right answer, and I think it’s too early to tell.”

Brose said that perhaps entrectinib could be moved to the first-line setting because it targets more actionable biomarkers than larotrectinib, but Philip suggested that this might lead to more mutations.

Concluding Remarks

Although much still needs to be determined in terms of testing for and treating patients with NTRK fusions, the panelists expressed excitement about how precision medicine is enabling such “golden tickets” to be discovered and acted on. “I think the winner is the patient here. Patients finally get all of us in a room together. We’ve never all sat in a room together because we all do different diseases, even all under the umbrella of medical oncology. We will start to learn from each other, and I think the bottom line is that the patients are definitely going to win from this,” Agulnik concluded.

References

1. Hong DS, Kummar S, Farago AF, et al. Larotrectinib efficacy and safety in adult TRK fusion cancer patients. Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 3122. meetinglibrary.asco.org/record/174938/poster.
2. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. doi: 10.1136/esmoopen-2015-000023.
3. Créancier L, Vandenberghe I, Gomes B, et al. Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma. Cancer Lett. 2015;365(1):107-111. doi: 10.1016/j.canlet.2015.05.013.
4. Ion AmpliSeq NGS panels for targeted sequencing. ThermoFisher Scientific website. thermofisher.com/us/en/home/life-science/sequencing/next-generation-sequencing/ion-torrent-next-generation-sequencing-workflow/ion-torrent-next-generation-sequencing-select-targets/ampliseq-target-selection.html. Accessed June 23, 2019.
5. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 10009. meetinglibrary.asco.org/record/170962/abstract.
6. Japan becomes the first country to approve Roche’s personalized medicine Rozlytrek [media release]. Basel, Switzerland: Roche; June 18, 2019. roche.com/media/releases/med-cor-2019-06-18.htm. Accessed June 23, 2019.
7. Morgenstern D. On the right TRK. Finding the next success in pediatric precision oncology. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL.
8. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA website. www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0. Updated December 14, 2018. Accessed June 23, 2019. meetinglibrary.asco.org/record/178338/slide.
9. Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 1, 2019; Chicago, IL. Abstract 2006. meetinglibrary.asco.org/record/174568/abstract.