Larotrectinib Efficacy Withstands Various NTRK Gene Fusions in Non-Primary CNS TRK Fusion+ Cancer

Patients with NTRK fusions demonstrate a significant increase in survival and quality-of-life when treated with NTRK inhibitors, according to Marc Ladanyi, MD.

Larotectinib (Vitrakvi) is 1 such inhibitor that is FDA approved option for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.¹

To evaluate this more in depth, 3 studies, NCT02122913, NCT02576431, and NCT02637687, examined patients with non-primary central nervous system TRK fusion cancer treated with larotrectinib. NTRK gene fusion data were determined by local molecular testing. In a pooled analysis of these studies, investigators looked at the NTRK fusion exon junction organization in patients with NTRK fusion cancer who were treated with larotrectinib.²

Findings revealed NTRK fusion exon junction data available for 80 patients from 14 different tumor types with a median age of 47 years (range 0.5-84 years). The overall response rate (ORR) for these patients was 82.5% (95% CI, 72.4 - 90.1). Patients had gene fusions involving NTRK1 (40%), NTRK2 (4%), or NTRK3 (56%), a pattern similar to that seen in the larger dataset. Patients had gene fusions involving NTRK1 (40%), NTRK2 (4%), or NTRK3(56%).

There was a total of 20 different NTRK gene fusions detected in these patients, 55% of which occurred in only 1 patient each. Larotrectinib was found to be equally efficacious no matter the variability of the fusion structure.

In an interview with Targeted Oncology^TM, Marc Ladanyi, MD, chief of the Molecular Diagnostics Service; William J. Ruane Chair in Molecular Oncology at Memorial Sloan Kettering Cancer Center, further discussed variability in NTRK gene fusions.

Can you provide a brief overview your research on the variability in NTRK gene fusions?

This was a survey of patients who had been enrolled in several clinical trials of NTRK inhibitor, where the exact structure of the and NTRK fusion was determined through molecular methods, usually RNA based but sometimes DNA based. The overall message is that there is a remarkable variability in the NTRK fusion partners. There's also variability for a given partner in how the 2 genes recombined, like for ETV6-NTRK3, there can be variations and exactly how they're fused.

It's important to have diagnostic methods that will pick up and track fusions regardless of what any track is fused to, regardless of the fusion partner. So far there's no evidence that different fusion partners are associated with different degrees of response to NTRK inhibitors.

This kind of study is only made possible by the fact that so many patients enrolled on clinical trials. As you can see from the waterfall plots, most of them got a benefit from the drug. We're grateful to the patients, and we're trying to do our best for them.

What were the key takeaways were from your presentation?

The key takeaways are that there is great variability and NTRK fusions including NTRK1, NTRK2, or NTRK3. Diagnostic methods should be able to pick up these fusions regardless of what the NTRK gene is fused to. Those are the critical take home messages, and the other message is that so far, we don't see differences in response according to which gene the NTRK gene is fused to.

What challenges still exist within this space?

I think we have to establish more standard ways of screening and detecting NTRK fusions and tumors. We need to be better at identifying patients where there might be a fusion and for most cancers, those are patients where the cancer doesn't contain some of the more common alterations like KRAS, BRAF, or EGFR. Those are what we call driver negative cancers. Those should be screened for any kind of fusions. We need to do the testing guided by an understanding of the biology.

In what ways have NTRK inhibitors benefitinhibitors benefited ed this patient population?

NTRK inhibitors have proven to be extremely effective and the initial response rates are very high. There are complete responses. It is a class of kinase inhibitors that is among the most potent. Like all single agent kinase inhibitors, the tumors do eventually figure out mechanisms of resistance. That is also seen with NTRK fusions, and there are second generation and NTRK inhibitors that work even in the presence of certain resistance mutations. For these patients, it's a huge advance and translates into a significant increase in survival and quality of life.

What can individuals expect to see within the future of this space? What are you most excited for?

I'm personally excited about taking the approaches 1 step further and doing combination therapies including combining the kinase inhibitor with other inhibitors that might target other pathways in the patient's tumor that are activated. That's something that is personally interesting to me. I think it's the next step beyond a single agent kinase inhibitors.

There's very little work on that approach so I'm being forward looking. It's something that we are currently looking at in my research lab and we are hoping to have the opportunity to also evaluate inpatients eventually.

What advice can you give on when and how to conduct biomarker testing for NTRK fusions?

Well, my advice would be to not be shy about having the patient's tumor sent for testing. There are many excellent commercial apps that provide this kind of testing. When all the tests come back negative, they should ask whether the tests were designed to pick up NTRK fusions or other kinase fusions because if they were not, then it may still be worth doing some additional testing, RNA based testing typically, whereas most of the front-line commercial testing is DNA based NGS. If that turns up nothing, it may be worth it to go to RNA based testing.

Again, you do have to approach it with an understanding of the typical profiles of mutations in every major cancer. In pancreatic cancer, for instance, the vast majority of pancreatic carcinomas have KRAS mutations. If you have a patient with pancreatic cancer, and the tests come back negative for KRAS mutations, that patient needs additional testing because they may have a kinase fusion that could be targeted. I think that commercial labs, if that is what is being used in community oncology, can also provide some guidance in terms of further testing.

REFERENCES:

FDA approves larotrectinib for solid tumors with NTRK gene fusions. News release. FDA. November 26, 2018. Accessed April 28, 2022.

Ladanyi M, Roy-Chowdhuri S, Ritterhouse L, et al. Variability in NTRK gene fusions does not appear to impact response to larotrectinib. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT545