Larotrectinib Yields Promising Efficacy in NTRK+ Lung Cancer, Is Active Against CNS Metastases

The TRK inhibitor Larotrectinib (Vitrakvi) yielded not only durable responses, but also induced prolonged survival benefit and a favorable safety profile in patients with NTRK fusion–positive lung cancer, according to Jessica J. Lin, MD, a medical oncologist specializing in lung cancers. She added that the agent was also active in patients with baseline central nervous system (CNS) metastases.

Results from an analysis of patients from 2 clinical trials, a phase 1 trial (NCT02122913) and the phase 2 NAVIGATE trial (NCT02576431), showed that among 15 evaluable patients with NTRK fusions, the overall response rate (ORR) with larotrectinib was 73%, with treatment duration ranging from 0.03 to 51.5 months. Additionally, all patients reported tumor shrinkage.

Moreover, at 12 months, the progression-free survival rate was 65%, the overall survival rate was 86%, and the 12-month duration of response (DOR) rate was 81%. Although there were no unexpected safety signals, and most adverse effects (AEs) were grades 1 or 2 in severity, 2 patients reposted experiencing grade 3 treatment-related AEs, including myalgia, hypersensitivity, and weight increase.

“What was affirmative was the continued robust efficacy and the safety [demonstrated by] this drug,” Lin said. “[We now have] an increasing level of experience with targeted therapies in advanced lung cancer, and these small molecule TKIs are turning out to be increasingly effective for patients, [as well as] generally better tolerated than other [treatments, such as] chemotherapy. That is what is being seen with the larotrectinib data as it continues to mature.”

In an interview with OncLive^®, Lin, an assistant professor of medicine at Harvard Medical School, attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital, and attending physician in the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital, discussed the impact of larotrectinib in patients with NTRK fusion–positive lung cancer, and the importance of further understanding mechanism of resistance to targeted therapies.

OncLive^®: What's the importance of screening for NTRK fusions?

Right now, we are fortunate to have 2 FDA approved small molecule inhibitors targeting TRK, larotrectinib and entrectinib [Rozlytrek]. There is data that has demonstrated that both drugs are highly effective, and generally well tolerated. However, it is not helpful to have 2 highly effective drugs if we are not identifying patients who have NTRK gene fusions, [which is where] everything starts. The first step is the identification of patients for whom these targeted therapies could be a viable option. I cannot emphasize enough the importance of screening for NTRK gene fusions for patients who are newly diagnosed with advanced lung cancer.

What methods were used to conduct a longer-term analysis and what did that analysis show?

At the 2021 ASCO Annual meeting, updated [data from the] the long-term efficacy and safety analysis for patients with NTRK gene fusion-positive metastatic lung cancer who were treated with larotrectinib was presented. This [included] data from 2 clinical trials; an integrated analysis from the adult phase 1 trial, and the adult and adolescent phase 2 NAVIGATE trial. There were 20 patients included in this analysis, approximately half of [whom] had baseline brain metastases and most were heavily pretreated.

The key finding was that larotrectinib was highly effective in this patient population. There were 15 patients who had evaluable disease at baseline, and among those patients, the ORR was 73%. [Notably], these responses were durable. After a median follow up of 17.4 months, the median DOR was approximately 34 months.

Another noteworthy finding from the integrated analysis was that [the agent] was CNS active. Among 8 patients with baseline CNS metastases who had evaluable disease, the ORR was 63%. That is important because brain metastases is a major problem in terms of [available] treatment options, quality of life, and survival in patients with advanced lung cancer.

Finally, this updated analysis continues to support that the drug is very well tolerated. Most of the associated AEs reported were grades 1 and 2, and there were no unexpected safety signals that came up with a longer follow-up. Only 10% of patients required dose reduction, and importantly, there were no treatment discontinuations that were attributed to treatment-related AEs.

What clinical impact will this data have?

[These data] provide increasing confidence in thinking of these TRK inhibitors are in line with other targeted therapies, that are more familiar, such as EGFR and ALK inhibitors. The continued efficacy and safety that we are seeing with mature data really provides comfort in using larotrectinib or TRK inhibitors in general, for patients with NTRK gene fusion-positive lung cancer.

What we must drive home now that we have these data in hand, is that the NTRK gene-fusion screening has to be performed. [Much of this] must come from the physician side, but patients [must] also be aware that there are these highly effective drug options available [to them], and [ask] when they are seeing their physician if the appropriate testing have been performed, and advocate for having next-generation sequencing [NGS] testing at their initial diagnosis.

What next steps would you like to see?

The first important next step is going to be expanding our understanding of mechanisms of resistance to the currently available TRK inhibitors, larotrectinib and entrectinib. In targeted therapies [in general], the major challenge is acquired resistance to these drugs as tumors evolve and develop, leading to disease relapse. Only by understanding why that happens can we then begin to develop effective strategies [against it].

The second important next step is thinking about combination strategies. NTRK gene fusions are not only found at initial diagnosis, but also at acquired resistance to other targeted therapies. For example, NTRK gene fusions have been identified in tumors with resistance to EGFR inhibitors, like osimertinib [Tagrisso]. [Additionally], there was a recent report of an NTRK fusion identified in a [patient with] RET-rearranged lung cancer with resistance to selpercatinib [Retevmo]. It is important to understand that while these actionable targets are generally mutually exclusive at initial diagnosis, at acquired resistance to targeted therapies there can still be overlap, and we have these effective therapies available that we could potentially think about combining.

Is there anything you wanted to emphasize?

The experiences so far with the TRK inhibitors are key in highlighting 2 important points in lung cancer. One is that there are actionable gene targets that are rare in each disease entity but shared across various tumor types. When there are targets like this, it is important when looking at trial design to consider the basket trial design, and to enroll patients with a particular gene alteration of interest, regardless of their tumor histology.

The second point is that gene specific testing at initial diagnosis may not be as helpful as the NGS panel, where we are able to concurrently test for multiple actionable alterations. As years go on, we are seeing an increasing number of actionable targets. It is only with NGS that we can make sure that no actionable target is missed for a given patient.

Reference

1. Lin JJ, Kummar S, Tan DSW, et al. Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer. J Clin Oncol. 2021;39(15):9109. doi: 10.1200/JCO.2021.39.15_suppl.9109