Larotrectinib Exhibits Sustained Efficacy and Favorable Safety in TRK Fusion Lung Cancer

Rapid onset and sustained responses translating to extended survival and a favorable toxicity profile were seen with larotrectinib (Vitrakvi) in patients with advanced lung cancer harboring NTRK gene fusions, including in those with central nervous system (CNS) metastases, according to results from an expanded cohort presented at the 2022 ASCO Annual Meeting.

These findings come from an analysis of 2 clinical trials of larotrectinib in this patient population (NCT02576431 and NCT02122913).

“In this larger dataset with longer follow-up, larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including patients with CNS metastases. These results support testing for NTRK gene fusions in patients with lung cancer,” wrote the study authors in the poster.

The highly selective, CNS-active TRK inhibitor, larotrectinib, has previously demonstrated an objective response rate (ORR) of 73% in a total of 15 investigator-assessed patients with lung cancer harboring NTRK gene fusions.

Within the analysis, 26 patients with TRK fusion lung cancer were enrolled, including 12 with known CNS metastases at baseline, and administered larotrectinib at a dose of 100 mg twice a day. Response was then assessed by an independent review committee (IRC) per RECIST v1.1.

Prior to enrollment, those included in the trial had their NTRK gene status determined by local testing, consisting of 81% NTRK1 (n = 21) and 19% NTRK3 (n = 5). Tumor histologies included in the trial consisted of non-small cell lung cancer (n = 24; 92%), atypical carcinoid (n = 1; 4%), and neuroendocrine (n = 1; 4%).

Additionally, 10 patients with CNS metastases at baseline were included. The median age for those enrolled was 51.5 years (range 25.0-76.0), and a median of 2 prior lines of systemic therapy were administered to patients, with a total of 19 individuals (73%) having received 2 lines or more.

For all evaluable patients per IRC enrolled, the duration of treatment ranged from 2.1 to 52.7+ months. Six patients had progressed at the time of the data cut-off, with all of them continuing treatment post-progression for 4 or more weeks.

Of the 23 evaluable patients per IRC, the ORR demonstrated was 83% (95% CI, 61–95), which consisted of 2 complete responses, 17 partial responses (PR), and 4 stable disease (SD). Median time to response was 1.8 months (range 1.5-7.3 months), and the ORR of the 10 evaluable patients who had baseline CNS metastases was 80% (95% CI, 44–97). Eight of these patients had a PR and 2 had SD.

Both the median duration of response (DoR) and progression-free survival (PFS) were not reached, (95% CI, 9.5- not estimable [NE]; 95% CI, 9.9-NE), and the 12- and 24-month rates were 72% and 67%. Additionally, the median OS was 40.7 months (95% CI 19.4-NE) with a 12-month OS rate of 90% and a 24-month rate of 72%.

Among the 10 evaluable patients who had CNS metastases, the DoR, PFS, and OS rates at 12 months were reported as 26%, 22%, and 78%, respectively.

As for safety, treatment-related adverse events (TRAEs) were mostly grade 1 or 2 (n = 23) with grade 3 or 4 TRAES reported in only 5 patients. Grade 3 or 4 TRAES included increased alanine aminotransferase, increased aspartate aminotransferase, hypersensitivity, myalgia, and increased weight. No treatment discontinuations due to TRAEs occurred within the trial.

Reference

Drilion A, Lin JJ, Kummar S et al. Updated efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer. J Clin Oncol. 2022; 40 (suppl 16): 9024). doi: 10.1200/JCO.2022.40.16_suppl.9024