Larotrectinib Continues to Demonstrate Durable Responses in TRK Fusion Cancer

Alexander E. Drilon, MD

In an expanded analysis with extended follow-up of efficacy data pooled from 3 clinical trials (NCT02576431, NCT02122913, and NCT02637687), larotrectinib demonstrated rapid and durable responses, extended survival benefit, and a favorable safety profile.¹

These findings were presented in a poster during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting by Alexander E. Drilon, MD of Memorial Sloan Kettering Cancer Center, and highlight the importance of neurotrophic tyrosine receptor kinase (NTRK) gene fusion testing in patients across various cancer types.

Investigators examined patients with non-primary central nervous system (CNS) TRK fusion cancer to determine the efficacy and safety of larotrectinib, a first-in-class, highly selective, CNS-active TRK inhibitor, in this patient population.

At the time of the data cut-off, 244 patients were treated with larotrectinib across 25 different tumor types who were deemed to be evaluable for efficacy by independent review committee (IRC). The most common tumor type included was soft tissue sarcoma (43%), followed by thyroid (11%), lung (10%), salivary gland (9%), and colorectal (7%).

Those examined in the updated dataset were male and female patients ranging from 0.1-84 years of age. Many had an ECOG or an equivalent Lansky performance status of 0-1 (52% and 36%, respectively), and the median number of prior systemic therapies patients had was 1 (range, 0-10). NTRK1 gene fusions were found in 46% of patients (n = 113), NTRK2 in 3% (n = 7), and NTRK3 in 51% (n=124). Further, 27%, 28%, and 45% of patients had 0, 1, and 2 or more prior lines of systemic therapy, respectively.

The overall response rate (ORR) was 69% (95% CI; 63-75) with 64 patients having a (26%) complete response (CR), including 13 (5%) who had a pathological CR. There were 104 patients (43%) who had partial response, 41 (17%) with stable disease, 20 (8%) with progressive disease, and 15 (6%) who were not determined.

The ORR of the 18 patients who had known baseline CNS metastases evaluable per IRC was 83% (95% CI, 59-96). Including adult patients (n=157), the ORR was 64% (95% CI, 56-72) with a median duration of response (DoR) of 41.7 months (95% CI, 32.5-NE) at a median follow-up of 28.5 months.

In regard to the treatment duration, median time to response was 1.8 months (range, 0.9-16.2) with the duration of treatment ranging from 0.1 to 67.9 months. Median DoR was 32.9 months (95% CI, 27.3-41.7) with a median follow-up of 28.3 months.Additionally, the median PFS was 29.4 months (95% CI 19.3-34.3) and median follow-up was 29.3 months. The median overall survival (OS) was not reached at the time of the median follow-up of 32.2 months. However, the 48-month OS rate was 64% (95% CI 55-73).

In order to exclude the possible confounding effect of ongoing enrollment on median DoR, an exploratory analysis was also conducted in a subset of 164 patients with a median follow-up of 28.1 months. The ORR in this subset of patients was 74% (95% CI 67–81), the median DoR was 34.5 months (95% CI 27.6–43.3), and the median follow-up was 34.1 months.

In regard to safety, treatment-related adverse events (TRAEs) were mainly grade 1 or 2, with no new or unexpected safety signals seen. However, 53 (20%) patients had grade 3 or 4 TRAEs, including an alanine and aspartate aminotransferase increase, a neutrophil count decrease, lymphocyte count decrease, and more.

“Things to watch out for with TRK inhibitors include neurologic side effects such as dizziness, weight gain, and withdrawal pain when these drugs are temporarily or permanently discontinued. But overall, despite the longer follow-up and increase of the total number, there were no new or unexpected safety signals observed with larotrectinib,” stated Drilon during a presentation of his poster.

A total of 5 (2%) patients ended up discontinuing treatment due to TRAEs consisting of emotional poverty, hypoventilation, neutropenia, decrease in neutrophil count, alanine aminotransferase increases, and aspartate aminotransferase increases, all occurring in one patient each.

“Larotrectinib, regardless of tumor type in adult and pediatric and adult cancers with an NTRK fusion, can demonstrate very robust responses and durable responses in patients with TRK fusion cancer,” said Drilon.

_Reference:

_{Drilon AE, Hong DS, M Martinus van Tilburg et al. Long-term efficacy and safety of larotrectinib in a pooled analysis of patients with tropomyosin receptor kinase (TRK) fusion cancer. J Clin Oncol. 2022;40 (suppl 16): 3100. doi: 10.1200/JCO.2022.40.16_suppl.3100}