Larotrectinib Data Further Demonstrate Strong Efficacy in TRK+ Tumors

David S. Hong, MD

Larotrectinib, which has been FDA approved since late 2018, continued to show strong tumor-agnostic efficacy in patients with TRK fusion—positive cancers, according to results from an integrated analysis of 3 clinical trials published in The Lancet Oncology.

In the analysis, larotrectinib induced an objective response rate (ORR) of 79%(n = 121; 95% CI, 72-85) in 153 evaluable patients across multiple tumor types. The ORR comprised a complete response rate of 16% (n = 24) and a partial response rate of 63% (n = 97). Stable disease was achieved as best response in 12% of patients, leading to a 91% clinical benefit rate.

“These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumors for which larotrectinib is highly active,” lead study author David S. Hong, MD, The University of Texas MD Anderson Cancer Center, and coauthors wrote. “Testing for TRK fusions in the clinic remains crucial to identify patients likely to benefit from treatment with this agent,” added Hong et al.

Overall, the integrated analysis comprised 159 patients enrolled in the primary and supplementary cohorts in an adult phase I trial (n = 12), the phase I/II SCOUT pediatric trial (n = 50), and the phase II adult/adolescent NAVIGATE basket trial (n = 97). Patients were enrolled and treated with larotrectinib between May 1, 2014, and February 19, 2019

Among the 159 patients, the median age was 43 (range, <1 to 84). The cohort consisted of 52 (33%) pediatric patients and 107 (67%) adult patients, with an almost even distribution between male and female patients. The ECOG performance status was 0 (48%), 1 (38%), 2 (12%), or 3 (2%).

Tumor types represented in the analysis population included infantile fibrosarcoma (18%), gastrointestinal stromal tumor (3%), other soft tissue sarcomas (23%), thyroid cancer (16%), salivary gland cancer (13%), lung cancer (8%), colon cancer (5%), melanoma (4%), breast cancer (3%), bone sarcoma (1%), cholangiocarcinoma (1%), pancreatic cancer (1%), appendix cancer (<1%), congenital mesoblastic nephroma (<1%), hepatocellular carcinoma (<1%), prostate cancer (<1%), and cancer of unknown primary origin (<1%).

Regarding prior treatment, 35 (22%) patients were treatment-naïve, 48 (30%) patients had received 1 prior systemic therapy, 34 (21%) had received 2, and 42 (26%) had received 3 or more prior lines.

The gene fusions associated with the cancers were NTRK1 in 64 cases, NTRK2 in 4 patients, NTRK3 in 88 patients, and unconfirmed in 3 patients.

The 79% overall response rate in the integrated analysis was virtually identical to response rates observed in the primary (80%; 95% CI, 67-90) and supplementary (79%; 95% CI, 69-86) data sets. Among 12 evaluable patients with brain metastases, the overall response rate was 75%.

Across the efficacy-evaluable group, the median time to objective response was 1.8 months (range, 0.9-6.1), and the median treatment duration was 8.0 months (range, 0.03-47.2). The median progression-free survival (PFS) was 28.3 months and the 12-month PFS rate was 67%. The median overall survival (OS) was 44.4 months, and the 12-month OS rate was 88%.

The safety analysis involved an expanded population of 260 patients treated with larotrectinib and showed no new safety signals. Increased alanine aminotransferase (ALT; 3%), anemia (2%), and decreased neutrophil count (2%) were the most common grade 3/4 treatment-related adverse events (TRAEs). The most frequently reported serious TRAEs were ALT increase (n = 2), increased aspartate aminotransferase (n = 2), and nausea (n = 2). There were no treatment-related deaths on the trial.

The FDA granted an accelerated approval to larotrectinib in November 2018 for the treatment of 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. The 159-patient analysis set evaluated by Hong et al included the 55 patients who comprised the dataset on which the FDA based the approval.

Hong DS, DuBois SG, Kummar S. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials [published online February 24, 2020]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30856