Chicago, IL—In 2018, larotrectinib (Vitrakvi) became the first drug to be approved by the FDA as a tumor-agnostic therapy based solely on the presence of a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation TRK fusion biomarker. Several analyses presented at ASCO 2019 confirm the wide-ranging efficacy of larotrectinib in pediatric and adult patients with advanced cancer and NTRK gene fusion cancer, as well as those whose tumor involves the central nervous system (CNS).
Testing for NTRK Fusion
In an analysis of 34 evaluable children or adolescents aged <18 years with TRK fusion cancer who received treatment with larotrectinib twice daily, the overall response rate (ORR) was 94%, and these responses were durable, reported Cornelis M. van Tilburg, MD, Senior Physician, Pediatric Oncology and Hematology, Hopp Children’s Cancer Center Heidelberg, Heidelberg University Hospital, and German Cancer Research Center, Germany.
“Larotrectinib reduced the need for mutilating, disfiguring surgery,” Dr van Tilburg said, adding that the data from this analysis are strong enough to consider routine testing for NTRK fusions in all pediatric patients with advanced solid tumors.
The tumor types included in the analysis were mostly infantile fibrosarcoma (47%) and other soft-tissue sarcomas (42%). Thyroid tumors accounted for 5% of the patients, with melanoma and congenital mesoblastic nephroma comprising 3% each.
In this study, TRK fusions involved NTRK1 (47%), NTRK2 (5%), and NTRK3 (47%). A total of 61% of the patients previously had surgery, 11% had received radiotherapy, and 68% had received systemic therapy, of which 16% had received ≥3 lines of systemic therapy. At enrollment, 50% of the patients had locally advanced TRK fusion cancer, and 50% had metastatic disease.
At the time of the data cutoff (in July 2018), 12 of the 34 (35%) patients had a complete response to larotrectinib, 18 (59%) had a partial response, and 2 (6%) had stable disease, said Dr van Tilburg. In addition, 33 of 38 (87%) patients continued to receive treatment or underwent surgery with curative intent. With a median follow-up of 8.9 months, the median duration of response had not been reached; 84% of the responding patients had an estimated duration of response lasting ≥1 years.
At median follow-up of 10.7 months, the median progression-free survival (PFS) had not been reached, and at median follow-up of 12.3 months, the median overall survival (OS) had not been reached.
Second Analysis of 3 Studies
In a separate analysis of 83 adult patients (median age, 57 years) with TRK fusion cancer who participated in 3 clinical trials with larotrectinib, the ORR (by an independent central review) was 68%, including 17% complete responses, 51% partial responses, as well as 15% of patients with stable disease, reported David S. Hong, MD, Deputy Chair, Department of Investigational Cancer Therapeutics, M.D. Anderson Cancer Center, Houston, TX, in a poster presentation.
At a median follow-up of 17.5 months, the median duration of response had not been reached, and 79% of the responding patients were estimated to have a response lasting >12 months. At a median follow-up of 13.6 months, the median PFS was 25.8 months and the median OS had not been reached. Most of the TRK fusions observed in these studies involved NTRK1 (40%) or NTRK3 (57%) gene fusions.
Echoing Dr van Tilburg, Dr Hong and colleagues noted in their poster that “these data provide strong evidence in support of testing for TRK fusions in adult patients with advanced solid tumors, regardless of the site of primary diagnosis.”
Larotrectinib has also shown to be highly active against tumors with TRK fusion and CNS involvement.
An analysis of 3 clinical trials with larotrectinib involved 24 patients with intracranial disease, including 18 primary CNS tumors (median age, 10 years), and 6 nonprimary CNS tumors and brain metastases. The response rate to larotrectinib was 60% among 5 evaluable patients with TRK fusion–positive solid tumors and brain metastases, and 36% among 14 evaluable patients with TRK fusion–positive primary CNS tumors, reported Alexander E. Drilon, MD, Research Director, Early Drug Development, Memorial Sloan Kettering Cancer Center, New York, NY.
Many solid tumors with TRK fusion have a propensity for brain metastases, according to Dr Drilon. “TRK fusions are found in primary brain tumors, such as high-grade gliomas, and the activity of larotrectinib in these patients has not previously been presented,” said Dr Drilon.
The patients in this analysis were eligible for inclusion if they had untreated, asymptomatic, and stable brain metastases. Those with primary CNS tumors had to be neurologically stable and be using a stable dose of steroids before study initiation.
The cohort included 10 patients with high-grade CNS disease. Overall, 76% of tumors harbored the NTRK2 fusion.
Of the 5 evaluable patients with nonprimary CNS tumors and brain metastases, 3 patients had a response to treatment, which were partial responses. Of the total 6 patients, 4 continued to receive treatment with larotrectinib at the time of data cutoff. The 3 patients in whom assessment of intracranial response was possible had intracranial disease regression, including a patient with lung cancer and TRK fusion who had complete resolution of the target lesions in the brain after using larotrectinib.
In the 14 patients with evaluable disease, 2 (14%) had complete responses, 3 (21%) had partial responses, and 9 (64%) patients had stable disease. At ≥16 weeks, the disease control rate was 79%, which was still high by ≥24 weeks at 71%.
The ORR was 45% in the 11 evaluable pediatric patients, and the longest duration of therapy was ongoing at 16.6 months. “This durability of disease control is further highlighted by the median PFS of 11 months,” said Dr Drilon.