Robust Responses Seen with Larotrectinib in TRK Fusion Cancer

Promising responses rates were seen with larotrectinib, a highly selective, central nervous system-active TRK inhibitor, in patients with TRK fusion cancer, including in those with CNS metastases at baseline.

Promising responses rates were seen with larotrectinib (Vitrakvi), a highly selective, central nervous system (CNS)-active TRK inhibitor, in patients with TRK fusion cancer, including in those with CNS metastases at baseline, according to the results of an integrated dataset presented virtually during the 2021 ASCO Annual Meeting.1

Patients within the integrated dataset who were treated with the drug (n = 218) achieved an overall response rate (ORR) of 75% (95% CI, 68%-81%), while patients with CNS metastases at baseline (n = 19) had an ORR of 73% (95% CI, 45%-92%).

The overall patient population had a median progression-free survival (PFS) of 35.4 months (95% CI, 23.4-55.7) after a median follow up of 20.3 months, while the 24-month PFS rate was 57%, and the 36-month PFS rate was 48%. Additionally, after a median follow up of 22.3 months, the median overall survival (OS) was not reached (95% CI, not evaluable [NE]-NE), and patients had a 24-month OS rate of 81%, and a 36-month OS rate of 77%.

"This expanded cohort of 218 patients with TRK fusion cancer demonstrated durable and robust objective responses,” David S. Hong, MD, the deputy chair of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said during a presentation of the data. “These results support the use of routine NTRK gene fusion testing regardless of tumor type.”

NTRK gene fusions are oncogenic drivers in several adult and pediatric tumor types. They can occur in more than 80% of certain rare cancers, such as infantile fibrosarcoma, as well as in less than 1% of common cancer types, such as lung cancer.2 Due to the limited findings on the natural history and responses to standard therapies in patients with NTRK fusions, it is believed that the presence of these genetic aberrations do not improve prognosis, leaving a notable unmet need within this patient population.3

Larotrectinib, a first-in-class TRK inhibitor, was approved by the FDA in November 2018 for adult and pediatric patients with TRK fusion cancer.4 The agent has previous demonstrated an ORR of 79% in a population of adult and pediatric patients (n = 159) with non-primary CNS TRK fusion solid tumors.5

The analysis reported on updated efficacy and safety data with a longer follow up. The expanded dataset included adult and pediatric patients with TRK fusion cancer who had been treated with larotrectinib across 3 studies: a phase 1 trial (NCT02122913) that included 13 patients with advanced solid tumors; the phase 1/2 SCOUT trial (NCT02637687) that enrolled 79 pediatric patients, aged 21 years or younger, with advanced solid tumors; the phase 2 NAVIGATE basket trial (NCT02576431) which enrolled 126 adults and adolescent patients with advanced solid tumors harboring TRK fusions.

Combined, these trials yielded a population of 218 patients with non-primary CNS TRK fusion cancer. Larotrectinib was administered at a dose of 100 mg twice daily (BID) in adult patients, and 100 mg/m2 BID in pediatric patients, with a maximum dose of 100 mg BID.

The primary end point was ORR, with key secondary end points including PFS, OS, duration of response (DOR), and safety.

The most common tumor types reported in the analysis included soft tissue sarcoma (26%), infantile fibrosarcoma (20%), thyroid (13%), salivary gland (11%), and lung (9%). Other malignancies included colon (4%), melanoma (3%), breast (3%), and gastrointestinal stromal tumors (2%).

Among patients examined on the analysis, the median age was 38 years old (range, 0.1-84), and 9% had known CNS metastases at enrollment. In total, 52% of patients had an ECOG performance status of 0, 36% had a performance status of 1, 11% had a status of 2, and 1% had a status of 3. Patients had received a median of 1 prior line of therapy (range, 1-10), with 27% receiving no prior treatments, 28% receiving 1, 19% receiving 2, and 26% receiving 3 or more. Additionally, 44% of patients were positive for NTRK1, 3% has NTRK2, and 53% had NTRK3.

Additional data indicated that 22% of patients within the integrated data set achieved a complete response (CR), 53% achieved a partial response (PR), 16% had stable disease, 6% had progressive disease, and 3% were undetermined. In the cohort of patients who had CNS metastases at baseline, 73% achieved a PR, 13% had stable disease, and 13% developed progressive disease.

“Larotrectinib was efficacious regardless of tumor type, with 83% of patients experiencing tumor shrinkage," Hong added.

The duration of treatment ranged from 0.03 to 60.4 months, with a median time to response of 1.84 months (range, 0.89-9.07). At the time of data cut-off, half of all patients (n = 108) were still on treatment, while 22% (n = 48) continued to receive treatment following progression.

After a median follow up of 22.3 months, the median DOR was 49.3 months (95% CI, 27.3-NE)., while the 24-month DOR rate was 64%, and the 36-month DOR rate was 54%.

No new safety signals were observed in the safety analysis set, which included 53 patients who were on treatment for more than 24 months. Treatment-related adverse effects (TRAEs) were primarily grade 1 or 2 in severity, with 2% of patients discontinuing treatment due to TRAEs. In total, 18% of patients experienced grade 3 or 4 TRAEs.

The most common grade 4 TRAEs included neutrophil count decrease (1%), ALT increase (1%), and an aspartate aminotransferase (AST) increase reported in 1 patient. Additionally, common grade 3 TRAEs include neutrophil count decrease (6%), alanine aminotransferase (ALT) increase (2%), AST increase (1%), and weight increase (1%).

Grade 4 treatment-emergent AEs (TEAEs) included neutrophil count decrease (2%), ALT increase (1%), and AST and constipation, both reported in one patient each. Moreover, grade 3 TEAEs included neutrophil count decrease (10%), anemia (8%), and weight increase (5%), while grade 1/2 TEAEs included cough (33%), vomiting (31%), and constipation (31%).

References
  1. Hong DS, Shen L, van Tilburg CM, et al. Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer. J Clin Oncol. 2021;39(suppl 15; abstr 3108). doi:10.1200/JCO.2021.39.15_suppl.3108
  2. Amatu A, Sartore-Bianchi A, Bencardino K, et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019;30(Suppl 8):viii5-viii5. doi:10.1093/annonc/mdz383
  3. Bazhenova L, Lokker A, Snider J, et al. TRK fusion cancer: patient characteristics and survival analysis in the real-world setting. Target Oncol. 2021;16(3):389-399. doi:10.1007/s11523-021-00815-4.
  4. FDA approves larotrectinib for solid tumors with NTRK gene fusions. News release. FDA. December 14, 2018. Accessed June 5, 2021. https://bit.ly/2SbQqzg
  5. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2021;21(4):P531-540. doi:10.1016/S1470-2045(19)30856-3