Targeting the TRK Pathway in Pediatric or Adult Patients with Advanced or Surgically Unresectable NTRK Fusion-positive Solid Tumors
FDA-approved TRK inhibitors entrectinib and larotrectinib have demonstrated safety and efficacy in the treatment of a variety of solid tumors.
Neurotrophic receptor tyrosine kinase (NTRK) genes, such as NTRK1, NTRK2, and NTRK3, may help stimulate oncogenesis by forming fusions with a number of other gene partners.1,2 Although the overall prevalence of NTRK gene fusions in solid tumors is less than 1%, NTRK fusions identified in multiple solid tumor types, including breast, cervical, colorectal, lung, salivary gland, thyroid, sarcomas, and gliomas.1,3 For patients with NTRK fusion-positive cancer, TRK inhibitors may provide treatment benefits and potentially improving patient outcomes.
FDA-approved therapies for the treatment of NTRK fusion-positive solid tumors
Two therapies have been approved by the US Food and Drug Administration (FDA) for the treatment of NTRK fusion-positive solid tumors. Larotrectinib, an oral, selective pan-TRK inhibitor, was approved in November 2018 for the treatment of pediatric or adult patients with solid tumors who have an NTRK gene fusion without a known acquired resistance mutation, who are either metastatic or in whom surgical resection is likely. will occur. lead to severe morbidity and who do not have satisfactory alternative treatments or whose cancer has progressed after treatment.4 The FDA’s approval by the FDA was supported by data from 3 open-label, single-arm clinical studies: LOXO-TRK-14001 ( NCT02122913), NAVIGATE (NCT02576431), and SCOUT (NCT02637687).4 The primary, integrated efficacy analysis included pooled data from the first 55 adult or pediatric patients with NTRK fusion-positive, non-central nervous system (CNS) solid tumors that developed in the 3 studies were included. and had received 1 or more doses of larotrectinib
The primary endpoint for the pooled analysis was independent radiology review committee-assessed overall response rate (ORR), and secondary endpoints were investigator-assessed response duration (DOR), progression-free survival (PFS), and safety.5 Independently-assessed ORR was 75% (95% CI, 61-85) and investigator-assessed ORR was 80% (95% CI, 67-90).5 Median DOR and PFS were not achieved.5 Ninety-three percent of adverse reactions (AEs) were Grade 1 or 2 in earnest. The most common adverse reactions were anemia (11%), increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level (7%), weight gain (7%) and decreased neutrophil count (7%). No Grade 4 or 5 AEs were treatment-related, and no Grade 3 treatment-related AEs (TRAEs) occurred in more than 5% of patients enrolled. None of the patients who responded to larotrectinib discontinued treatment due to an AE.5
Entrectinib, an oral inhibitor of multiple kinases, including TRKs, received FDA approval in August 2019 for the treatment of pediatric patients 12 years of age and older or adults with solid tumors who have an NTRK gene fusion without a known acquired resistance mutation that metastatically or where surgical resection is likely to result in severe morbidity and who have progressed after treatment or do not have satisfactory standard therapy. Entrectinib is also FDA-approved for the treatment of adults with ROS1-positive metastatic non-small cell lung cancer.6,7 Entrectinib’s approval for patients with NTRK fusions was based on data from 3 studies: ALKA-372-001 (EudraCT , 2012-000148 –88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267).6 The integrated efficacy analysis included pooled data from 54 evaluable adult patients with advanced or metastatic NTRK fusion-positive solid tumors admitted to a of the 3 trials. All 54 patients had received 1 or more doses of entrectinib, had measurable disease at baseline, and were followed for at least 6 months after initiation of treatment.8
Co-primary endpoints for the pooled analysis were ORR and DOR, both assessed by blinded independent central review. The key secondary endpoints were overall survival (OS), PFS and safety.8 ORR was 57% (95% CI, 43.2-70.8) and median DOR was 10.0 months (95% CI, 7 ,1-not estimable). [NE]). The median OS and PFS were 21 months (95% CI, 14.9-NE) and 11.0 months (95% CI, 8.0-14.9), respectively.8 An integrated safety analysis included 68 patients with NTRK fusion positive tumors.8 The most common grade 3 or 4 TRAEs in these patients were weight gain (10%) and anemia (12%). Three severe TRAEs (ie, cerebellar ataxia, cognitive impairment, vertigo) occurred and 3 patients in the NTRK fusion-positive population discontinued treatment due to TRAEs.8
Emerging larotrectinib data
In 2020, comprehensive efficacy data from the LOXO-TRK-14001, NAVIGATE, and SCOUT studies were reported.9 Data from the same 55 patients included in the primary pooled analysis were combined with data from an additional 104 adult or pediatric patients with non-CNS solid tumors participating in any of the 3 studies. All patients received 1 or more doses of larotrectinib.9 At the time of data analysis, 102 of 159 patients (64%) were still on treatment. The ORR was similar to that reported in the primary analysis: of 153 evaluable patients, 121 (79%; [95% CI, 72-85]) responded to treatment.9 ORR was higher in pediatric patients (92%) than in adults (73%).9 The median DOR was 35.2 months (95% CI, 22.8-NE) and the median PFS was 28.3 months (95% CI, 22.1-NE).9 No new adverse reactions have been identified since the previous analysis. Anemia occurred in 10% of patients and decreased neutrophil counts occurred in 5%. Most adverse reactions were Grade 1 or 2 in severity.9 Grade 3 and 4 TRAEs occurred in 13% and less than 1% of patients, respectively; of these, the most common were elevated ALT (3%), anemia (2%) and decreased neutrophil counts (2%). Five percent of patients had serious adverse events, most commonly nausea, elevated ALT, or elevated AST (all <1%).9
In addition, a summary of the 2021 conference reported data from a total of 206 adult or pediatric patients enrolled in one of the 3 studies. The investigator-assessed ORR was similar to that reported in the previous 2 analyzes (75%; [95% CI, 68-81]).10 Median OS was not achieved and median PFS was 35.4 months (95% CI, 23.4-55.7).10 TRAEs were mainly Grade 1 or 2 in severity. Eighteen percent of patients had Grade 3 or 4 TRAEs and 2% of patients discontinued larotrectinib due to TRAEs.10
In 2021, 2 conference abstracts reported tumor type-specific data from patients enrolled in the LOXO-TRK-14001, SCOUT, and/or NAVIGATE studies. A conference summary reported long-term, pooled follow-up data from 20 adult patients with small cell (n = 1) or non-small cell (n = 19) lung cancer enrolled in either the LOXO-TRK-14001 or NAVIGATE study.11 the investigator-assessed ORR was 73% (95% CI, 45-92) in the 15 patients evaluable for response. Eight evaluable patients had baseline CNS metastases. In these patients, the ORR was 63% (95% CI, 25-91).11 The median OS was 40.7 months (95% CI, 17.2-NE).11 Most adverse reactions were Grade 1 or 2 seriously. Sixteen of 20 patients received TRAEs and 2 patients had Grade 3 TRAEs (ie, hypersensitivity, myalgia, weight gain).11
The other conference summary reported data from 29 adult or pediatric patients with papillary (n = 20), follicular (n = 2), or anaplastic (n = 7) thyroid cancer who enrolled in one of the LOXO-TRK-14001, NAVIGATE, and SCOUT studies.12 In the pooled analysis of data from 28 evaluable patients, the investigator-assessed ORR was 71% (95% CI, 51-87).12 ORR was higher in patients with differentiated thyroid cancer (86%; [95% CI, 64-97]) than in people with anaplastic thyroid cancer (29%; [95% CI, 4-71]).12 Two patients had Grade 3 or greater TRAEs and none of the patients discontinued treatment due to AEs.12
In addition, an accepted manuscript reported data from 33 adult or pediatric patients with primary CNS tumors (high-grade glioma, n = 19; low-grade glioma, n = 8) enrolled in either the SCOUT or the NAVIGATE study. The primary endpoint for the pooled analysis was investigator-assessed ORR. Among 28 evaluable patients, the ORR was 30% (95% CI, 16-49).13 Twenty patients developed TRAEs of any grade, while Grade 3 or 4 TRAEs occurred in 3 patients.13
Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Patol. 2019;32(1):147-53. doi:10.1038/s41379-018-0118-3Vitrakvi. Prescribing Information. Bayer HealthCare Pharmaceuticals, Inc; 2018. Accessed December 20, 2021. http://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdfSolomon JP, Linkov I, Rosado A, et al. NTRK Fusion Detection Across Multiple Tests and 33,997 Cases: Diagnostic Implications and pitfalls. Mod Patol. 2020;33(1):38-46. doi:10.1038/s41379-019-0324-7FDA approves larotrectinib for solid tumors with NTRK gene fusions. news item. Food and Drug Administration; November 26, 2018. Accessed December 15, 2021. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusionsDrilon A, Laetsch TW, Kummar S, et al. larotrectinib in TRK Fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-9. doi:10.1056/NEJMoa1714448FDA approves entrectinib for solid NTRK tumors and ROS-1 NSCLC. news item. Food and Drug Administration; August 16, 2019. Accessed December 15, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclcRozlytrek. Prescribing Information. Genentech USA, Inc; 2019. Accessed December 20, 2021. https://www.gene.com/download/pdf/rozlytrek_prescribe.pdfDoebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion positive solid tumors: integrated analysis of three phase 1-2 studies. Lancet Oncol. 2020;21(2):271-82. doi:10.1016/S1470-2045(19)30691-6Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumors: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;219(4):531-40. doi:10.1016/S1470-2045(19)30856-3Hong 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 [abstract 3108]. J Clin Oncol. 2021;39(suppl 15):3108. doi:10.1200/JCO.2021.39.15_suppl.3108Lin JJ, Kummar S, Shao-Weng D, et al. Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer [abstract 9109]. J Clin Oncol. 2021;39(suppl 15):9109. doi:10.1200/JCO.2021.39.15_suppl.9109Waguespack SG, Drilon A, Lin JJ, et al. Long-term efficacy and safety of larotrectinib in patients with advanced TRK fusion-positive thyroid carcinoma. Presented at: The 90th Annual Meeting of the American Thyroid Association; September 30 – October 3, 2021. Summary Oral 15. https://virtual.oxfordabstracts.com/#/event/public/2083/submission/169Doz F, van Tilburg CM, Geoerger B, et al. Efficacy and safety of larotrectinib in TRK fusion positive primary tumors of the central nervous system. Accepted manuscript. Posted online Nov 27, 2021. Neuro-Oncology, noab274. doi:10.1093/neuonc/noab274