Advances in the Treatment of NTRK Fusion-positive Cancers

EP. 1: 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 treating a variety of solid tumors.


Neurotrophic receptor tyrosine kinase (NTRK) genes, such as NTRK1, NTRK2, and NTRK3, can help to drive 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 have been 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 offer treatment benefits and potentially improve patient outcomes.

FDA-approved Therapies for Treating NTRK Fusion-positive Solid Tumors

Two therapies are approved by the United States Food and Drug Administration (FDA) for treating 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 where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.4 Larotrectinib’s FDA approval was supported by data from 3 open-label, single-arm clinical trials: 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 who were enrolled across the 3 trials and had received 1 or more doses of larotrectinib.5

The primary end point for the pooled analysis was independent radiology review committee-assessed overall response rate (ORR), and secondary end points included investigator-assessed duration of response (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 reached.5 Ninety-three percent of adverse events (AEs) were grade 1 or 2 in severity. The most common AEs were anemia (11%), increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level (7%), increased weight (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 the included patients. No 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 that have an NTRK gene fusion without a known acquired resistance mutation who are metastatic or where surgical resection is likely to result in severe morbidity and who have progressed following treatment or have no satisfactory standard therapy. Entrectinib is also FDA-approved for treating 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 trials: 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 who were enrolled in one of the 3 trials. All 54 patients had received 1 or more doses of entrectinib, had measurable disease at baseline, and were followed up for at least 6 months post-treatment initiation.8

Coprimary end points for the pooled analysis were ORR and DOR, both as assessed by blinded independent central review. Key secondary end points included 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]). 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 increased weight (10%) and anemia (12%). Three serious TRAEs (ie, cerebellar ataxia, cognitive disorder, dizziness) occurred, and 3 patients in the NTRK-fusion positive population discontinued treatment due to TRAEs.8

Emerging Larotrectinib Data

In 2020, expanded efficacy data from the LOXO-TRK-14001, NAVIGATE, and SCOUT trials 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 who were enrolled in one of the 3 trials. All patients received 1 or more doses of larotrectinib.9 At the time of data analysis, 102 of the 159 patients (64%) were still receiving 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 Median DOR was 35.2 months (95% CI, 22.8- NE), and median PFS was 28.3 months (95% CI, 22.1-NE).9 No new AEs were identified since the previous analysis. Anemia occurred in 10% of patients and decreased neutrophil count occurred in 5%. Most AEs 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 increased ALT (3%), anemia (2%), and decreased neutrophil count (2%). Five percent of patients had serious AEs, most commonly nausea, increased ALT, or increased AST (all <1%).9

Additionally, a 2021 conference abstract reported data from a total of 206 adult or pediatric patients enrolled in one of the 3 trials. Investigator-assessed ORR was similar to that reported in the previous 2 analyses (75%; [95% CI, 68-81]).10 Median OS was not reached, 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 trials. One conference abstract reported long-term, pooled follow-up data from 20 adult patients with small cell (n = 1) or non-small cell (n = 19) lung cancer who were enrolled in either the LOXO-TRK-14001 or NAVIGATE trial.11 Investigator-assessed ORR was 73% (95% CI, 45-92) in the 15 patients who were evaluable for response. Eight evaluable patients had baseline CNS metastases. In these patients, ORR was 63% (95% CI, 25-91).11 Median OS was 40.7 months (95% CI, 17.2-NE).11 Most AEs were grade 1 or 2 in severity. Sixteen of the 20 patients experienced TRAEs, and 2 patients had grade 3 TRAEs (ie, hypersensitivity, myalgia, weight increase).11

The other conference abstract reported data from 29 adult or pediatric patients with papillary (n = 20), follicular (n = 2), or anaplastic (n = 7) thyroid cancer who were enrolled in one of the LOXO-TRK-14001, NAVIGATE, and SCOUT trials.12 In the pooled analysis of data from 28 evaluable patients, 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 those with anaplastic thyroid cancer (29%; [95% CI, 4-71]).12 Two patients had grade 3 or higher TRAEs, and no patients discontinued treatment due to AEs.12

Additionally, 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) who were enrolled in either the SCOUT or the NAVIGATE trial. The primary end point for the pooled analysis was investigator-assessed ORR. Among 28 evaluable patients, ORR was 30% (95% CI, 16-49).13 Twenty patients experienced TRAEs of any grade, while grade 3 or 4 TRAEs occurred in 3 patients.13



REFERENCES

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  2. Vitrakvi. Prescribing Information. Bayer HealthCare Pharmaceuticals, Inc; 2018. Accessed December 20, 2021. http://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf
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  4. FDA approves larotrectinib for solid tumors with NTRK gene fusions. News Release. Food and Drug Administration; November 26, 2018. Accessed December 15, 2021. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions
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  6. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. News Release. 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-nsclc
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  10. 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 [abstract 3108]. J Clin Oncol. 2021;39(suppl 15):3108. doi:10.1200/JCO.2021.39.15_suppl.3108
  11. Lin 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.9109
  12. Waguespack 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. Abstract Oral 15. https://virtual.oxfordabstracts.com/#/event/public/2083/submission/169
  13. Doz F, van Tilburg CM, Geoerger B, et al. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Accepted manuscript. Posted online November 27, 2021. Neuro-Oncology, noab274. doi:10.1093/neuonc/noab274