Abstract P6-20-02: Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancers

Abstract

Background: Tropomyosin receptor kinase (TRK fusions) involving the genes NTRK1, NTRK2, and NTRK3 occur in a broad range of malignancies including breast cancers (BC) with secretory features. Larotrectinib, the first selective TRK inhibitor in clinical development, has demonstrated an overall response rate of 75% by independent radiology review across various solid tumors, with a favorable safety profile. Here we report on a case series of TRK fusion BC patients treated with larotrectinib alone or in combination. Methods: Patients were treated with oral larotrectinib in the NAVIGATE global phase II study or in single-patient compassionate-use protocols. All patients received the Phase 2 dose of 100mg BID on a continuous 28d schedule. Efficacy was evaluated using RECIST v1.1. Results: As of June 2018, 5 TRK fusion BC patients had been treated, all with secretory characteristics, but diverse ER/PR/HER2 positivity (Table); 2 patients were triple negative. Four patients harbored ETV6-NTRK3 fusions. Larotrectinib treatment yielded a response rate of 80% (4/5 PRs). All responses occurred within the first 2 cycles of therapy and cancer-related symptoms resolved rapidly. No treatment-related Grade ≥3 adverse events have been reported. Patient 2 (14 yr) presented with a recurrent fungating mass (10.4x8.5 cm) having failed multiple rounds of chemotherapy. Significant reduction in tumor size was noted after one week of larotrectinib treatment with near complete resolution after 2 months.1 Patient 3 (37 yr) had extensive involvement of the lung and pleura, bilateral pleural effusions, peritoneal infiltration with ascites, severe dyspnea with PS=3. There was rapid improvement with larotrectinib treatment and the patient was PS=1 after 2 weeks. At 6 weeks, there was >80% reduction in tumor size.2 Patient 5 had a synchronous, locally advanced TRK fusion positive, ER+/HER2- secretory BC and TRK fusion negative, ER+/HER2- metastatic lobular BC. Prior to TRK inhibition, this patient received 2-months of palbociclib/letrozole to which the TRKfusion negative lobular cancer responded, while the TRK fusion SBC did not. The patient tolerated the larotrectinib/letrozole combination with no notable toxicities and experienced a PR in both sites, now ongoing for 11 months. Conclusions: We provide the first evidence that larotrectinib is effective in the treatment of BC harboring NTRK gene fusions. Assays capable of identifying NTRK gene fusions should be considered when profiling patients with BC, especially for patients with secretory BC. Table:Subject summarySubject IDSubtypeRegimenNTRK gene fusionER/PR/HER2 statusBest ResponseProtocol1Invasive ductal carcinoma (NOS)larotrectinibTPM3-NTRK1ER+/PR+/HER2-PDNAVIGATE Ph II2SecretorylarotrectinibETV6-NTRK3ER-/PR-/HER2-PRCompassionate use3Invasive ductal with secretory featureslarotrectinibETV6-NTRK3ER-/PR-/HER2-PRCompassionate use4Invasive ductal with secretory featureslarotrectinibETV6-NTRK3ER+/PR+/HER2+PRCompassionate use5*Secretorylarotrectinib + letrozoleETV6-NTRK3ER+/PR-/HER2-PRCompassionate use*- synchronous TRK fusion negative invasive lobular 1. Shukla et al., JCO Precis Oncol 2017, epub 2. Landman et al., Clin Breast Cancer, 2018, 18:e267-e270. Citation Format: Meric-Bernstam F, Shukla N, Peled N, Landman Y, Onitilo A, Montez S, Ku NC, Hyman DM, Drilon A, Hong DS. Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-02.

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

“…172 NTRK fusions are identified by fluorescence in situ hybridization, next generation sequencing, or polymerase chain reaction. Larotrectinib [173][174][175] and entrectinib 175,176 are 2 NTRKinhibitors that are FDA approved for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance mutation and have no satisfactory alternative treatments or that have progressed following treatment. If a patient with recurrent or stage IV breast cancer presents with a tumor with an NTRK fusion, treatment with an NTRK inhibitor is an option if no satisfactory alternative treatment exists or that have progressed following treatment.…”

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

“…This highlights the molecular heterogeneity of TNBCs [178]. To date, in 15 patients with metastatic breast cancer treated with these tropomysin receptor kinase inhibitors, response rates of approximately 80% were reported [171,172,179]. Metastatic breast cancer harboring NTRK fusions and progressing despite previous treatment is approved for receiving TRK inhibitors [12,13].…”

Fusion‐associatedcarcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

“…Larotrectinib was granted accelerated approval by the FDA in 2018 as the first tumor‐agnostic therapy for pediatric and adult tumors harboring NTRK gene fusions. Larotrectinib has shown striking clinical outcomes in the treatment of SBC patients harboring ETV6::NTRK3 fusions with a response rate of 80% 91–94 . Remarkably, patients were reported to respond within the first two cycles of treatment with larotrectinib, with rapid resolution of cancer‐related symptoms and tolerable adverse events 94 .…”

“…Larotrectinib has shown striking clinical outcomes in the treatment of SBC patients harboring ETV6::NTRK3 fusions with a response rate of 80% 91–94 . Remarkably, patients were reported to respond within the first two cycles of treatment with larotrectinib, with rapid resolution of cancer‐related symptoms and tolerable adverse events 94 . Entrectinib, another NTRKi, which is potent but less selective than larotrectinib, targets the fusion proteins involving NTRK, c‐ros oncogene 1 (ROS1) or anaplastic lymphoma kinase (ALK).…”

“…[91][92][93][94] Remarkably, patients were reported to respond within the first two cycles of treatment with larotrectinib, with rapid resolution of cancer-related symptoms and tolerable adverse events. 94 Entrectinib, another NTRKi, which is potent but less selective than larotrectinib, targets the fusion proteins involving NTRK, cros oncogene 1 (ROS1) or anaplastic lymphoma kinase (ALK). The results from three global phase I/II entrectinib trials on breast cancer revealed that the response rate for NTRK fusion-positive breast cancer was 83.3%.…”