Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer

Abstract

NTRK gene fusions • The neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, 2 and 3 encode the tropomyosin receptor kinases (TRK) A, B and C, respectively, and are expressed during normal neuronal development. 1,2 • Rearrangements involving the NTRK genes can generate fusion oncoproteins that drive tumour development and survival through constitutively activated or overexpressed kinase function. 3,4 • NTRK gene fusions have been identified in >20 paediatric and adult tumour types with an estimated frequency of 1% in all solid tumours. 4 • The identification of NTRK gene fusions as oncogenic drivers in a range of tumour types has provided actionable targets that have advanced therapeutic options. Larotrectinib • Larotrectinib is a first-in-class, highly selective TRK inhibitor 4 approved by the US Food and Drug Administration for the treatment of patients with solid tumours harbouring an NTRK gene fusion. 5 • Findings from three clinical trials revealed that larotrectinib induced an overall response rate of 80% by investigator assessment in the primary dataset of 55 patients with solid tumours harbouring NTRK gene fusions. 1 • In an integrated dataset of 109 patients, larotrectinib demonstrated robust tumour-agnostic efficacy regardless of tumour type or age and was well tolerated. 6 • In this analysis, the median duration of response (DOR) data in the primary dataset are reported for the first time, as well as updated data for an integrated dataset of 159 patients with TRK fusion cancer treated with larotrectinib. BACKGROUND RESULTS • The integrated dataset included 55 patients from the primary dataset and 104 patients in the supplementary dataset (Figure 1). Table 1. Baseline characteristics Characteristic Integrated dataset (N=159) Sex, n (%) Male 77 (48) Female 82 (52) Age, median (range), years 43.0 (<0.1-84.0) Paediatric (<18), n (%) 52 (33) Adult (≥18), n (%) 107 (67) ECOG performance status, n (%) 0 76 (48) 1 61 (38) 2 19 (12) 3 3 (2) Known brain metastasis at enrolment, n (%) 13 (8) Prior cancer treatments a Surgery 122 (77) Systemic therapy 122 (77) Radiotherapy 74 (47) No. of prior systemic regimens, n (%) 0 35 (22) 1 48 (30) 2 34 (21) ≥3 42 (26) NTRK gene fusion, n (%) NTRK1 64 (40) NTRK2 4 (3) NTRK3 b 88 (55) Not confirmed c 3 (2) a Patients may be counted in more than one row. b Directly demonstrated or inferred (8 of 88 patients) by ETV6 break-apart fluorescence in situ hybridisation in patients with infantile fibrosarcoma. c Molecular profiling test used not certified by CLIA (or other similar accrediting body). CLIA, Clinical Laboratory Improvement Amendments; ECOG, Eastern Cooperative Oncology Group; NTRK, neurotrophic tyrosine receptor kinase. Table 2. Efficacy assessments Integrated dataset (N=159) Response Evaluable patients, n 153 a ORR (95% CI) 79% (72-85) Best overall response, n (%) Complete response 24 (16) b Partial response 97 (63) c Stable disease 19 (12) Progressive disease 9 (6) Not determined 4 (3) Duration of response Median, months (95% CI) d 35.2 (22.8-NE) Range, months 1.6+ to 44.2+ Rate of ongoing response at 12 months, % (95% CI) e 80% Median follow-up, months 12.9 Progression-free survival Median, months (95% CI) 28.3 (22.1-NE) PFS rate at 12 months, % (95% CI) e 67 (58-76) Median follow-up, months 11.1 Overall survival Median, months (95% CI) 44.4 (36.5-NE) OS rate at 12 months, % (95% CI) e 88 (83-94) Median follow-up, months 13.9 a Six patients not evaluable because post-baseline assessments were not yet done at data cutoff. Best response percentages are calculated from the evaluable patient population. b Including three patients with pathological complete response; two patients had complete responses pending confirmation. c 13 partial responses pending confirmation. d In patients with confirmed responses (n=108). e Kaplan-Meier estimates. CI, confidence interval; DOR, duration of response; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Table 3. Adverse events in the expanded safety dataset (N=260) a Treatment-emergent AEs (%) Treatment-related AEs (%) Grade 1 or 2 Grade The AEs listed here are those that occurred at any grade in at least 15% of patients, or at grade 3 or 4 in at least 3% of patients, regardless of attribution. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. References 1. Drilon A et al.