Indirect Treatment Comparison of Larotrectinib versus Entrectinib in Treating Patients with TRK Gene Fusion Cancers

SIMPLE SUMMARY: Larotrectinib and entrectinib have never been directly compared in a clinical trial for the treatment of TRK fusion-positive cancer, so a comparison must use separate data from each drug’s trials. This study used established statistical methods to balance the patient populations across trials and found that, compared to entrectinib, larotrectinib was associated with a higher overall survival, longer duration of response, and higher complete response rates, and numerically better progression-free survival and similar overall response and safety rates. Based on treatment guidelines, healthcare stakeholders have only one opportunity to decide which TRK inhibitor to select for patients. The results of this analysis can help physicians decide between available treatment options for TRK fusion-positive solid cancer. ABSTRACT: Information regarding the comparative efficacy of first-generation receptor tyrosine kinase inhibitors is limited. This matching-adjusted indirect comparison (MAIC) evaluated differences in efficacy and safety across larotrectinib and entrectinib trials. Data from clinical trials for larotrectinib (LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431)) and entrectinib (ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)) were used. Adults (≥18 years) across trials were matched on available baseline characteristics. Outcomes evaluated included overall response rate (ORR), complete response (CR) rate, duration of response (DoR), overall survival (OS), progression-free survival (PFS), any serious treatment-related adverse events of grade ≥ 3 (TRAEs), and TRAEs leading to treatment discontinuation. The MAIC included 74 patients from entrectinib trials and 117 and 147 patients for the larotrectinib efficacy and safety populations, respectively. Post-matching, larotrectinib was associated with a significantly longer median duration of OS than entrectinib (p < 0.05) and a numerically longer median PFS (p = 0.07). ORR was similar for both agents (p = 0.63). The CR rate was higher (p < 0.05) and the DoR was longer for larotrectinib (p < 0.05). Safety outcomes were comparable and low for both treatments. Results were consistent in sensitivity analyses. These findings suggest favorable efficacy for larotrectinib and comparable safety profiles versus entrectinib in treating tropomyosin receptor kinase fusion cancer.