Intra-patient comparison from larotrectinib clinical trials in TRK fusion cancer: An expanded dataset.
Authors: Hong David S. , Italiano Antoine , Briggs Andrew , Garcia-Foncillas Jesus , Lassen Ulrik Niels , Vassal Gilles , Kummar Shivaani , van Tilburg Cornelis Martinus , Keating Karen N , Reeves John A. , Fellous Marc Mardoche , Nogai Hendrik , Laetsch Theodore Willis , Drilon Alexander E. 
Published: June 2021

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Background: Larotrectinib is a highly selective, CNS-active tropomyosin receptor kinase (TRK) inhibitor that demonstrated rapid and durable responses in three phase I/II single-arm studies of patients (pts) with TRK fusion cancer. In single-arm studies the growth modulation index (GMI) can be used to provide a comparative analysis. GMI is an intra-patient comparison that uses pts as their own control by comparing progression-free survival (PFS) on current therapy to time to progression or treatment failure (TTP) on the most recent prior therapy; namely the ratio of PFS/TTP (EMA Guidelines. Guideline on the Evaluation of Anticancer Medicinal Products in Man, EMA/CHMP/205/95 Rev.5). A GMI ratio ≥1.33 has been used as a threshold of meaningful clinical activity. In a previous analysis of 122 pts with TRK fusion cancer treated with larotrectinib, 84 pts (69%) had a GMI ≥1.33. Conversely, 38 pts (31%) had a GMI < 1.33, but of these, 9 pts were ongoing treatment and censored for PFS as of July 2019 (Italiano et al, ESMO 2020). Here, we report the GMI of this initial group with a longer follow-up as well as an expanded dataset to more accurately assess the treatment effect of larotrectinib in pts with TRK fusion cancer previously treated with ≥1 line of therapy. Methods: Pts with TRK fusion cancer from three clinical trials on larotrectinib treatment with ≥1 prior line of systemic therapy were eligible for retrospective GMI analysis. TTP on the prior line of therapy was investigator-assessed. PFS on larotrectinib was determined by independent review committee per RECIST v1.1. Pts who had not progressed were censored as of date of last visit. Kaplan–Meier (KM) analyses were used to estimate median GMI, in addition to median PFS and TTP. The data cut-off was July 2020. Results: With an extended follow up of the original 122 pts, 90 (74%) pts had a GMI ≥1.33, including 6 of the 9 pts who were previously censored with a GMI < 1.33 and ongoing treatment; 6 pts (5%) had a GMI ≥1 to < 1.33 and 26 (21%) had a GMI < 1. The KM estimated median GMI increased from 7.6 (95% CI 5.7–88.0) to 9.5 (95% CI 5.7–17.4). In the expanded dataset of 140 pts, 103 pts (74%) had GMI ≥1.33, 7 (5%) had a GMI ≥1 to < 1.33 and 30 (21%) had a GMI < 1. Six of the 37 pts with a GMI < 1.33 were censored and still ongoing treatment. The KM estimated median GMI was 8.9 (95% CI 6.2–17.4). Among pts who had received 1, 2, or ≥3 prior lines of therapy, 74%, 65%, and 80%, respectively, had GMI of ≥1.33. Median TTP on the prior therapy was 3.0 months (95% CI 2.1–3.5) and median PFS on larotrectinib was 33.0 months (95% CI 16.6–34.9). Conclusions: With a longer follow-up, nearly three-quarters of pts with TRK fusion cancer treated with larotrectinib had a prolonged PFS compared to their most recent prior therapy. These results further validate the use of larotrectinib in treating patients with TRK fusion cancer. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.