Real-world survival outcomes in patients with locally advanced or metastatic NTRK fusion-positive solid tumors receiving standard-of-care therapies other than targeted TRK inhibitors

Abstract

The clinical profiles and outcomes of patients with neurotrophic tropomyosin receptor kinase fusion-positive (NTRK+) solid tumors receiving standard of care other than tropomyosin receptor kinase inhibitor (TRKi) targeted therapy have not been well documented. Here, we describe the clinical characteristics of patients with NTRK+ tumors treated in clinical practice using information from a United States electronic health record-derived clinicogenomic database. We also compared survival outcomes in NTRK+ patients and matched NTRK fusion-negative (NTRK–) patients and investigated the clinical prognostic value of NTRK fusions. NTRK positivity was defined by the presence of a fusion or rearrangement involving NTRK1/2/3, determined using NGS (Foundation Medicine, Inc.). NTRK+ patients (n = 28) were diagnosed with locally advanced/metastatic solid tumors between January 1, 2011 and December 31, 2019 and had received no TRKis (e.g., entrectinib or larotrectinib) during their patient journey. The unselected NTRK−population comprised 24,903 patients, and the matched NTRK−cohort included 280 patients. NTRK+ patients tended to be younger, were more commonly not smokers, and had a shorter time from advanced diagnosis to first NGS report, compared with unselected NTRK−patients; however, these differences were not significant. Median overall survival (OS) from advanced/metastatic diagnosis was 10.2 months (95% CI, 7.2–14.1) for the NTRK+ cohort versus 10.4 months (95% CI, 6.7–14.3) for the matched NTRK−cohort; hazard ratio for death in NTRK+ versus matched NTRK−patients was 1.6 (95% CI, 1.0–2.5; P = 0.05). Genomic co-alterations were rare in the NTRK+ cohort (only two of 28 patients had a co-alteration). Overall, while hazard ratios suggest NTRK fusions may be a negative prognostic factor of survival, there are no significant indications of any favorable impact of NTRK fusions on patient outcomes. TRKis, with their high response rate and good tolerability, are likely to improve outcomes for patients compared with existing standard-of-care treatments.

Survival Outcomes of Patients With Tropomyosin Receptor Kinase Fusion-Positive Cancer Receiving Larotrectinib Versus Standard of Care: A Matching-Adjusted Indirect Comparison Using Real-World Data

“…We identified five studies that enrolled TRK fusion-positive cancer patients who received non–TRK-inhibitor SoC regimens: Voyager 1/Bazhenova et al, 23 Voyager 2/Bridgewater et al, 24 Santi et al, 25 Zhu et al, 26 and Hibar et al/Demetri et al 27 , 28 Because of limitations of statistical methods used, it was important that the studies identified report Kaplan-Meier (KM) estimates of OS and comprehensive baseline characteristics. Three studies were omitted for further analysis because of the following limitations: Voyager 1/Bazhenova et al 23 was missing data on ECOG PS, CNS metastasis, and line of therapy, and had differences/misalignment in index date.…”

“…We selected the following published sources for comparative effectiveness studies: Voyager 1/Bazhenova et al, 23 Voyager 2/Bridgewater et al, 24 Santi et al, 25 Zhu et al, 26 and Hibar et al 27 (previously presented by Demetri et al 28 ). Studies that did not provide sufficient patient data were omitted, and the study by Hibar et al/Demetri et al was selected as the non–TRK-inhibitor SoC comparator.…”

“…For the non–TRK-inhibitor SoC comparator, Hibar et al/Demetri et al used the Flatiron/FMI database to identify NTRK fusion-positive patients who did not receive TRK inhibitors. 27 , 28 Briefly, adult patients were selected using deidentified demographic and clinical data who had ≥ 1 test by next-generation sequencing on tumor tissue and ≥ 1 NTRK fusion-positive test result (defined by presence of a fusion or rearrangement involving NTRK1 , NTRK2 , or NTRK3 , with predicted known or likely functional status; fusion cells were excluded if they had nonprotein coding gene partners or intragenic fusions), locally advanced or metastatic diagnosis between January 2011 and December 2019, no prior treatment with a TRK inhibitor, no visit gap of > 90 days after diagnosis, and no prior unlabeled study drug as part of a clinical trial. This cohort of patients is defined as SoC for this comparison.…”

“… 21 , 22 Individual patient data from the larotrectinib trials were matched to the average baseline characteristics from Hibar et al/Demetri et al (Table 2 ). 27 , 28 Baseline characteristics selected were based on data availability. Hazard ratio (HR) from Cox model was used to compare the two groups.…”

“…For SoC patients with missing data in the number of lines of therapy since diagnosis (17.9%) and Eastern Cooperative Oncology Group performance status (ECOG PS; 42.9%), 27 , 28 variables were imputed such that patients with missing values were assumed to be in the more severe categories (ie, ≥ 3 lines of therapy; ECOG PS 2-4). These assumptions were made to estimate a conservative HR, which were subsequently tested in a sensitivity analysis that used less conservative assumptions.…”