Background
ARROW — Phase I/II open-label, multi-cohort basket trial. Pralsetinib (BLU-667) is a highly selective, potent oral RET inhibitor. Thyroid cancer cohorts reported by Subbiah V et al, Lancet Diabetes Endocrinol 2021. Enrolled patients with RET-altered locally advanced or metastatic solid tumors at 71 global sites across 13 countries. Thyroid cancer cohorts: (1) RET-mutant MTC previously treated with cabozantinib and/or vandetanib; (2) treatment-naive RET-mutant MTC ineligible for standard therapy; (3) previously treated RET fusion-positive thyroid cancer (DTC). Registration NCT03037385. Data cutoff: March–July 2019 (efficacy), May 2020 (safety).
Interventions and follow up
Regimen: Pralsetinib 400 mg PO QD until progression; thyroid cohorts: RET-mutant MTC previously treated with cabozantinib/vandetanib (n=55); treatment-naive RET-mutant MTC ineligible for standard therapy (n=29); RET fusion-positive thyroid cancer (n=9)
Primary endpoint: ORR (masked independent central review, RECIST 1.1) and safety
mFollow up: Cohort-dependent; interim analysis at cutoff
Primary endpoint: ORR (masked independent central review, RECIST 1.1) and safety
mFollow up: Cohort-dependent; interim analysis at cutoff
Results
RET-mutant MTC (prior cab/van, n=55 with measurable disease): ORR 60% (95% CI 46–73%)
RET-mutant MTC (treatment-naive, n=21): ORR 71% (95% CI 48–89%)
RET fusion-positive thyroid cancer (previously treated, n=9): ORR 89% (95% CI 52–100%); all responses confirmed
All responses: Confirmed (stable ≥4 weeks after first response)
RET-mutant MTC (treatment-naive, n=21): ORR 71% (95% CI 48–89%)
RET fusion-positive thyroid cancer (previously treated, n=9): ORR 89% (95% CI 52–100%); all responses confirmed
All responses: Confirmed (stable ≥4 weeks after first response)
Adverse events
Main adverse events (all RET-altered thyroid, n=142): Grade ≥3 treatment-related AEs: hypertension 17%, neutropenia 13%, lymphopenia 12%, anemia 10%. Pneumonitis (serious): 4% (5 patients); 1 patient died from treatment-related event. Discontinuation due to AEs: 4%.
Conclusions
Pralsetinib achieved confirmed ORRs of 60–89% across RET-mutant MTC (pretreated and naive) and RET fusion-positive thyroid cancer. Results are consistent with selpercatinib (LIBRETTO-001) and establish pralsetinib as the second approved selective RET inhibitor for RET-altered thyroid cancers.
Key Limitations
Single-arm basket design; no randomized comparator. Relatively small cohort sizes with wide CIs in some groups. 4% rate of treatment-related serious pneumonitis is notable — higher than selpercatinib. Interim analysis with immature duration-of-response data. Head-to-head data vs selpercatinib are lacking; both are considered equivalent options. Once-daily dosing may offer adherence advantage but the higher pneumonitis rate requires attention.
Clinical Context
FDA approved pralsetinib for RET-mutant MTC (any line) and RET fusion-positive thyroid cancer in September 2020 based on ARROW — the second approved selective RET inhibitor after selpercatinib. Both agents have comparable ORRs in RET-mutant MTC (~60–73%) and RET fusion-positive thyroid cancer (~79–89%). NCCN lists both as category 1 preferred options for RET-altered thyroid cancers. Pralsetinib's once-daily schedule vs selpercatinib's twice-daily may influence prescribing preference. RET mutational testing is required for all MTC and RET-rearranged thyroid cancers.