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Ref Type
PMID
Authors M. Hu V. Subbiah L.J. Wirth M. Schuler A.S. Mansfield M.S. Brose G. Curigliano S. Leboulleux V.W. Zhu B. Keam I. Matos C-C. Lin D. Adkins C.S. Baik G. Lopes Y. Godbert D. Sarker H. Zhang C. Turner M. Taylor
Title Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer (RET+ MTC)
Journal Vol Issue Date Pages Journal Short Title
Ann Oncol. 31 SUPPLEMENT 4
URL https://www.annalsofoncology.org/article/S0923-7534(20)41397-3/fulltext
Abstract Text Background: Pralsetinib is a highly potent, selective RET inhibitor targeting oncogenic RET alterations. We provide the registrational data for pts with RET+ MTC from the ARROW study. Methods: ARROW (75 sites in 11 countries; NCT03037385) consists of a phase I dose escalation to establish the recommended phase II dose (400 mg once daily [QD] orally), and phase II expansion cohorts defined by tumour type and/or RET alteration. Primary phase II objectives are overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. We report efficacy for response-evaluable pts (REP) with RET+ MTC and safety for all pts who initiated pralsetinib 400 mg QD, both as of data cut-off date 13 Feb 2020. Results: In 79 REP with RET+ MTC (mutation: 61% M918T, 28% C634X, 4% V804X, 8% other), ORR was 65% (95% CI, 53–75; n=51/79, 5% complete response [CR]; 59% partial response [PR; 1 pending confirmation]). ORR for pts with prior cabozantinib and/or vandetanib (C/V) was 60% (95% CI, 46–74; n=32/53; 2% CR; 58% PR [1 pending]) and in treatment-naïve pts ORR was 74% (95% CI, 49–91; n=14/19; 5% CR; 68% PR; all confirmed). Disease control rate was 97% (95% CI, 91–100); 99% (78/79) of pts experienced tumour shrinkage. Median progression-free survival (PFS) and duration of response (DOR) were not reached. In pts previously treated with C/V 18-mo PFS was 71% (95% CI, 58–85), and 18-mo DOR was 90% (95% CI, 77–100). In treatment-naïve pts, 18-mo PFS was 85% (95% CI, 65–100) and 86% (12/14) of responses were ongoing at data cut-off (up to 15 mo). Responses occurred regardless of RET genotypes (somatic or germline), including 5 of 6 pts with V804X gatekeeper mutation. In the safety population (n=438), treatment-related adverse events (TRAEs) were primarily grade 1–2; most common any-grade TRAEs were increased aspartate aminotransferase (34%), anaemia (24%), increased alanine aminotransferase (23%), constipation (23%) and hypertension (22%). 4% of pts discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated potent and durable clinical activity in RET+ MTC regardless of prior treatment with approved multikinase inhibitors or RET-mutation and was well tolerated. Clinical trial identification NCT03037385.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET C634X medullary thyroid carcinoma sensitive Pralsetinib Phase Ib/II Actionable In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, and resulted in an overall response rate (ORR) of 65% (51/79, 5% complete response, 59% partial response) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations, 28% of the patients harbored RET C634X (Ann Oncol. Vol 31, Supplement 4, S1084, Sep 1, 2020; NCT03037385). detail...
RET V804X medullary thyroid carcinoma sensitive Pralsetinib Phase Ib/II Actionable In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, and resulted in an overall response rate (ORR) of 65% (51/79, 5% complete response, 59% partial response) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations, 4% of the patients harbored RET V804X (Ann Oncol. Vol 31, Supplement 4, S1084, Sep 1, 2020; NCT03037385). detail...
RET M918T medullary thyroid carcinoma sensitive Pralsetinib Phase Ib/II Actionable In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated, and resulted in an overall response rate (ORR) of 65% (51/79, 5% complete response, 59% partial response) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations, 61% of the patients harbored RET M918T (Ann Oncol. Vol 31, Supplement 4, S1084, Sep 1, 2020; NCT03037385). detail...