Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial

Abstract

Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW ( NCT03037385 , ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion-positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35-77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib's potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion-positive solid tumors.

Conflict of interest statement

V.S. reports research funding/grant support for clinical trials from AbbVie, Agensys, Alfasigma, Altum, Amgen, Bayer, BERG Health, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3 Bio, Dragonfly Therapeutics, Exelixis, Fujifilm, GlaxoSmithKline, Idera Pharmaceuticals, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, NanoCarrier, National Comprehensive Cancer Network, NCI-CTEP, Northwest Biotherapeutics, Novartis, PharmaMar, Pfizer, Relay Therapeutics, Roche/Genentech, Takeda, Turning Point Therapeutics, MD Anderson Cancer Center and Vegenics; travel support from ASCO, ESMO, Helsinn Healthcare, Incyte, Novartis and PharmaMar; consultancy/advisory board participation for Helsinn Healthcare, Incyte, Loxo Oncology/Eli Lilly, MedImmune, Novartis, QED Therapeutics, Relay Therapeutics, Daiichi-Sankyo, and R-Pharm US; and other relationship with Medscape. P.A.C. reports receiving honoraria from Amgen, Blueprint Medicines, Merck Serono, Merck Sharp & Dohme, Novartis, and Roche/Genentech; travel, accommodations and expenses from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, NETRIS Pharma, Novartis and Roche; non-financial support from Merck Sharpe & Dohme, Novartis and Plexxikon; research funding from Novartis and Merck Sharpe & Dohme; and research funding to institution from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Innate Pharma, Janssen Pharmaceuticals, Loxo Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, Plexxikon, Roche/Genentech, Taiho Pharmaceutical, Toray Industries and Transgene. S.S. is an advisory board member for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Checkmab, Daiichi-Sankyo, Merck, Roche/Genentech and Seattle Genetics. E.G. reports personal fees from Alkermes, Bristol Myers Squibb, Boehringer Ingelheim, Ellipses Pharma, Genentech, F. Hoffmann-La Roche, Janssen Pharmaceuticals, Merck Sharpe & Dohme, Neomed Therapeutics, Seattle Genetics, TFS Health Science and Thermo Fisher Scientific; research funding from Novartis, Roche and Thermo Fisher Scientific; and travel grants from Glycotope and Menarini. L.P.A. reports personal fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Eli Lilly, Merck, Merck Sharpe & Dohme, Ipsen, Mirati Therapeutics, Novartis, Pfizer, PharmaMar, Roche, Sanofi and Servier; grants from AstraZeneca, Bristol Myers Squibb, Merck Sharpe & Dohme and Pfizer; and other funding from Altum Sequencing and Genomica. P.G. reports a consulting or advisory role for AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Guardant Health, Janssen Pharmaceuticals, Novartis, Merck Sharpe & Dohme, Pfizer, Roche and Takeda; speakers bureau for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences, MSD Oncology, Novartis, Pfizer, ROVI, Roche and Takeda; travel, accommodations and expenses support from AstraZeneca, Bristol Myers Squibb and Roche; and research funding from Guardant Health and Sysmex. E.N. reports consulting or advisory role and lectures for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck-Serono, MSD Oncology, Pfizer, Roche and Takeda; and research funding from Bristol Myers Squibb, Merck-Serono, Pfizer and Roche. J.V. reports having consulted and/or having advisory roles for AstraZeneca, Bristol Myers Squibb and Seattle Genetics/Astellas; and institutional research funding from Agendia, Arvinas, Astellas Pharma, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Celldex, Clovis Oncology, Deciphera, Eisai, Exelixis, Fortis, Roche/Genetech, Ignyta, Incyte, Innocrin Pharma, Eli Lilly, Loxo, Merck, Novartis, Pfizer, Polyphor and Rgenix. G.L. reports having consulted and/or having advisory roles for AstraZeneca and Pfizer; received travel, accommodations and expenses from Boehringer Ingelheim, E.R. Squibb & Sons, Janssen Pharmaceuticals and Pfizer; received honoraria from Boehringer Ingelheim; received research funding from AstraZeneca; and received research funding to their institution from AbbVie, Adaptimmune Therapeutics, AstraZeneca, Bavarian Nordic, Blueprint Medicines, Bristol Myers Squibb, Eli Lilly, EMD Serono, G1 Therapeutics, GlaxoSmithKline, Janssen Pharmaceuticals, Merck Sharpe & Dohme, Novartis, Pfizer, Rgenix, Roche/Genentech and Tesaro. G.P.K. received research funding/grant support for clinical trials from AbbVie, Blueprint Medicines, Daiichi, Merck, Cullinan and Takeda. D.W.B. declares no conflicts of interest. M. Seetharam. reports having consulted and/or having an advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, MorphoSys, Novartis, Roche and Takeda; and received honoraria from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharpe & Dohme and Novartis; and institutional research funding from AstraZeneca and Bristol Myers Squibb. J.C. declares no conflicts of interest. H.Z. is an employee and shareholder of Blueprint Medicines. J.G. reports having a consulting or advisory role with Arvinas, Blueprint Medicines, Genocea Biosciences and Tesaro. A.Z. is an employee and shareholder of Blueprint Medicines. M. Schuler. reports having a consulting or advisory role for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Roche, Sanofi and Takeda; having received honoraria from Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis and Roche; having received research funding to his institution from AstraZeneca and Bristol Myers Squibb; and his institution has patents, royalties and other intellectual property of a highly sensitive method for mutation detection by PCR. Y.F. received honoraria as a speaker from AstraZeneca, Bristol Myers Squibb, CStone, Hengrui, Innovent Biologics, Lilly China, Roche, Merck Sharpe & Dohme, Novartis and Pfizer. G.C. reports having a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, Foundation Medicine, GlaxoSmithKline, Novartis, Pfizer, Roche/Genentech, Samsung, Exact Sciences, Merck and Seagent; having served on speakers bureau for Daiichi-Sankyo, Eli Lilly, Foundation Medicine, Novartis, Pfizer, Roche/Genentech and Samsung; having received travel, accommodations and expenses support from Roche/Genentech, Daichii-Sankyo and Pfizer; having received honoraria from Ellipses Pharma; and having received research funding from Merck.

© 2022. The Author(s).

Figures

Fig. 1. Patient disposition.

A flowchart that illustrates enrollment of patients with RET fusion–positive solid tumors in the safety (n = 29) and efficacy-evaluable (n = 23) populations in the context of the overall study population of 587 patients, as well as the status of these patients at the data cutoff. aOther RET-mutant tumors (n = 15), no or unknown RET status (n = 2) and prior treatment with a RET inhibitor (n = 23). bThree patients (two with colon cancer and one with cholangiocarcinoma) had additional driver mutations (KRAS, PIK3CB and BRAF).

Fig. 2. Individual tumor response and treatment duration waterfall and swimlane plots for the efficacy-evaluable population.

In 23 patients eligible for efficacy analyses: a, tumor response by BICR and maximum change from baseline in target lesion size, showing each patient’s tumor type and RET fusion partner; b, treatment duration, indicating the corresponding tumor type and the timeline for response, where the dotted line represents median time to response (1.9 months). One patient with progression based on a new site of disease did not have post-baseline assessment of RECIST target lesions and so is not shown in a.

Fig. 3. Time-dependent disease evaluations in two patients after pralsetinib treatment.

Baseline and 8-week disease evaluation in a 51-year-old woman with RET–NCOA4 fusion–positive cholangiocarcinoma: a, at first disease evaluation after 8 weeks receiving pralsetinib, a left hepatic lobe lesion measuring 2 × 3 cm at baseline had reduced to 1.2 × 1.9 cm; b, a prior heterogeneously enhancing soft tissue mass in the right gluteal muscles had decreased in size and enhancement and showed increased cystic and necrotic components compared to baseline scans. c, Baseline, 5-month and 19-month disease evaluation in a 60-year-old woman with a RET–CCDC6 fusion–positive sarcoma presenting as two muscular masses in the right upper arm.

Extended Data Fig. 1. Prior therapies at baseline.

All Ns are target enrollment. Safety and efficacy analyses presented herein were based on the shaded group (5).

Extended Data Fig. 2. Co-occurring alterations in patients with RET fusions in the ARROW trial at study entry.

a12 patients from the efficacy population did not have any genomics carried out except CRF before the first treatment and were therefore not included. bTwo patients with colorectal cancer and one patient with cholangiocarcinoma were excluded from efficacy analyses due to additional co-occurring driver alterations of PIK3CB E1051G, KRAS Q61H and BRAF V600E, respectively. After enrollment, although the patients were allowed to continue on-study, considering concurrent activating events the sponsor later excluded these patients from the efficacy cohort as the concurrent drivers were adjudicated centrally.

Extended Data Fig. 3. Phase 2 study design.

aEnrollment as of 18 February 2021 and data cutoff date 18 October 2021. bEnrollment and data cutoff date as of 18 October 2021. PD-1, programmed death-1; PD-L1, programmed death ligand-1.

Extended Data Fig. 4

a, Duration of response in 13 patients with RET fusion–positive tumors in the efficacy-evaluable population with a confirmed CR or PR. b, Progression-free survival in 23 patients with RET fusion–positive tumors in the efficacy-evaluable population. c, Overall survival in 23 patients with RET fusion–positive tumors in the efficacy-evaluable population.

Extended Data Fig. 5. Treatment-emergent adverse events occurring in ≥15% of patients.

aEnrollment and data cutoff date as of 18 October 2021.