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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1640-1645 |
| Number of pages | 6 |
| Journal | Nature medicine |
| Volume | 28 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2022 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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In: Nature medicine, Vol. 28, No. 8, 08.2022, p. 1640-1645.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial
AU - Subbiah, Vivek
AU - Cassier, Philippe A.
AU - Siena, Salvatore
AU - Garralda, Elena
AU - Paz-Ares, Luis
AU - Garrido, Pilar
AU - Nadal, Ernest
AU - Vuky, Jacqueline
AU - Lopes, Gilberto
AU - Kalemkerian, Gregory P.
AU - Bowles, Daniel W.
AU - Seetharam, Mahesh
AU - Chang, Jianhua
AU - Zhang, Hui
AU - Green, Jennifer
AU - Zalutskaya, Alena
AU - Schuler, Martin
AU - Fan, Yun
AU - Curigliano, Giuseppe
N1 - Funding Information: 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. Funding Information: The authors would like to thank the patients, their families and all investigators involved in this study. V.S. is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. V.S. acknowledges support of the Jacquelyn A. Brady Fund. V.S. is supported by US National Institutes of Health grants R01CA242845 and R01CA273168. MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (1U01 CA180964), a National Center for Advancing Translational Sciences grant (UL1 TR000371) and the MD Anderson Cancer Center Support grant (P30 CA016672). Medical writing support, including assisting authors with the development of the outline as well as initial draft and incorporation of comments, was provided by N. Tracey and W. Wheddon; editorial support, including submission, was provided by E. Sims and T. Taylor, all of Paragon (Knutsford, United Kingdom), supported by Blueprint Medicines, according to Good Publication Practice guidelines. The sponsor was involved in the study design and collection, analysis and interpretation of data, as well as data checking of information provided in the article. However, ultimate responsibility for opinions, conclusions and data interpretation lies with the authors. E.G. is supported by the Caixa Research Advanced Oncology Research Program (supported by Fundació La Caixa, LCF/PR/CE07/50610001). E.N. is supported by the Carlos III National Health Institute grant (PI21/00789) and Horizon 2020 (H2020-SC1-2019-Single-Stage-RTD). M. Schuler is supported by the Oncology Center of Excellence Grant/German Cancer Aid (70112273) and the German Cancer Consortium, partner site: University Hospital Essen (BMBF 613-71043-1). G.C. is supported by an OPTIMA (optimal treatment for patients with solid tumors in Europe through artificial intelligence) grant (101034347). The ARROW study (NCT03037385) was supported by Blueprint Medicines and F. Hoffmann-La Roche. Publisher Copyright: © 2022, The Author(s).
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-022-01931-y
DO - 10.1038/s41591-022-01931-y
M3 - Article
C2 - 35962206
AN - SCOPUS:85135806891
SN - 1078-8956
VL - 28
SP - 1640
EP - 1645
JO - Nature Medicine
JF - Nature Medicine
IS - 8
ER -