Abstract
BACKGROUND RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly lowgrade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 825-835 |
| Number of pages | 11 |
| Journal | New England Journal of Medicine |
| Volume | 383 |
| Issue number | 9 |
| DOIs | |
| State | Published - Aug 27 2020 |
ASJC Scopus subject areas
- Medicine(all)
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Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. / Wirth, L. J.; Sherman, E.; Robinson, B.; Solomon, B.; Kang, H.; Lorch, J.; Worden, F.; Brose, M.; Patel, J.; Leboulleux, S.; Godbert, Y.; Barlesi, F.; Morris, J. C.; Owonikoko, T. K.; Tan, D. S.W.; Gautschi, O.; Weiss, J.; De La Fouchardière, C.; Burkard, M. E.; Laskin, J.; Taylor, M. H.; Kroiss, M.; Medioni, J.; Goldman, J. W.; Bauer, T. M.; Levy, B.; Zhu, V. W.; Lakhani, N.; Moreno, V.; Ebata, K.; Nguyen, M.; Heirich, D.; Zhu, E. Y.; Huang, X.; Yang, L.; Kherani, J.; Rothenberg, S. M.; Drilon, A.; Subbiah, V.; Shah, M. H.; Cabanillas, M. E.; Wirth, L. J.
In: New England Journal of Medicine, Vol. 383, No. 9, 27.08.2020, p. 825-835.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
AU - Wirth, L. J.
AU - Sherman, E.
AU - Robinson, B.
AU - Solomon, B.
AU - Kang, H.
AU - Lorch, J.
AU - Worden, F.
AU - Brose, M.
AU - Patel, J.
AU - Leboulleux, S.
AU - Godbert, Y.
AU - Barlesi, F.
AU - Morris, J. C.
AU - Owonikoko, T. K.
AU - Tan, D. S.W.
AU - Gautschi, O.
AU - Weiss, J.
AU - De La Fouchardière, C.
AU - Burkard, M. E.
AU - Laskin, J.
AU - Taylor, M. H.
AU - Kroiss, M.
AU - Medioni, J.
AU - Goldman, J. W.
AU - Bauer, T. M.
AU - Levy, B.
AU - Zhu, V. W.
AU - Lakhani, N.
AU - Moreno, V.
AU - Ebata, K.
AU - Nguyen, M.
AU - Heirich, D.
AU - Zhu, E. Y.
AU - Huang, X.
AU - Yang, L.
AU - Kherani, J.
AU - Rothenberg, S. M.
AU - Drilon, A.
AU - Subbiah, V.
AU - Shah, M. H.
AU - Cabanillas, M. E.
AU - Wirth, L. J.
N1 - Funding Information: This trial was designed jointly by the sponsor (Loxo Oncology, a wholly owned subsidiary of Eli Lilly) and the investigators. The sponsor collected, analyzed, and interpreted the trial data in collaboration with the authors. The first draft of the manuscript was written by the first author and the last three authors in collaboration with the sponsor. All the authors provided critical input for the manuscript and approved the final version. A medical writer who was funded by the sponsor provided writing assistance. All the authors vouch for the completeness and accuracy of the clinical data and for the adherence of the trial to the protocol. Funding Information: Supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly, and by grants from the National Institutes of Health (1R01CA242845-01A1, to Dr. Subbiah) and the University of Texas M.D. Anderson Cancer Center (P30 CA016672). Funding Information: Dr. Wirth reports receiving advisory board fees from Ayala Pharmaceuticals, Blueprint Medicines, Cue Biopharma, Cullinan Oncology, Genentech USA, Loxo Oncology, Merck, NewLink Genetics, Novartis, and Rakuten Medical, consulting fees and advisory board fees from Bayer HealthCare Pharmaceuticals and Eisai, advisory board fees and fees for serving on a steering committee from Eli Lilly, and fees for serving on a data and safety monitoring board from Iovance Biotherapeutics; Dr. Sherman, receiving consulting fees from Eisai, Eli Lilly, Loxo Oncology, and Regeneron Pharmaceuticals; Dr. Robinson, receiving consulting fees from Eisai and Eli Lilly; Dr. Solomon, receiving advisory board fees from Amgen, AstraZeneca, F. Hoffmann–La Roche, Genentech, Loxo Oncology, Merck, Novartis, and Pfizer and consulting fees from Bristol-Myers Squibb; Dr. Kang, receiv- ing advisory board fees from Bayer HealthCare Pharmaceuticals, GlaxoSmithKline, and Prelude Therapeutics and grant support, paid to the University of California, San Francisco, from Elevar Therapeutics, Eli Lilly, Exelixis, and Kura Oncology; Dr. Lorch, receiving consulting fees from Bayer HealthCare Pharmaceuticals and Genentech USA and advisory board fees from Novartis; Dr. Worden, receiving grant support, paid to his institution, from Bristol-Myers Squibb, Eisai, and Pfizer and advisory board fees from Eli Lilly and Merck; Dr. Brose, receiving advisory board fees from Loxo Oncology; Dr. Patel, receiving consulting fees from AbbVie, AstraZeneca, Genentech USA, and Takeda Oncology and grant support, paid to her institution, from Bristol-Myers Squibb; Dr. Leboulleux, receiving advisory board fees from Bayer HealthCare Pharmaceuticals and Loxo Oncology, consulting fees from Eisai, and grant support, paid to her institution, from Novartis Pharma and Sanofi Genzyme; Dr. Barlesi, receiving consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann–La Roche, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, and Takeda Oncology; Dr. Owonikoko, receiving advisory board fees from Cambium Oncology and grant support, paid to Emory University, from Eli Lilly; Dr. Tan, receiving grant support, paid to National Cancer Center Singapore, and consulting fees from AstraZeneca and Novartis, consulting fees from Bayer, Merck, and Pfizer, and grant support, paid to the Genome Institute of Singapore/National Cancer Center Singapore, from GlaxoSmithKline; Dr. Gautschi, receiving consulting fees from Amgen; Dr. Weiss, receiving consulting fees from AbbVie, Asitra, Blueprint Medicines, Genentech, Inivata, Nanobio-tix, Rakuten Medical, and Saatchi and Saatchi Wellness, grant support, paid to the University of North Carolina Lineberger Comprehensive Cancer Center (UNC LCCC), from Amgen, CareFusion, Immunicum, and Merck, grant support, paid to the UNC LCCC, and consulting fees from AstraZeneca, Celgene, Eli Lilly, G1 Therapeutics, and Pfizer, and fees for serving on a data and safety monitoring board from EMD Serono and Jounce Therapeutics; Dr. de la Fouchardière, receiving travel support from Amgen and Bristol-Myers Squibb, grant support from Bayer, and advisory board fees from Eisai, Merck Sharp & Dohme, Pierre Fabre Médicament, and Servier; Dr. Laskin, receiving grant support, paid to BC Cancer–Vancouver, and advisory board fees from AstraZeneca Canada, grant support, paid to BC Cancer–Vancouver, from Eli Lilly, and advisory board fees from F. Hoffmann–La Roche and Pfizer; Dr. Taylor, receiving advisory board fees from ArQule, Array BioPharma, Bayer, Blueprint Medicines, Loxo Oncology, and Sanofi and Genzyme US and advisory board fees and fees for serving on a speakers bureau from Bristol-Myers Squibb and Eisai; Dr. Kroiss, receiving consulting fees from Lilly Deutschland; Dr. Medioni, receiving consulting fees from Grünenthal and Novartis; Dr. Goldman, receiving grant support, paid to the University of California, Los Angeles, from Eli Lilly; Dr. Bauer, receiving grant support, paid to the Sarah Cannon Research Institute, from AbbVie, Aileron Therapeutics, Amgen, ARMO BioSciences, Boehringer Ingel-heim, Bristol-Myers Squibb, Calithera, Daiichi Sankyo, Deciphera Pharmaceuticals, Five Prime Therapeutics, GlaxoSmithKline, Immunocore, ImmunoGen, Incyte, Jacobio Pharmaceuticals, Janssen Biotech, Karyopharm Therapeutics, Kolltan Pharmaceuticals, Leap Therapeutics, Loxo Oncology, MabVax Therapeutics, MedImmune, MedPacto, Merrimack Pharmaceuticals, Millennium Pharmaceuticals, Mirati Therapeutics, Onyx Pharmaceuticals, Peloton Therapeutics, Phosplatin Therapeutics, Principia Bio-pharma, Roche, Sanofi Pasteur, Takeda Oncology, and Top Alliance BioScience, grant support, paid to the Sarah Cannon Research Institute, and travel support from Astellas Pharma, AstraZeneca, Clovis Oncology, Genentech USA, Merck, and No-vartis, fees for serving on a speakers bureau from Bayer, con- sulting fees from Blueprint Medicines, Exelixis, and Guardant Health, travel support from Celgene, EMD Serono, and Sysmex America, grant support, paid to the Sarah Cannon Research Institute, consulting fees, and travel support from Eli Lilly and Pfizer, and grant support, paid to the Sarah Cannon Research Institute, and consulting fees from Foundation Medicine, Ignyta, and Moderna Therapeutics; Dr. Levy, receiving advisory board fees and consulting fees from AstraZeneca, Eli Lilly, and Pfizer and advisory board fees from Celgene, Genentech, Merck, No-vartis Pharma, and Takeda Oncology; Dr. V. Zhu, receiving consulting fees and lecture fees from AstraZeneca, Genentech, and Takeda Oncology, receiving lecture fees from Roche–Foundation Medicine, and owning stock in Turning Point Therapeutics; Dr. Lakhani, receiving research funding, paid to his institution, from Alexion Pharmaceuticals, ALX Oncology, Apexian Pharmaceuticals, Asana BioSciences, Ascentage Pharma, BeiGene, Cerulean Pharma, Constellation Pharmaceuticals, CytomX Therapeutics, Formation Biologics, Forty Seven, Ikena Oncology, Incyte, InhibRx, Jounce Therapeutics, Loxo Oncology, Macro-Genics, Merck, Northern Biologics, Odonate Therapeutics, Pfizer, Regeneron Pharmaceuticals, Symphogen, and TaiRx and research funding, paid to his institution, and consulting fees from Innovent Biologics; Dr. Moreno, receiving consulting fees from Bayer and Bristol-Myers Squibb; Dr. Ebata, being employed by and owning stock in Loxo Oncology; Ms. Nguyen, being employed by Eli Lilly; Drs. E. Zhu, Huang, and Kherani, being employed by Loxo Oncology; Dr. Rothenberg, being employed by and owning stock options in Loxo Oncology and Pfizer; Dr. Drilon, receiving consulting fees from 14ner Oncology, AbbVie, AstraZeneca, Bayer, BeiGene, BerGenBio, Blueprint Medicines, Boehringer Ingelheim, Eli Lilly, Exelixis, GlaxoSmithKline, Hel-sinn, Hengrui Therapeutics, Merus, MORE Health, Pfizer, Pharma-Mar, Puma Biotechnology, Roche Health Solutions, Taiho Pharmaceutical, Teva Pharmaceuticals USA, Turning Point Therapeutics, Tyra Biosciences, and Verastem, advisory board fees from Genentech, Ignyta, Loxo Oncology, and Takeda–Ariad Pharmaceuticals–Millennium Pharmaceuticals, and meal reimbursement from Merck; Dr. Subbiah, receiving grant support, paid to his institution, from AbbVie, Agensys, Alfasigma, Altum Pharmaceuticals, Amgen, Bayer HealthCare Pharmaceuticals, Berg Health, Blueprint Medicines, Boston Pharmaceuticals, Boston Biomedical, Celgene, D3 Pharma, Dragonfly Therapeutics, Eli Lilly, Exelixis, Fujifilm Medical Systems USA, Genentech USA, GlaxoSmithKline, Idera Pharmaceuticals, Incyte, InhibRx, Loxo Oncology, MedImmune, MultiVir, NanoCarrier, Northwest Bio-therapeutics, Novartis Pharma, Pfizer, Pharmamar, R-Pharm US, Takeda Oncology, and Vegenics, grant support, paid to his institution, consulting fees, and travel support from Incyte, travel support from Helsinn Healthcare, lecture fees from Medscape, and consulting fees from QED Therapeutics; Dr. Shah, receiving grant support, paid to Ohio State University, and consulting fees from Eli Lilly; and Dr. Cabanillas, receiving grant support, paid to her institution, from Eisai, Exelixis, Genentech USA, Kura Oncology, and Merck and advisory board fees from Ignyta and Loxo Oncology. No other potential conflict of interest relevant to this article was reported.
PY - 2020/8/27
Y1 - 2020/8/27
N2 - BACKGROUND RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly lowgrade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
AB - BACKGROUND RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly lowgrade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
UR - http://www.scopus.com/inward/record.url?scp=85089988559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089988559&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2005651
DO - 10.1056/NEJMoa2005651
M3 - Article
C2 - 32846061
AN - SCOPUS:85089988559
VL - 383
SP - 825
EP - 835
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 9
ER -