Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

L. J. Wirth; E. Sherman; B. Robinson; B. Solomon; H. Kang; J. Lorch; F. Worden; M. Brose; J. Patel; S. Leboulleux; Y. Godbert; F. Barlesi; J. C. Morris; T. K. Owonikoko; D. S.W. Tan; O. Gautschi; J. Weiss; C. De La Fouchardière; M. E. Burkard; J. Laskin; M. H. Taylor; M. Kroiss; J. Medioni; J. W. Goldman; T. M. Bauer; B. Levy; V. W. Zhu; N. Lakhani; V. Moreno; K. Ebata; M. Nguyen; D. Heirich; E. Y. Zhu; X. Huang; L. Yang; J. Kherani; S. M. Rothenberg; A. Drilon; V. Subbiah; M. H. Shah; M. E. Cabanillas; L. J. Wirth

doi:10.1056/NEJMoa2005651

Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

L. J. Wirth, E. Sherman, B. Robinson, B. Solomon, H. Kang, J. Lorch, F. Worden, M. Brose, J. Patel, S. Leboulleux, Y. Godbert, F. Barlesi, J. C. Morris, T. K. Owonikoko, D. S.W. Tan, O. Gautschi, J. Weiss, C. De La Fouchardière, M. E. Burkard, J. LaskinM. H. Taylor, M. Kroiss, J. Medioni, J. W. Goldman, T. M. Bauer, B. Levy, V. W. Zhu, N. Lakhani, V. Moreno, K. Ebata, M. Nguyen, D. Heirich, E. Y. Zhu, X. Huang, L. Yang, J. Kherani, S. M. Rothenberg, A. Drilon, V. Subbiah, M. H. Shah, M. E. Cabanillas, L. J. Wirth

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

545 Scopus citations

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	https://doi.org/10.1056/NEJMoa2005651
State	Published - Aug 27 2020

Funding

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.

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General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1056/NEJMoa2005651

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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., ... Wirth, L. J. (2020). Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. New England Journal of Medicine, 383(9), 825-835. https://doi.org/10.1056/NEJMoa2005651

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title = "Efficacy of Selpercatinib in RET-Altered Thyroid Cancers",

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.).",

author = "Wirth, {L. J.} and E. Sherman and B. Robinson and B. Solomon and H. Kang and J. Lorch and F. Worden and M. Brose and J. Patel and S. Leboulleux and Y. Godbert and F. Barlesi and Morris, {J. C.} and Owonikoko, {T. K.} and Tan, {D. S.W.} and O. Gautschi and J. Weiss and {De La Fouchardi{\`e}re}, C. and Burkard, {M. E.} and J. Laskin and Taylor, {M. H.} and M. Kroiss and J. Medioni and Goldman, {J. W.} and Bauer, {T. M.} and B. Levy and Zhu, {V. W.} and N. Lakhani and V. Moreno and K. Ebata and M. Nguyen and D. Heirich and Zhu, {E. Y.} and X. Huang and L. Yang and J. Kherani and Rothenberg, {S. M.} and A. Drilon and V. Subbiah and Shah, {M. H.} and Cabanillas, {M. E.} and Wirth, {L. J.}",

year = "2020",

month = aug,

day = "27",

doi = "10.1056/NEJMoa2005651",

language = "English (US)",

volume = "383",

pages = "825--835",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "9",

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Wirth, LJ, Sherman, E, Robinson, B, Solomon, B, Kang, H, Lorch, J, Worden, F, Brose, M, Patel, J, Leboulleux, S, Godbert, Y, Barlesi, F, Morris, JC, Owonikoko, TK, Tan, DSW, Gautschi, O, Weiss, J, De La Fouchardière, C, Burkard, ME, Laskin, J, Taylor, MH, Kroiss, M, Medioni, J, Goldman, JW, Bauer, TM, Levy, B, Zhu, VW, Lakhani, N, Moreno, V, Ebata, K, Nguyen, M, Heirich, D, Zhu, EY, Huang, X, Yang, L, Kherani, J, Rothenberg, SM, Drilon, A, Subbiah, V, Shah, MH, Cabanillas, ME & Wirth, LJ 2020, 'Efficacy of Selpercatinib in RET-Altered Thyroid Cancers', New England Journal of Medicine, vol. 383, no. 9, pp. 825-835. https://doi.org/10.1056/NEJMoa2005651

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.

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.).

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DO - 10.1056/NEJMoa2005651

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 9

ER -

Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

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