Efficacy of selpercatinib in RET-altered thyroid cancers Journal Article
| Authors: | 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. |
| Article 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.). © 2020 Massachussetts Medical Society. All rights reserved. |
| Keywords: | adolescent; adult; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; young adult; gene mutation; major clinical study; genetics; mutation; clinical trial; constipation; fatigue; sorafenib; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypertension; side effect; treatment duration; pyridines; outcome assessment; prospective study; progression free survival; phase 2 clinical trial; protein kinase inhibitor; nausea; vomiting; qt prolongation; cohort analysis; creatinine; creatinine blood level; abdominal pain; arthralgia; backache; coughing; dizziness; drug dose escalation; drug hypersensitivity; rash; protein kinase inhibitors; oncogene; alanine aminotransferase; aspartate aminotransferase; hyponatremia; blood; radioactive iodine; pyrazole derivative; multicenter study; pyrazoles; drug response; gene fusion; vandetanib; peripheral edema; xerostomia; open study; thyroid neoplasms; headache; phase 1 clinical trial; kaplan meier method; hypothyroidism; aminotransferase; protein ret; ret protein, human; proto-oncogene proteins c-ret; thyroid tumor; hypocalcemia; pyridine derivative; abdominal distension; progression-free survival; thyroid medullary carcinoma; kaplan-meier estimate; ret gene; cabozantinib; very elderly; lenvatinib; intention to treat analysis; transaminases; humans; human; male; female; priority journal; article; loxo-292; body weight gain; selpercatinib |
| Journal Title: | New England Journal of Medicine |
| Volume: | 383 |
| Issue: | 9 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2020-08-27 |
| Start Page: | 825 |
| End Page: | 835 |
| Language: | English |
| DOI: | 10.1056/NEJMoa2005651 |
| PUBMED: | 32846061 |
| PROVIDER: | scopus |
| PMCID: | PMC10777663 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2020 -- Source: Scopus |
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