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.

• Authors: Vivek Subbiah, Philippe A Cassier, Salvatore Siena, Elena Garralda, Luis Paz-Ares, Pilar Garrido, Ernest Nadal, Jacqueline Vuky, Gilberto Lopes, Gregory P Kalemkerian, Daniel W Bowles, Mahesh Seetharam, Jianhua Chang, Hui Zhang, Jennifer Green, Alena Zalutskaya, Martin Schuler, Yun Fan, Giuseppe Curigliano
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 8 Pg. 1640-1645 (08 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35962206 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022. The Author(s).

Chemical References

• Pyrazoles
• Pyridines
• Pyrimidines
• pralsetinib
• Proto-Oncogene Proteins c-ret
• RET protein, human

Topics

• Gene Fusion
• Humans
• Neoplasms (drug therapy, genetics, pathology)
• Proto-Oncogene Proteins c-ret (genetics)
• Pyrazoles (adverse effects)
• Pyridines (adverse effects)
• Pyrimidines (adverse effects)