Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations
Autor: | Yosef Tobi, Neal Rosen, Amanda Johnson, Michelle S. Ginsberg, Alyssa Shannon, Eusebio Manchado, Charles M. Rudin, Victoria Perron, Mark G. Kris, Gregory J Riely, Piro Lito, Andy Ni, Kathryn C. Arbour, Matthew J. Bott, Helena A. Yu, Andrei I. Holodny, Linda Ahn, Scott W. Lowe, Marc Ladanyi |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: |
Pulmonary and Respiratory Medicine
Oncology medicine.medical_specialty Combination therapy Phases of clinical research medicine.disease_cause NSCLC chemistry.chemical_compound Internal medicine KRAS Medicine Adverse effect neoplasms RC254-282 Trametinib business.industry MEK inhibitor Ponatinib Neoplasms. Tumors. Oncology. Including cancer and carcinogens targeted therapy MEK respiratory tract diseases FGFR1 chemistry Tolerability business |
Zdroj: | JTO Clinical and Research Reports, Vol 3, Iss 1, Pp 100256-(2022) |
ISSN: | 2666-3643 |
Popis: | Introduction: Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. Methods: A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. Results: A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. Conclusions: In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability. |
Databáze: | OpenAIRE |
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