Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations

Kathryn C. Arbour, MD; Eusebio Manchado, PhD; Matthew J. Bott, MD; Linda Ahn, NP; Yosef Tobi, BA; Andy Ai Ni; Helena A. Yu, MD; Alyssa Shannon, BA; Marc Ladanyi, MD; Victoria Perron, BS; Michelle S. Ginsberg, MD; Amanda Johnson, BA; Andrei Holodny, MD; Mark G. Kris, MD; Charles M. Rudin, MD, PhD; Piro Lito, MD, PhD; Neal Rosen, MD, PhD; Scott Lowe, PhD; Gregory J. Riely, MD, PhD

JTO Clinical and Research Reports (Jan 2022)

Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations

Kathryn C. Arbour, MD,
Eusebio Manchado, PhD,
Matthew J. Bott, MD,
Linda Ahn, NP,
Yosef Tobi, BA,
Andy Ai Ni,
Helena A. Yu, MD,
Alyssa Shannon, BA,
Marc Ladanyi, MD,
Victoria Perron, BS,
Michelle S. Ginsberg, MD,
Amanda Johnson, BA,
Andrei Holodny, MD,
Mark G. Kris, MD,
Charles M. Rudin, MD, PhD,
Piro Lito, MD, PhD,
Neal Rosen, MD, PhD,
Scott Lowe, PhD,
Gregory J. Riely, MD, PhD

Affiliations

Kathryn C. Arbour, MD: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York; Corresponding author. Address for correspondence: Kathryn C. Arbour, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 540 East 74th Street, New York, NY 10021.
Eusebio Manchado, PhD: Oncology Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland
Matthew J. Bott, MD: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
Linda Ahn, NP: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
Yosef Tobi, BA: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
Andy Ai Ni: Department of Biostatistics, The Ohio State University College of Public Health, Columbus, Ohio
Helena A. Yu, MD: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
Alyssa Shannon, BA: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
Marc Ladanyi, MD: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
Victoria Perron, BS: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
Michelle S. Ginsberg, MD: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
Amanda Johnson, BA: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
Andrei Holodny, MD: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
Mark G. Kris, MD: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
Charles M. Rudin, MD, PhD: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
Piro Lito, MD, PhD: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
Neal Rosen, MD, PhD: Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York
Scott Lowe, PhD: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
Gregory J. Riely, MD, PhD: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York

Journal volume & issue: Vol. 3, no. 1
p. 100256

Abstract

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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.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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