Phase 1 clinical trial of trametinib and ponatinib in patients with NSCLC harboring KRAS mutations Journal Article


Authors: Arbour, K. C.; Manchado, E.; Bott, M. J.; Ahn, L.; Tobi, Y.; Ni, A. A.; Yu, H. A.; Shannon, A.; Ladanyi, M.; Perron, V.; Ginsberg, M. S.; Johnson, A.; Holodny, A.; Kris, M. G.; Rudin, C. M.; Lito, P.; Rosen, N.; Lowe, S.; Riely, G. J.
Article Title: Phase 1 clinical trial of trametinib and ponatinib in patients with NSCLC harboring KRAS mutations
Abstract: 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. © 2021 The Authors
Keywords: targeted therapy; kras; mek; nsclc; fgfr1
Journal Title: JTO Clinical and Research Reports
Volume: 3
Issue: 1
ISSN: 2666-3643
Publisher: Elsevier BV  
Date Published: 2022-01-01
Start Page: 100256
Language: English
DOI: 10.1016/j.jtocrr.2021.100256
PROVIDER: scopus
PMCID: PMC8693267
PUBMED: 34984405
DOI/URL:
Notes: Article -- Export Date: 3 January 2022 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    425 Rosen
  2. Michelle S Ginsberg
    235 Ginsberg
  3. Helena Alexandra Yu
    281 Yu
  4. Piro Lito
    58 Lito
  5. Marc Ladanyi
    1326 Ladanyi
  6. Gregory J Riely
    599 Riely
  7. Linda Su Hyun Ahn
    25 Ahn
  8. Matthew Bott
    135 Bott
  9. Andrei Holodny
    206 Holodny
  10. Mark Kris
    869 Kris
  11. Scott W Lowe
    249 Lowe
  12. Charles Rudin
    488 Rudin
  13. Kathryn Cecilia Arbour
    88 Arbour
  14. Yosef Y Tobi
    6 Tobi
  15. Victoria Perron
    1 Perron