A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer

David R Gandara, Natasha Leighl, Jean Pierre Delord, Fabrice Barlesi, Jaafar Bennouna, Gerald Zalcman, Jeffrey R. Infante, Karen L. Reckamp, Karen Kelly, Frances A. Shepherd, Julien Mazieres, Filip Janku, Olivia S. Gardner, Bijoyesh Mookerjee, Yuehui Wu, Donna S. Cox, Dan Schramek, Vijay Peddareddigari, Yuan Liu, Anthony M. D'AmelioGeorge Blumenschein

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Abstract

Objectives This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. Results The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable. Conclusions Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.

Original languageEnglish (US)
Pages (from-to)556-566
Number of pages11
JournalJournal of Thoracic Oncology
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2017

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docetaxel
Pemetrexed
Lung Neoplasms
trametinib
Mutation
Mitogen-Activated Protein Kinase Kinases
Combination Drug Therapy

Keywords

  • KRAS mutations
  • MEK inhibitor
  • NSCLC
  • Trametinib

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer. / Gandara, David R; Leighl, Natasha; Delord, Jean Pierre; Barlesi, Fabrice; Bennouna, Jaafar; Zalcman, Gerald; Infante, Jeffrey R.; Reckamp, Karen L.; Kelly, Karen; Shepherd, Frances A.; Mazieres, Julien; Janku, Filip; Gardner, Olivia S.; Mookerjee, Bijoyesh; Wu, Yuehui; Cox, Donna S.; Schramek, Dan; Peddareddigari, Vijay; Liu, Yuan; D'Amelio, Anthony M.; Blumenschein, George.

In: Journal of Thoracic Oncology, Vol. 12, No. 3, 01.03.2017, p. 556-566.

Research output: Contribution to journalArticle

Gandara, DR, Leighl, N, Delord, JP, Barlesi, F, Bennouna, J, Zalcman, G, Infante, JR, Reckamp, KL, Kelly, K, Shepherd, FA, Mazieres, J, Janku, F, Gardner, OS, Mookerjee, B, Wu, Y, Cox, DS, Schramek, D, Peddareddigari, V, Liu, Y, D'Amelio, AM & Blumenschein, G 2017, 'A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer', Journal of Thoracic Oncology, vol. 12, no. 3, pp. 556-566. https://doi.org/10.1016/j.jtho.2016.11.2218
Gandara, David R ; Leighl, Natasha ; Delord, Jean Pierre ; Barlesi, Fabrice ; Bennouna, Jaafar ; Zalcman, Gerald ; Infante, Jeffrey R. ; Reckamp, Karen L. ; Kelly, Karen ; Shepherd, Frances A. ; Mazieres, Julien ; Janku, Filip ; Gardner, Olivia S. ; Mookerjee, Bijoyesh ; Wu, Yuehui ; Cox, Donna S. ; Schramek, Dan ; Peddareddigari, Vijay ; Liu, Yuan ; D'Amelio, Anthony M. ; Blumenschein, George. / A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer. In: Journal of Thoracic Oncology. 2017 ; Vol. 12, No. 3. pp. 556-566.
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abstract = "Objectives This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. Results The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21{\%}). The ORR was 18{\%} (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24{\%} (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14{\%}) had a PR; the ORR was 17{\%} (four of 23) in patients with KRAS-mutated NSCLC versus 11{\%} (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable. Conclusions Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.",
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T1 - A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer

AU - Gandara, David R

AU - Leighl, Natasha

AU - Delord, Jean Pierre

AU - Barlesi, Fabrice

AU - Bennouna, Jaafar

AU - Zalcman, Gerald

AU - Infante, Jeffrey R.

AU - Reckamp, Karen L.

AU - Kelly, Karen

AU - Shepherd, Frances A.

AU - Mazieres, Julien

AU - Janku, Filip

AU - Gardner, Olivia S.

AU - Mookerjee, Bijoyesh

AU - Wu, Yuehui

AU - Cox, Donna S.

AU - Schramek, Dan

AU - Peddareddigari, Vijay

AU - Liu, Yuan

AU - D'Amelio, Anthony M.

AU - Blumenschein, George

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Objectives This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. Results The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable. Conclusions Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.

AB - Objectives This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. Results The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable. Conclusions Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.

KW - KRAS mutations

KW - MEK inhibitor

KW - NSCLC

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