TY - JOUR
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
N1 - Publisher Copyright:
© 2016 International Association for the Study of Lung Cancer
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
KW - Trametinib
UR - http://www.scopus.com/inward/record.url?scp=85015272871&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2016.11.2218
DO - 10.1016/j.jtho.2016.11.2218
M3 - Article
C2 - 27876675
AN - SCOPUS:85015272871
SN - 1556-0864
VL - 12
SP - 556
EP - 566
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 3
ER -