Lung cancer is the most common cause of cancer-related death worldwide. Approximately 85% to 90% of lung cancer cases are non-small cell lung cancer (NSCLC), of which KRAS is one of the most common driver genes, occurring in 25-30% of lung adenocarcinomas and 3-5% of squamous cell carcinomas. KRAS-mutant NSCLC had been considered undruggable in past decades. This research sought to address a significant challenge in treating NSCLC with KRAS mutations, which are notoriously difficult to target effectively. Here, we proposal that the combined use of anlotinib and trametinib combined with tislelizumab may form an effective strategy for the treatment of KRAS-mutant NSCLC patients.
This is a phase 1/2, open-label, multi-center study aimed at exploring the potential therapeutic efficacy of tislelizumab (intravenous), trametinib (oral) and anlotinib (oral) in KRAS-mutant advanced non-small cell lung cancer patients. The primary objectives were safety, recommended phase 2 dose (RP2D) in Phase I and PFS in Phase II. The secondary aim of the study is to evaluate the progression-free survival (PFS), overall survival (OS), adverse events (AEs), and duration of response (DOR) of the combined strategy in these patients. If the RP2D is reached in Phase I, Phase II will be started; if RP2D is not reached in Phase I, Phase II will not be started. The number of subjects is determined according to the actual situation of dose climbing. All patients will be of histo- and/or cytopathology confirmed. Determination of the KRAS mutation type will be performed in the pathological department of Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine. Both ARMS method or targeted sequencing are acceptable. It is not acceptable for subjects with the presence of other driver gene mutation. All eligible subjects must have adequate renal, hepatic, and hematologic function, as defined in "inclusion criteria".
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Trametinib will be administrated orally every day.
Anlotinib will be administrated orally from day 1 to day 14 per 21-day cycle.
Tislelizumab will be administered at full dose (200mg, Q3W) on the patient who received the efficacy evaluation of stable disease (SD) or partial response (PR) or complete response (CR) after 2 cycles' treatment of trametinib plus anlotinib.
Shanghai Chest Hospital
Shanghai, China
RP2D
recommended phase 2 dose
Time frame: up to 12 months
PFS
progression-free survival
Time frame: up to 18 months
ORR
objective response rate
Time frame: up to 12 months
OS
overall survival
Time frame: up to 24 months
DOR
duration of response
Time frame: up to 18 months
AEs
adverse events
Time frame: up to 24 months
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