S1507: Phase II study of docetaxel and trametinib in patients with G12C or non-G12C KRAS mutation positive (+) recurrent non-small cell lung cancer (NSCLC).

Abstract

9021 Background: KRAS+ NSCLC remains the most common genetically defined subset of NSCLC. Despite promising pre-clinical data, MEK inhibitors have failed to provide meaningful clinical benefit both as single agents and in combination with chemotherapy in KRAS+ NSCLC patients. Pre-clinical data suggest that efficacy of MEK inhibitors in KRAS+ NSCLC differs based on specific KRAS mutations such as G12C and by status of p53 or LKB1 mutations. We conducted a phase II study to assess the efficacy of docetaxel plus trametinib in KRAS+ NSCLC patients and in specific genetic subsets. Methods: KRAS+ NSCLC patients who had progressive cancer following 1 or 2 prior regimens were eligible. Docetaxel was given at 75 mg/m2 every 3 weeks and trametinib orally at 2 mg daily. The study was 2-stage design to rule out a response rate (RR) of 17% at the 3% level with 90% power if the true rate were 37%. The study required 45 pts with a futility analysis at 30 pts; 13/45 responses would indicate a success. RR was also assessed in G12C and non-G12C cohorts and will be assessed according to presence of co-mutations in p53 and LKB1. Progression free survival (PFS) and overall survival (OS) were secondary endpoints. Multivariate analysis including age, sex, number of prior treatments, prior immunotherapy (IO) and G12C status was conducted. Results: The study enrolled 54 evaluable pts (19 G12C, 9 G12D, 9 G12A); median age 65 years; female 57%; never smokers 7%; adenocarcinoma 89%; liver metastases 31%; 2 prior regimens 70%; prior IO 57%. Outcomes are summarized in Table. Median duration of therapy was 2.2 months and most common toxicities were fatigue (78%), diarrhea (68%), nausea (57%) and vomiting (28%). One patient died of treatment related respiratory failure. There was a trend for worse PFS (HR- 1.86, p = 0.06) and survival (HR- 1.80, p = 0.14) in G12C patients. Analysis of efficacy data according to co-mutations in p53 or LKB1 is ongoing. Conclusions: Docetaxel plus trametinib met the primary endpoint of the study, with a RR of 33% and median survival of 11.1 months in patients with KRAS+ NSCLC, 70% of whom had received 2 prior regimens. Although, there was no statistical difference between KRAS+ subtypes, these data suggest that outcomes may differ between G12C and non-G12C patients. Clinical trial information: NCT02642042. [Table: see text]

My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

“…This is consistent with the findings in a previous study [39]. In addition, there have been a number of clinical trials involving trametinib alone [45] or in combination with other drugs [46] for non-small cell lung cancer. Another drug, gefitinib, targets the epidermal growth factor receptor (EGFR) by inhibiting the tyrosine kinases associated with EGFR [47].…”

Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update

“…The ASCO systematic review found two studies, one published RCT and the second, a single-arm study, including those with KRAS mutations (the study by Carter et al also included patients with KRAS wild type) and previous treatment. 65,66 The study by Carter et al investigated erlotinib versus selumetinib plus erlotinib versus selumetinib. The primary outcome was RR, and the results were minimal.…”

New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness

“…In a phase II trial, trametinib as a monotherapy showed RR and PFS similar to docetaxel in previously treated KRAS -mutant NSCLC (49). Another phase II study with KRAS -mutant NSCLC (n = 54, including 19 with G12C, 9 with G12D, 9 with G12A) documented a trend toward worse PFS (HR = 1.86, p = 0.06) and survival (HR = 1.80, p = 0.14) in G12C patients compared to non-G12C patients (50). Trametinib plus docetaxel had a RR of 33% and median survival of 11.1 months in patients with recurrent KRAS -mutant NSCLC.…”