Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non-Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042)

Abstract

Purpose: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC.

Patients and methods: S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level.

Results: Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22-48] overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers.

Conclusions: RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563.

Trial registration: ClinicalTrials.gov NCT02642042.

Figure1:

A. Statistical Design of the Study 1 based on test of alternative (RR = 37%) at the 1-sided 2% level and 1st stage sample size of 30 patients. The G12C stratum will remain open until at least 9 G12C patients have been enrolled. 2 If sample size at 45 patients includes less than 25 with G12C, study would accrue an additional 5 patients with KRAS G12C NSCLC 3 if total N = 45, then ≥ 13 responses (13/45 (29%) would be evidence to reject a 17% RR at the 3% level 4 if total N = 50, then ≥ 14 responses (14/50 (28%) would be evidence to reject a 17% RR at the 3.5% level 5 if total G12C N = 25, then ≥ 8 responses (8/25 (32%) would be evidence to reject a 17% RR at the 5% level 6 if total G12C N = 30, then ≥ 10 responses (10/30 (33%) would be evidence to reject a 17% RR at the 5% level 7 If 1st stage G12C N = 10, then the study would continue accrual in the G12C subset if > 0 responses were observed and close to accrual if no responses were observed. 8 If 1st stage G12C N = 15, then the study would continue accrual in the G12C subset if ≥2 responses were observed and close to accrual if 0 or 1 responses were observed. 9 if total G12C N = 35, then ≥ 11 responses (11/35(31%) would be evidence to reject a 17% RR at the 3% level. B. Study Consort Diagram

Figure 2:

Waterfall plots of best change in measurements from baseline *: Non-G12C **: absolute change from baseline < 0.5 cm All eligible patients who received at least one dose of protocol treatment are represented in this plot. From left to right, best change in tumor measurements included in the plot are displayed as; • IA: Measurements for patients who did not have any follow-up tumor disease assessments are labeled with ‘IA’ and displayed as a 20% increase, the threshold for progressive disease. • NL: Measurements for patients who had progressive disease at their first assessment based on new lesions are labeled by “NL” and displayed as a 100% increase • SN: Measurements for patients who had symptomatic deterioration at first disease assessment are labeled as “SN” and displayed as a 20% increase, the threshold for progressive disease. • Unlabeled bars: To the right of the labeled bars are bars representing the best change in measurements for patients not coded as IA, SN, or NL with at least one follow-up disease assessment. Bars extending above the dashed line at +20% or labeled as IA, SN, or NL are coded as progressive disease, with one exception, where an absolute increase of < 0.5 cm was coded as stable disease. Unlabeled bars between the dashed lines (+20% to −30%) are coded as best response of stable disease and unlabeled bars extending below the −30% line are coded as best response of partial or complete response.

Figure 3:

Progression Survival and Overall Survival in all patients and in patients with G12C and non-G12C tumors Kaplan-Meier estimates of Progression Free Survival in A) all patients and B) by G12C status; Kaplan-Meier estimates of Overall Survival in C) all patients and D) by G12C status.