The effect of RAS/BRAF mutation status on survival and treatment efficacy in vulnerable older patients with metastatic colorectal cancer – a post-hoc exploratory analysis of the randomized NORDIC9-study
Colorectal cancer has the highest incidence and mortality rate in individuals ≥70 years. Survival has substantially improved in young and fit patients with metastatic colorectal cancer (mCRC) eligible for intensive treatment (doublet/triplet chemotherapy ± targeted agents) through the past decades, however, this benefit is less clear in the older population, especially in vulnerable/frail patients. In the NORDIC9-study, patients received either reduced-dose combination chemotherapy or full-dose monotherapy (bevacizumab (Bev) was optional in both groups) irrespective of RAS/BRAF status. Here, we present the post-hoc exploratory analyses of the RAS/BRAF mutation status on survival and treatment efficacy in a cohort comprising vulnerable older patients with mCRC. Of the very few randomized trials investigating the efficacy of chemotherapy in older adults with mCRC, none has reported specific outcomes in a BRAF mutated population.
In the randomized NORDIC9-study, we included patients ≥70 years with mCRC considered ineligible for full-dose combination chemotherapy. Patients were randomized (1:1) to receive either reduced-dose SOx (S1 20 mg/m 2 twice daily on days 1-14 + oxaliplatin 100 mg/m 2 on day 1, q3w) or full-dose S1 (30 mg/m 2 twice daily on days 1-14, q3w); ± Bev (7.5 mg/kg on day 1, q3w). Overall survival (OS) and progression-free survival (PFS) for subgroups based on RAS/BRAF status were compared by log-rank test. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated by Cox regression. The prognostic value of RAS/BRAF status was evaluated by C-statistics. For multivariate analyses, Cox proportional hazards regression models were applied.
Between March 2015 and October 2017, 160 patients were enrolled; the median age was 78 years (interquartile range (IQR): 75-81). The median follow-up was 23.8 months (IQR: 18.8-30.9). RAS and BRAF status were established in 116 patients with the following distribution: RAS/BRAF wild type ( RAS/BRAF wt) in 36 (31%), RAS mutation ( RAS mut) in 59 (51%), and BRAF V600E mutation ( BRAF mut) in 21 patients (18%). Median OS for RAS/BRAF wt, RAS mut, and BRAF mut subgroups were 16.0, 14.5, and 10.8 months, respectively. In multivariable analysis, BRAF mut patients had significantly higher risk for shorter OS and PFS (OS: HR=2.78 (95%CI: 1.37-5.64), p=0.005; PFS: HR=1.93 (95%CI: 1.04-3.56), p=0.037). Estimating C-statistics, the model indicated a good prognostic value for OS: Harrell’s C=0.73 (95%CI: 0.69-0.78). In the BRAF mut subgroup, patients receiving SOx ± Bev had a significant longer OS (21.4 vs 5.7 months) compared to those receiving S1 ± Bev (HR=0.13 (95%CI: 0.04-0.49), p=0.003) in univariate analysis, and the difference remained statistically significant in the multivariate analysis: HR=0.20 (95%CI: 0.05-0.84), p=0.028).
Our post-hoc exploratory analysis demonstrated a substantial difference in OS favoring patients with BRAF mut tumors receiving reduced-dose combination chemotherapy (± Bev) compared to those treated with full-dose monotherapy (± Bev). The relatively high proportion of patients with BRAF mut in our cohort is representative for the Nordic population. Further investigation is needed in larger cohorts of vulnerable older patients with BRAF mut mCRC to confirm these results.
The NORDIC9-study is registered with EudraCT number 2014-000394-39.
The authors.
This investigator-initiated study was partly funded by Taiho Pharmaceuticals, Nordic Group, The Danish Cancer Society (grant number: R269-A15859), Academy of Geriatric Cancer Research (AgeCare), The Swedish Cancer Society and the Region of Southern Denmark. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
C. Shah: Shareholder / Stockholder / Stock options: Roche AG; Full / Part-time employment: Roche AB. P. Osterlund: Honoraria (self): Eisai, Fresenius Kabi, Incyte, Novartis, Nutricia, ; Advisory / Consultancy: Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Merck, MSD, Nordic Drugs, Pierre Fabre, Roche, Sanofi, Servier, Sobi, ; Speaker Bureau / Expert testimony: BMS; Research grant / Funding (institution): Amgen, Lilly, Merck, Roche, Sanofi, Servier, Incyte, Eisai, MSD. All other authors have declared no conflicts of interest.
