Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study.

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. ClinicalTrials.gov: NCT01689519.

Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized, controlled trials.

BACKGROUND: Adjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens. PATIENTS AND METHODS: Individual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, MC (low versus high), or age (<70 versus ≥70), and compared for disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Multivariable Cox proportional hazards regression controlled for gender, T stage, and N stage. RESULTS: DFS benefits were shown for XELOX/FOLFOX versus LV/5-FU regardless of age or MC, although benefits were modestly attenuated for patients aged ≥70. Hazard ratios were 0.68 (P < 0.0001) and 0.77 (P < 0.014) for <70 and ≥70 age groups; 0.69 (P < 0.0001) and 0.59 (P < 0.0001) for Charlson Comorbidity Index ≤1 and >1 groups; and 0.70 (P < 0.0001) and 0.58 (P < 0.0001) for National Cancer Institute Combined Index ≤1 and >1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and MC scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and MC scores. CONCLUSIONS: Results further support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III CC in all age groups and in patients with comorbidities, consistent with those who were eligible for these clinical trials.

Treatment effect of capecitabine and docetaxel or docetaxel alone by oestrogen receptor status in patients with metastatic breast cancer: results of an exploratory analysis.

We investigated treatment effects by oestrogen receptor (ER) status among women with metastatic breast cancer (MBC) receiving capecitabine (C) plus docetaxel (D) or D alone in a randomised phase III trial. Data were retrospectively analysed from patients whose disease had recurred following (neo)adjuvant anthracyclines. ER status was identified in 356/506 patients. In patients with ER-positive tumours, median overall survival from enrolment was 17.7 months with CD versus 12.5 months with D (hazard ratio [HR] 0.65, 95% confidence interval [CI]: 0.47-0.89; P = 0.007) and median time to progression (TTP) was 6.8 and 5.4 months, respectively (HR 0.62, 95% CI: 0.46-0.84; P = 0.002). For patients with ER-negative tumours, significantly longer TTP was seen with CD (5.2 versus 3.5 months; HR 0.73, 95% CI: 0.53-0.98; P = 0.038). Whether there is an additional C to D treatment benefit in ER-positive versus ER-negative MBC requires further evaluation.