Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation-positive melanoma.

BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAFV600-mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported. METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful. RESULTS: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment. CONCLUSIONS: In patients with advanced/metastatic BRAFV600-mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy.

Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.

BACKGROUND: The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. METHODS: In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. FINDINGS: Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. INTERPRETATION: These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. FUNDING: F Hoffmann-La Roche-Genentech.

Risk of subsequent cutaneous squamous cell carcinoma in patients with melanoma.

BACKGROUND: Patients with melanoma are at increased risk for cutaneous squamous cell carcinomas (SCCs). OBJECTIVE: We sought to examine the incidence of subsequent SCC among melanoma survivors and the impact of patient and melanoma characteristics on SCC risk. METHODS: Kaiser Permanente Northern California members given the diagnosis of melanoma from 2000 to 2005 (n = 6378) were followed up through 2009 for a pathology-confirmed SCC. Cox models were used to estimate SCC risk. RESULTS: The crude SCC incidence rate was 2.41 per 100 person-years, and was higher among males and older subjects. In adjusted models stratified by age, SCC risk was higher among males (hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.22-1.67), those with history of nonmelanoma skin cancer (HR 2.56, 95% CI 2.19-2.98), and those with higher tumor sequence numbers (HR 1.35, 95% CI 1.01-1.80). SCC risk was lower among non-Hispanic whites (HR 0.39, 95% CI 0.17-0.86). LIMITATIONS: SCC risk was not examined among members without melanoma. CONCLUSIONS: SCCs arise in approximately 12% of patients with melanoma over a 5-year period and are more common among males, whites, patients older than 60 years, those with prior reportable cancers, and those with history of nonmelanoma skin cancer. Clinicians should be vigilant for SCCs among these individuals at high risk, and counsel melanoma survivors about their increased risk for SCCs.

GRT-R910: a self-amplifying mRNA SARS-CoV-2 vaccine boosts immunity for ≥6 months in previously-vaccinated older adults.

SARS-CoV-2 has resulted in high levels of morbidity and mortality world-wide, and severe complications can occur in older populations. Humoral immunity induced by authorized vaccines wanes within 6 months, and frequent boosts may only offer transient protection. GRT-R910 is an investigational self-amplifying mRNA (samRNA)-based SARS-CoV-2 vaccine delivering full-length Spike and selected conserved non-Spike T cell epitopes. This study reports interim analyses for a phase I open-label dose-escalation trial evaluating GRT-R910 in previously vaccinated healthy older adults (NCT05148962). Primary endpoints of safety and tolerability were assessed. Most solicited local and systemic adverse events (AEs) following GRT-R910 dosing were mild to moderate and transient, and no treatment-related serious AEs were observed. The secondary endpoint of immunogenicity was assessed via IgG binding assays, neutralization assays, interferon-gamma ELISpot, and intracellular cytokine staining. Neutralizing antibody titers against ancestral Spike and variants of concern were boosted or induced by GRT-R910 and, contrasting to authorized vaccines, persisted through at least 6 months after the booster dose. GRT-R910 increased and/or broadened functional Spike-specific T cell responses and primed functional T cell responses to conserved non-Spike epitopes. This study is limited due to small sample size, and additional data from ongoing studies will be required to corroborate these interim findings.

Lung Cancer-Related Mortality With Inhaled Insulin or a Comparator: Follow-Up Study of patients previously enrolled in Exubera Controlled Clinical Trials (FUSE) Final Results.

OBJECTIVE: The Follow-Up Study of patients previously enrolled in Exubera controlled clinical trials (FUSE) was designed to evaluate whether patients previously treated with Exubera (EXU; insulin human [rDNA origin], inhaled powder) in controlled clinical trials died because of incident primary lung cancer at a substantially higher rate than patients treated with a comparator. RESEARCH DESIGN AND METHODS: FUSE is a hybrid, randomized, controlled trial/cohort study including participants of 17 prior EXU clinical trials. Pooled patient data from these trials were used, and the subset of patients enrolled in the follow-up cohort study was followed prospectively for 2 years in order to evaluate the incidence of fatal and nonfatal primary lung cancers and all-cause mortality. RESULTS: There were 24,409 person-years (PY) of observation among 7,439 trial patients, with 4,017 PY (16.5%) from the period after the trials but before the prospective follow-up and 5,299 PY (21.7%) from the prospective follow-up. Just over half of the 2,631 patients (51.6%) in the prospective follow-up were randomized to EXU in the original trial. The incidence density ratio was 2.8 (95% CI 0.5, 28.5) for lung cancer-related mortality and 3.7 (95% CI 1.0, 20.7) for incident primary lung cancer. The hazard ratio for all-cause mortality was 0.81 (95% CI 0.60, 1.10). CONCLUSIONS: These data cannot exclude an increased risk of lung cancer-related mortality associated with EXU use. If real, the absolute increased risk of lung cancer-related mortality was small (0.48 cases per 1,000 PY). For all-cause mortality-the most reliably measured end point with the clearest interpretation-EXU users did not experience an excess all-cause death rate (relative or absolute) compared with users of other diabetes treatments over the study period.

Obesity and screening for breast, cervical, and colorectal cancer in women: a review.

The literature examining obesity as a barrier to screening for breast, cervical, and colorectal cancer has not been evaluated systematically. With the increasing prevalence of obesity and its impact on cancer incidence and mortality, it is important to determine whether obesity is a barrier to screening so that cancers among women at increased risk because of their body size can be detected early or prevented entirely. On the basis of 32 relevant published studies (10 breast cancer studies, 14 cervical cancer studies, and 8 colorectal cancer studies), the authors reviewed the literature regarding associations between obesity and recommended screening tests for these cancer sites among women in the U.S. The most consistent associations between obesity and screening behavior were observed for cervical cancer. Most studies reported an inverse relation between decreased cervical cancer screening and increasing body size, and several studies reported that the association was more consistent among white women than among black women. For breast cancer, obesity was associated with decreased screening behavior among white women but not among black women. The literature regarding obesity and colorectal cancer screening adherence was mixed, with some studies reporting an inverse effect of body size on screening behavior and others reporting no effect. Overall, the results indicated that obesity most likely is a barrier to screening for breast and cervical cancers, particularly among white women; the evidence for colorectal cancer screening was inconclusive. Thus, efforts to identify barriers and increase screening for breast and cervical cancers may be targeted toward obese women, whereas outreach to all women should remain the objective for colorectal cancer screening programs.

Relationship between calcium, lactose, vitamin D, and dairy products and ovarian cancer.

Few prospective studies of the relationship between intake of dairy foods, calcium, vitamin D, and lactose and ovarian cancer have been conducted, and results have been largely inconsistent. Two recent studies found significant increased risk with frequent dairy consumption and perhaps with high intakes of calcium or lactose. The authors investigated the association between these foods and nutrients and ovarian cancer risk among 31,925 subjects in the Breast Cancer Detection Demonstration Project follow-up cohort. Multivariable (MV) relative risks (RRs) adjusted for age, parity, and other factors were estimated using Cox proportional hazards models. Over an average follow-up of 8.3 yr, 146 incident ovarian cancer cases were confirmed. Higher intakes of total dairy food (comparing four or more servings per day vs. less than one serving per day) were associated with a statistically significant decreased risk of ovarian cancer, although the trend was not significant (MV RR = 0.42; 95% confidence interval (CI) = 0.20-0.89; P for trend = 0.07). Comparing extreme quartiles, we observed a statistically nonsignificant inverse association between high dietary calcium intake and ovarian cancer (RR = 0.67; 95% CI = 0.43, 1.04; P for trend = 0.08). No statistically significant relations were found for consumption of specific dairy foods, lactose, or vitamin D and ovarian cancer risk. The possibility of a decreased risk of ovarian cancer for dietary calcium merits further evaluation.

A prospective study of dietary alpha-linolenic acid and the risk of prostate cancer (United States).

BACKGROUND: Alpha-linolenic acid (ALA) is the most common omega-3 fatty acid in the Western diet. The relation of dietary intake of ALA to prostate cancer risk remains unresolved. OBJECTIVE: We prospectively evaluated total ALA and ALA from specific food sources including animal, fish, and plant sources in relation to prostate cancer risk. DESIGN: A cohort of 29,592 male participants (age 55-74 years) in the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was followed for an average of 5.1 years. RESULTS: We ascertained 1,898 cases of total prostate cancer, of which 1,631 were organ-confined cases (stage T1b to T3a and N0M0) and 285 were advanced stage cases (stage>or=T3b, N1, or M1). We found no association between total ALA intake and overall prostate cancer (multivariate RR comparing extreme quintiles=0.94; 95% CI=0.81-1.09; P for trend=0.76). The corresponding RRs for organ-confined and advanced prostate cancer were 0.94 (95% CI=0.80-1.10; P for trend=0.80) and 0.83 (95% CI=0.58-1.19; P for trend=0.34), respectively. In addition, no relations were observed between ALA intake from any specific food source and the risks of total, organ-confined, or advanced prostate cancer. ALA intake also showed no association with low grade (Gleason sum<7; 1,221 cases) tumors (P for trend=0.23) or high grade (Gleason sum>or=7; n=677 cases) tumors (P for trend=0.26). CONCLUSIONS: In this prospective study of predominantly Caucasian men who were screened annually for newly incident prostate cancer, dietary intake of total ALA and ALA from specific food sources was not associated with risk of total prostate cancer or prostate tumors that were defined by stage and grade.