Background Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. Methods This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. Findings In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Interpretation Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations Funding ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM

Background: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC.

To determine rates of pathologic complete response (pCR) and near-complete response (npCR) in operable early-stage breast cancer using neoadjuvant capecitabine plus docetaxel, with or without trastuzumab, and investigate biomarkers of pathologic response. Women with operable early-stage breast cancer were enrolled in a multicenter study of neoadjuvant therapy for four 21-day cycles with capecitabine 825 mg/m(2) plus docetaxel 75 mg/m(2) if human epidermal growth factor receptor 2 (HER2)-negative, and additionally, a standard trastuzumab dose if HER2-positive. Primary endpoint was rate of pCR and npCR. Secondary endpoints were potential associations between response and TP53 mutational analysis using the AmpliChip TP53 assay or immunohistochemical (IHC) staining, and genomic subtyping using the PAM50 assay. In patients who completed treatment and surgery, pCR and npCR rates were 15.8% in patients with HER2-negative and 50% in patients with HER2-positive tumors. Stratified by genomic subtype, patients of HER2-enriched subtype had the best response (72.2%), and luminal A (9.1%) and B (4.8%) subtypes, the poorest. Of 147 patients tested for TP53 mutations using the AmpliChip assay, 78 variants were detected; 55 were missense. Response rate among TP53-mutated patients was 30%, significantly higher than TP53 wild-type patients (10%; P = 0.0032). Concordance between AmpliChip mutation status versus TP53 IHC staining was 65%, with AmpliChip status predictive of response and IHC status not predictive. Capecitabine plus docetaxel in HER2-negative, and with trastuzumab in HER2-positive patients, provided a good response rate with four cycles of non-anthracycline-containing therapy. TP53 mutational analysis and genomic subtyping were predictive.

This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.

Purpose:The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAF V600 mutation-positive advanced melanoma. We report long-term followup of coBRIM, with at least 5 years since the last patient was randomized.Experimental Design: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).Results: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAF V600 mutation-positive advanced melanoma.Research.