Memorial Sloan Kettering Cancer Center

About: Memorial Sloan Kettering Cancer Center is a healthcare organization based out in New York, New York, United States. It is known for research contribution in the topics: Cancer & Population. The organization has 30293 authors who have published 65381 publications receiving 4462534 citations. The organization is also known as: MSKCC & New York Cancer Hospital.

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.

Abstract: Summary Background Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. Methods In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. Findings Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9–51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5–51·4) in the nivolumab group, and 18·6 months (7·6–49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2–not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3–not reached) in the nivolumab group, and 19·9 months (16·9–24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44–0·67; p Interpretation The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma. Funding Bristol-Myers Squibb.

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.

Abstract: Background Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. Methods We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. Results Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or...

Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts

Abstract: Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Here we show that targeted disruption of the dominant negative helix–loop–helix proteins Id1 and Id3 in mice results in premature withdrawal of neuroblasts from the cell cycle and expression of neural-specific differentiation markers. The Id1–Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm. As angiogenesis both in the brain and in tumours requires invasion of avascular tissue by endothelial cells, we examined the Id knockout mice for their ability to support the growth of tumour xenografts. Three different tumours failed to grow and/or metastasize in Id1+/-Id3-/- mice, and any tumour growth present showed poor vascularization and extensive necrosis. Thus, the Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design.

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

Abstract: BackgroundPertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. MethodsWe randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease–free survival rate of 91.8% with pertuzumab and 89.2% with placebo. ResultsIn the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% ha...

Randomized Comparison of Surveillance Intervals after Colonoscopic Removal of Newly Diagnosed Adenomatous Polyps

Abstract: Background The identification and removal of adenomatous polyps and post-polypectomy surveillance are considered to be important for the control of colorectal cancer. In current practice, the intervals between colonoscopies after polypectomy are variable, often a year long, and not based on data from randomized clinical trials. We sought to determine whether follow-up colonoscopy at three years would detect important colonic lesions as well as follow-up colonoscopy at both one and three years. Methods Patients were eligible if they had one or more adenomas, no previous polypectomy, and a complete colonoscopy and if all their polyps had been removed. They were randomly assigned to have follow-up colonoscopy at one and three years or at three years only. The two study end points were the detection of any adenoma, and the detection of adenomas with advanced pathological features (defined as those >1 cm in diameter and those with high-grade dysplasia or invasive cancer). Results Of 2632 eligible patients, 141...