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PURPOSE: Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors. PATIENTS AND METHODS: We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily. RESULTS: Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles. CONCLUSION: The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted.

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Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1-4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0-2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5-5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6-5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2-8.8; P < 0.001).Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020-6. ©2017 AACR.

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OBJECTIVE: The aim of our study was to compare the age-standardized incidence of esophageal cancer (EC) in Puerto Ricans (PRs) with that for non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic (USH), groups in the United States (US) as reported by the Surveillance, Epidemiology, and End Results program for the 1992-2005 period. METHODS: We computed the age-standardized and age-specific incidence (per 100,000 individuals) of EC during 1992-2005 using the World Standard Population as reference. The percent changes for age-standardized rates (ASR), from 1992-1996 to 2001-2005, were calculated. The relative risks (RR) and the standardized rate ratios (SRR) were estimated, along with 95% confidence intervals (CIs). RESULTS: The ASR of adenocarcinomas (AC) showed increases for most racial/ethnic groups from 1992-1996 to 2001-2005. All racial/ethnic groups showed ASR reductions for squamous cell carcinomas (SCC). For both sexes, PRs had lower AC incidences than NHW and USH but higher than NHB. For those younger than 80 years of age, PR men showed higher SCC incidences than NHW but lower than NHB (P < 0.05). The incidence of SCC was about two times higher in PR men than USH men (SRR: 2.16; 95% CI = 1.65-2.88). Among women, the RR for SCC increased with age when comparing PRs to groups in the US. CONCLUSION: Incidence disparities were observed between PRs and other racial/ethnic groups in the US. These differences and trends may reflect lifestyles of each racial/ethnic group. Further studies are warranted to explain these disparities.

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