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Purpose:To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.Patients and Methods:This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAFV600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy–progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7).Results:Median OS was 31.8 months [95% confidence interval (CI), 24.5–not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, the median OS was 8.5 months (95% CI, 6.7–11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.Conclusions:A subset of patients with advanced BRAFV600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Purpose: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. Patients and Methods: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAFV600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy–progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). Results: Median OS was 31.8 months [95% confidence interval (CI), 24.5–not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, the median OS was 8.5 months (95% CI, 6.7–11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. Conclusions: A subset of patients with advanced BRAFV600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Introduction: Prior data indicate that within procedural specialties, women may be less likely to be first and senior authors of manuscripts during the COVID-19 pandemic, especially for studies pertaining to the pandemic. Women are more likely faced with challenges of balancing work and other duties such as household responsibilities and childcare, especially for those who are mothers. The purpose of this study was to determine the gender distribution of authorship of manuscripts in high-impact gastroenterology and hepatology journals during the early part of the COVID-19 pandemic. Methods: Manuscripts published between March 1, 2019 to January 1, 2020 and March 1, 2020 to January 1, 2021 in 16 high-impact gastroenterology and hepatology journals were identified using bibliometric data. Genders of first authors and senior authors were determined by matching first names with a predicted gender using a validated multinational database (Genderize.io). Number of women and men first and senior authors, and whether the manuscript was related to COVID-19 were recorded. Comparisons between female first and senior authorship of manuscripts from 2019 and 2020 were analyzed using Fisher exact testing. Results: In 2019, women were first authors of 777 (27.4%) manuscripts and senior authors of 546 (18.4%) manuscripts. In 2020, women were first authors of 999 (28.5%) manuscripts and senior authors of 646 (17.7%) manuscripts. There were no statistically significant differences of women first or senior authorship from 2019 to 2020. During the pandemic, women were first authors of 902 (28.9%) non-COVID-19 related manuscripts and 97 (25.7%) COVID-19 related manuscripts. Women were senior authors of 586 (18.0%) non-COVID-19 related manuscripts and 60 (15.6%) COVID-19 related manuscripts. There were no statistically significant differences of women authorship between non-COVID and COVID related manuscripts. Conclusion: The frequency and proportion of women first and senior authorship in 2020 was comparable to that in 2019. Women maintained scientific productivity in gastroenterology regarding publications in high-impact gastroenterology journals, despite facing increased challenges during the early part of the COVID-19 pandemic..

Lessons Learned Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug–drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1. Background Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors. Methods Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle. Results In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1–2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug–drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response. Conclusion The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor–related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.

PURPOSE: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. PATIENTS AND METHODS: This phase 1b, dose-finding and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAF(V600)-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naive (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy (vemurafenib monotherapy–progressive disease [PD]) (n = 66). Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off; 21 days on/7 days off; or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). RESULTS: Median OS was 31.8 months (95% CI: 24.5–not estimable) in the BRAFi-naive cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, median OS was 8.5 months (95% CI: 6.7–11.1) and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. CONCLUSION: A subset of patients with advanced BRAF(V600)-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Background: Dysregulation of the MAPK pathway, initiated by mutations in the RAS or BRAF oncogenes or through upstream growth factor signaling, has been implicated in ~30% of all human cancers. While targeting RAF and/or MEK has proven clinically effective, resistance frequently develops. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced activity in RAS-/RAF-mutant tumors and a reduced potential for acquired resistance. An open-label, dose-escalation Phase Ib study combining cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) to evaluate safety and tolerability, pharmacokinetics (PK), and preliminary signs of efficacy was conducted in patients with locally advanced or metastatic solid tumors. Methods: Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Schedule A consisted of concurrent cobimetinib and GDC-0994 once daily on a 21-day on/7-day off schedule, while Schedule B consisted of intermittent dosing of cobimetinib on Days 1, 4, 8, 11, 15, and 18 of a 28-day cycle concurrent with GDC-0994 QD for 21 consecutive days of a 28-day cycle. Results: In total, 23 patients were enrolled (Schedule A, n=8; Schedule B, n=15). The majority of adverse events (AE) were Grade 1 or Grade 2 and those occurring in ≥ 2 patients in each schedule included diarrhea, nausea, fatigue, decreased appetite, vomiting, blurred vision, dermatitis acneiform, peripheral edema, asthenia, rash, and increased blood creatinine. For Schedule A, a single dose-limiting toxicity (DLT) of Grade 3 diarrhea occurred in cohort A1 (at 40 mg of cobimetinib + 200 mg of GDC-0994). Due to cumulative Grade 1-2 toxicity, the dose of cobimetinib was decreased to 20 mg in cohort A0. For Schedule B, cohort B1 enrolled patients at a dose of 80 mg of cobimetinib + 200 mg of GDC-0994. Dose escalation to cohort B2 (GDC-0994 increased to 400 mg) and cohort B3 (cobimetinib dose increased to 100 mg) resulted in intolerability in both cohorts. As a result, 3 additional patients were enrolled in cohort B1. Two of these patients experienced a DLT of Grade 3 myocardial infarction and Grade 3 rash, respectively. PK data did not show evidence of a drug-drug interaction for either schedule. Overall, 6 patients had a best overall response of SD and 1 patient with pancreatic adenocarcinoma had an unconfirmed partial response. Conclusion: The safety profile of this combination of a MEK and ERK inhibition demonstrated classic MAPK-inhibitor related AEs. No new safety signals were identified. However, overlapping Grade 1-2 AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination. Citation Format: Colin D. Weekes, Albert Lockhard, Patricia LoRusso, Elaine Murray, Erica Park, Michael Tagen, Lars Mueller, Hatem Dokainish, Geoffrey Shapiro, Howard Burris. A Phase Ib study to evaluate the MEK inhibitor cobimetinib in combination with the ERK1/2 inhibitor GDC-0994 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT107. doi:10.1158/1538-7445.AM2017-CT107