5-year outcomes with cobimetinib plus vemurafenib in BRAFV600 mutation⇓positive advanced melanoma: extended follow-up of the coBRIM study

CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAF V600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study Paolo A. Ascierto 1 , Brigitte Dr eno 2 , James Larkin 3 , Antoni Ribas 4 , Gabriella Liszkay 5 , Michele Maio 6 , Mario Mandal a 7 , Lev Demidov 8 , Daniil Stroyakovskiy 9 , Luc Thomas 10 , Luis de la Cruz-Merino 11 , Victoria Atkinson 12 , Caroline Dutriaux 13 , Claus Garbe 14 , Jessie Hsu 15 , Surai Jones 15 , Haocheng Li 16 , Edward McKenna 15 , Athina Voulgari 17 , and Grant A. McArthur 18 ABSTRACT ◥ 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 follow-up of coBRIM, with at least 5 years since the last patient was randomized. Patients and Methods: 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 (n¼247) or placebo plus vemurafenib (n¼248). 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 longterm clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAF V600 mutation–positive advanced melanoma. Introduction In the last several years, combination regimens of BRAF- and MEK- targeted agents have improved treatment outcomes in patients with BRAF V600 mutation–positive metastatic melanoma (1–3). Long-term follow-up data from studies of BRAF and/or MEK inhibitors show that about a third of participating patients derive prolonged survival benefit from these regimens (4–7). Long-term follow-up of patients with BRAF inhibitor–na€ ve BRAF V600 mutation–positive metastatic melanoma in the phase Ib BRIM7 study of the cobimetinib plus vemurafenib combination showed that the overall survival (OS) rate plateaued at 39.2% at years 4 and 5 (4). Similarly, a pooled analysis of patients receiving dabrafenib plus trametinib in the COMBI-d and COMBI-v studies showed OS rates of 37% and 34% at 4 and 5 years, respectively (5). It is of interest to characterize and identify prognostic factors associated with the long-term survival benefits of these treatments, both to inform treatment decisions and to identify new unmet needs for this patient population. The phase III coBRIM study evaluated the combination of cobimetinib plus vemurafenib compared with placebo plus vemurafenib in previously untreated patients with advanced melanoma harboring BRAF V600 mutations (1). In the primary analysis, with a median follow-up of 7.3 months, median progression-free survival (PFS) was 9.9 versus 6.2 months with cobimetinib plus vemurafenib versus placebo plus vemurafenib [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.39–0.68; P<0.001]; OS data were immature (1). With a median follow-up of 14.2 months, updated PFS analysis showed that median PFS had improved to 12.3 months with cobimetinib plus vemurafenib versus 7.2 months with placebo plus vemurafenib (HR, 0.58; 95% CI, 0.46–0.72; P<0.0001; ref. 8). With a median 1 Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy. 2 University of Nantes, Nantes, France. 3 The Royal Marsden Hospital, London, UK. 4 Jonsson Comprehensive Cancer Center at the University of California at Los Angeles, Los Angeles, CA, USA. 5 National Institute of Oncology, Budapest, Hungary. 6 Azienda Ospedaliera Universitaria Senese, Siena, Italy. 7 Papa Giovanni XXIII Hospital, Bergamo, Italy. 8 N.N. Blokhin Russian Cancer Research Center, Moscow, Russia. 9 Moscow City Oncology Hospital 62, Krasnogorsk, Russia. 10 Centre Hospitalier Lyon Sud, Pierre-B enite, France. 11 Hospital Universitario Virgen Macarena, Seville, Spain. 12 Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; Gallipoli Medical Research Foundation, Greenslopes, Queensland, Australia; and University of Queensland, St. Lucia, Queensland, Australia. 13 H^ opital Saint Andr e, Bordeaux, France. 14 University of T€ ubingen, T€ ubingen, Germany. 15 Genentech, a Member of the Roche Group, South San Francisco, California. 16 F. Hoffmann-La Roche Ltd, Mississauga, ON, Canada. 17 Roche Products Ltd, Welwyn Garden City, UK. 18 Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Victoria, Australia. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Paolo A. Ascierto, Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Via Mariano Semmola, 80131 Napoli, Italy. Phone: 39-081-5903236; E-mail: [email protected] Clin Cancer Res 2021;27:5225–35 doi: 10.1158/1078-0432.CCR-21-0809 This open access article is distributed under Creative Commons Attribution- NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND). 2021 The Authors; Published by the American Association for Cancer Research AACRJournals.org | 5225 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 follow-up of 18.5 months, the final OS analysis showed that cobimetinib plus vemurafenib significantly improved median OS versus placebo plus vemurafenib (22.3 vs. 17.4 months; HR, 0.70; 95% CI, 0.55–0.90; P¼0.005; ref. 8). Herein, we present the extended follow-up analysis of the coBRIM study, after patients were followed for at least 5 years since the last patient was randomized, evaluating long-term treatment outcomes and prognostic characteristics of patients who derived long-term benefit from this regimen. Patients and Methods Study design and patients The coBRIM study was a multicenter, randomized, double-blind, placebo-controlled, phase III study that evaluated the efficacy and safety of the combination of cobimetinib plus vemurafenib compared with placebo plus vemurafenib. The study was conducted at 135 sites in the United States, Australia, New Zealand, Israel, and Europe. Detailed methods have previously been published, and the protocol is available online (1). Briefly, eligible patients were aged 18 years or older and had histologically confirmed unresectable stage IIIC or stage IV melanoma harboring a BRAF V600 mutation detected using the cobas4800 BRAF V600 Mutation Test (Roche Molecular Systems); measurable disease as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1; ref. 9); Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; and adequate hematologic, hepatic, renal, and cardiac function. Patients with previously treated brain metastases were eligible if they had a history of stable disease for at least 3 weeks. This study was registered with ClinicalTrials.gov (NCT01689519) and was conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol and its amendments were approved by the local institutional review board or independent ethics committee at each study site. All patients provided written informed consent. Treatment Patients were randomized in a 1:1 ratio to receive either oral 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), with stratification by disease stage and geographic region. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Following the primary analysis, the protocol was amended to allow patients in the placebo plus vemurafenib arm to cross over to the cobimetinib plus vemurafenib arm at the discretion of the investigator if they did not have disease progression and had not discontinued vemurafenib. Modification of the cobimetinib or vemurafenib dose was permitted for management of adverse events (AE). Tumor assessments were performed at baseline and every 8 weeks thereafter. Safety was monitored throughout treatment until 28 days after the last dose of study medication; thereafter, safety reporting included deaths, serious AEs (including new primary cancers), and other AEs of concern considered to be related to prior treatment with study medication. Safety data were regularly reviewed by an independent data and safety monitoring committee. Outcomes For the long-term follow-up analysis, outcomes of interest were OS (time from randomization until death from any cause), PFS (time from randomization until disease progression per RECIST v1.1 as assessed by the investigator or death from any cause), confirmed objective response rate (proportion of patients with complete response or partial response per RECIST v1.1), response duration (time from first documentation of response until disease progression or death from any cause), and safety. Statistical analysis Patients were enrolled between January 8, 2013 and January 31, 2014. The study was terminated by the sponsor because all patients had at least 5 years of follow-up from the time of randomization, with a final data cutoff date of July 21, 2019. All efficacy analyses were conducted in the intent-to-treat (ITT) population according to original randomized treatment assignment. Safety was assessed in patients who received at least one dose of study treatment according to the actual treatment received. PFS and OS were estimated using the Kaplan–Meier method. OS analyses were performed with and without censoring of data for patients in the placebo plus vemurafenib arm who crossed over to cobimetinib plus vemurafenib. HRs and two-sided 95% CIs were estimated using a stratified Cox proportional hazards model. Exploratory analyses were performed to evaluate PFS and OS outcomes in subgroups defined by baseline lactate dehydrogenase (LDH) level (normal vs. elevated) and confirmed best overall response per RECIST v1.1 (complete response vs. partial response vs. nonresponders). OS outcomes were further analyzed in cobimetinib plus vemurafenib–treated patients according to prognostic subgroups previously identified by Hauschild and colleagues [normal LDH level and sum of the product of longest diameters of target lesions (SLD) ≤45 mm; normal LDH level and SLD >45 mm; elevated LDH level ≤2upper limit of normal (ULN) and ECOG PS 0; elevated LDH level ≤2ULN and ECOG PS ≥1; and elevated LDH level >2 ULN; ref. 10] or Long and colleagues (normal LDH level and <3 organ sites; normal LDH level and ≥3 organ sites; elevated LDH level ≤2 ULN and ECOG PS 0; elevated LDH level ≤2ULN and ECOG PS ≥1; and elevated LDH level >2ULN; ref. 11). Data sharing statement Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche’s criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Translational Relevance Extended follow-up of the phase III coBRIM study of cobimetinib plus vemurafenib confirms the positive benefit/risk profile of cobimetinib plus vemurafenib in patients with BRAF V600 mutation–positive metastatic melanoma. With at least 5 years of followup since the last patient was randomized, results continue to demonstrate substantial progression-free survival and overall survival benefits for cobimetinib plus vemurafenib compared with vemurafenib monotherapy. The long-term safety profile is consistent with previously published reports, with no new safety signals detected. Among patients treated with cobimetinib plus vemurafenib, greatest overall survival benefit is observed in patients who achieve a complete response, and in those with normal lactate dehydrogenase levels and low tumor burden at baseline. Novel treatment strategies are needed to improve long-term outcomes for patients in poor prognosis subgroups, particularly those with elevated lactate dehydrogenase levels at baseline. Ascierto et al. Clin Cancer Res; 27(19) October 1, 2021 CLINICAL CANCER RESEARCH 5226 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https:// www.roche.com/research_and_development/who_we_are_how_we_ work/clinical_trials/our_commitment_to_data_sharing.htm). Results A total of 495 eligible patients were enrolled and randomized to receive either cobimetinib plus vemurafenib (n¼247) or placebo plus vemurafenib (n¼248). Two patients, one in each arm, were randomized into the study but did not receive any study treatment. Sixteen patients from the placebo plus vemurafenib arm crossed over to the cobimetinib plus vemurafenib arm following the primary analysis. Baseline characteristics were well balanced between treatment arms (Supplementary Table S1). At data cutoff, median follow-up duration was 21.2 months [interquartile range (IQR), 10.4–59.0] in the cobimetinib plus vemurafenib arm and 16.6 months (IQR, 7.3–42.5) in the placebo plus vemurafenib arm. The most common reasons for discontinuation from the study were death (64% vs. 67%) and withdrawal by patient (8.5% vs. 8.1%) in the cobimetinib plus vemurafenib arm versus the placebo plus vemurafenib arm (Table 1), whereas the most common reasons for discontinuation of study treatment were progressive disease (58% vs. 76%) and AEs (17% vs. 9%). Among patients who discontinued study treatment for reasons other than death, 122/240 patients (51%) in the cobimetinib plus vemurafenib arm and 130/227 patients (57%) in the placebo plus vemurafenib arm received subsequent anticancer treatments (Table 2), including immunotherapy (34% vs. 41%), targeted therapy (16% vs. 18%), and chemotherapy (14% vs. 16%). Overall survival At the time of data cutoff, 157/247 patients (64%) in the cobimetinib plus vemurafenib arm and 167/248 patients (67%) in the placebo plus vemurafenib arm had died. 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 (Fig. 1A). Landmark OS rates with cobimetinib plus vemurafenib versus placebo plus vemurafenib were 38% (95% CI, 32–45) versus 31% (95% CI, 25–37) at 3 years, 34% (95% CI, 28–40) versus 29% (95% CI, 23–35) at 4 years, and 31% (95% CI, 25–37) versus 26% (95% CI, 20–32) at 5 years. Results were similar when patients who crossed over to treatment with cobimetinib plus vemurafenib were censored at the date of crossover (Supplementary Table S2). A trend for OS benefit for cobimetinib plus vemurafenib over placebo plus vemurafenib was observed in most of the prespecified subgroups (Fig. 1B). Among patients treated with cobimetinib plus vemurafenib, median OS was 38.5 months [95% CI, 28.0 months to not estimable (NE)] for patients with normal baseline LDH level versus 14.8 months (95% CI, 11.3–18.6 months) for patients with elevated baseline LDH level; 5-year landmark OS rates were 43% and 16%, respectively (Fig. 1C). Among patients treated with cobimetinib plus vemurafenib,medianOSwasprolongedin patients who achieved a confirmed best response of complete response (not reached; 95% CI, 41.2–NE) or partial response (26.5 months; 95% CI, 19.7–33.4) compared with nonresponders (9.7months;95%CI,6.1–12.6), with 5-year landmark OS rates of 55%, 29%, and 13%, respectively (Fig. 1D). In cobimetinib plus vemurafenib–treated patients analyzed according to subgroups identified by Hauschild and colleagues (ref. 10; Fig. 2A), OS was most favorable in patients with normal baseline LDH and SLD ≤45 mm and least favorable in those with elevated baseline LDH >2ULN (Fig. 2B). Five-year OS rates were 52% in patients with normal LDH and SLD ≤45 mm, 34% in those with normal LDH and SLD >45 mm, 22% in those with elevated LDH ≤2ULN and ECOG PS 0, 15% in those with elevated LDH ≤2ULN and ECOG PS ≥1, and could not be evaluated in those with elevated LDH >2ULN because almost all patients had died by 3 years. According to subgroups identified by Long and colleagues (ref. 11; Fig. 2C), OS outcomes in the cobimetinib plus vemurafenib arm were most favorable in patients with normal baseline LDH and <3 organ sites with metastases and least favorable in those with elevated baseline LDH >2ULN (Fig. 2D). Five-year OS rates were 68% in patients with normal LDH and <3 organ sites, 33% in those with normal LDH and ≥3 organ sites, 22% in those with elevated LDH ≤2ULN and ECOG PS 0, 15% in those with elevated LDH ≤2ULN and ECOG PS ≥1, and could not be evaluated in those with elevated LDH >2ULN because almost all patients had died by 3 years. Progression-free survival At data cutoff, 195/247 patients (79%) in the cobimetinib plus vemurafenib arm and 207/248 patients (83%) in the placebo plus Table 1. Patient disposition. Patient disposition, n(%) Placebo þ vemurafenib Cobimetinib þ vemurafenib Study disposition n¼248 n¼247 Discontinued from study a 248 (100) 247 (100) Death 167 (67) 157 (64) Lost to follow-up 8 (3) 4 (2) Withdrawal by patient 20 (8) 21 (9) Physician decision 1 (<1) 4 (2) Other 4 (2) 2 (1) Treatment disposition n¼245 n¼248 Discontinued study treatment 245 (100) 248 (100) Progressive disease 185 (76) 145 (58) Adverse event 21 (9) 43 (17) Death 3 (1) 4 (2) Other 19 (8) 56 (23) a Forty-eight patients in the placebo þvemurafenib arm and 59 patients in the cobimetinib þvemurafenib arm remained on study at the time of study termination. Table 2. Subsequent anticancer treatments. a Subsequent treatment, n(%) Placebo þ vemurafenib (n¼227) Cobimetinib þ vemurafenib (n¼240) ≥1 subsequent treatment 130 (57) 122 (51) Chemotherapy 36 (16) 33 (14) Targeted therapy 40 (18) 38 (16) BRAF inhibitor 25 (11) 21 (9) Combined BRAF and MEK inhibitor 16 (7) 19 (8) MEK inhibitor 1 (<1) 3 (1) Immunotherapy 94 (41) 82 (34) Ipilimumab 83 (37) 53 (22) Anti–PD-1 agents 42 (19) 44 (18) Ipilimumab plus anti–PD-1 4 (2) 6 (3) Other 1 (<1) 0 a In patients who discontinued study treatment for reasons other than death. 5-Year Outcomes with Cobimetinib þVemurafenib in Melanoma AACRJournals.org Clin Cancer Res; 27(19) October 1, 2021 5227 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 All patients Disease stage IIIc M1a Disease stage group M1c Unresectable stage lllc, M1a, M1b Age <65 years ≥65 years Race White Non-White Sex Female Male Geographic region Australia, New Zealand, Others Europe North America ECOG PS Unknown 0 1 Baseline LDH Unknown Elevated Previously treated brain metastasis Yes No Prior adjuvant therapy Yes No BRAFV600 mutation status V600E V600K Normal 2 M1b M1c 248 13 40 153 95 179 69 235 13 108 140 38 184 26 2 166 80 4 104 2 246 24 224 174 32 140 42 153 167 6 17 118 49 118 49 158 9 70 97 19 131 17 2 166 80 4 77 1 166 17 150 122 19 86 26 118 19.1 17.4 19.1 58.6 14.8 34.6 18.3 14.7 17.4 19.3 20.5 14.9 23.0 16.1 21.4 NE 19.8 11.7 3.1 11.2 NE 17.4 17.4 17.5 16.7 23.8 23.3 14.8 24 247 21 40 146 101 183 64 227 20 101 146 40 182 25 4 184 58 4 112 1 246 223 170 24 131 1 40 146 16 157 8 18 103 54 117 40 142 15 60 97 20 116 21 3 117 37 1 90 0 157 141 113 13 66 0 28 103 34.6 22.5 NE 54.8 18.9 36.6 22.1 25.8 23.8 21.3 30.0 21.1 22.5 23.8 19.2 15.7 23.8 21.8 NE 14.8 NE 22.5 22.3 21.8 24.1 38.5 NE 19.4 18.9 0.91 0.80 0.52 1.06 0.73 0.95 0.87 0.64 0.78 1.04 0.80 0.78 0.96 0.74 1.01 1.59 0.94 0.57 <0.01 0.87 <0.01 0.80 0.79 0.82 0.81 0.71 NE 1.19 0.73 (0.46–1.80) (0.64–0.99) Cobimetinib + vemurafenib n = 247 Placebo + vemurafenib n = 248 nEvents Median (months) nEvents Median (months) Hazard Ratio 95% Wald Cl Favors cobimetinib + vemurafenib Favors placebo + vemurafenib (0.18–1.51) (0.54–2.05) (0.56–0.96) (0.64–1.39) (0.67–1.12) (0.42–0.98) (0.62–0.98) (0.45–2.38) (0.57–1.13) (0.58–1.03) (0.51–1.80) (0.58–0.96) (0.53–1.93) (0.16–16.07) (0.72–1.23) (0.38–0.86) (0.00–NE) (0.64–1.18) (0.00–NE) (0.64–1.00) (0.62–0.99) (0.63–1.06) (0.40–1.63) (0.52–0.98) (NE–NE) 0.70–2.03) (0.56–0.96) 1/10 1/5 1/2 1 2 5 10 B 100 80 60 40 20 0 Overall survival (%) Time (months) 012 24 36 48 7260 Patients at risk Cobimetinib + vemurafenib Placebo + vemurafenib 247 248 210 194 169 142 139 104 109 84 83 65 91 72 70 59 60 52 33 25 3 3 66 56 76 62 Cobimetinib + vemurafenib Placebo + vemurafenib Censored ++ 26% 31% 34% 29% 38% 31% 39% 49% Cobimetinib + vemurafenib n = 247 22.5 (20.3–28.8) 17.4 (15.0–19.8) Placebo + vemurafenib n = 248 Median OS, months (95% CI) A Figure 1. Overall survival. A, Kaplan–Meier curve of overall survival in the ITT population. B, Forest plot of hazard ratios for overall survival across patient subgroups. (Continued on the following page.) Ascierto et al. Clin Cancer Res; 27(19) October 1, 2021 CLINICAL CANCER RESEARCH 5228 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 vemurafenib arm had PFS events (disease progression per investigator assessment or death). 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 (Fig. 3A). Landmark PFS rates with cobimetinib plus vemurafenib compared with placebo plus vemurafenib were 23% (95% CI, 17–28) versus 13% (95% CI, 9–18) at 3 years, 17% (95% CI, 12–22) versus 12% (95% CI, 8–16) at 4 years, and 14% (95% CI, 9–19) versus 10% (95% CI, 6–14) at 5 years. Among patients treated with cobimetinib plus vemurafenib, median PFS was longer for patients with normal LDH level at baseline (15.0 months; 95% CI, 12.9–22.0) compared with those with elevated baseline LDH level (8.6 months; 95% CI, 7.3–10.0; Fig. 3B). Among patients treated with cobimetinib plus vemurafenib, median PFS was longer in patients who achieved a confirmed best response of complete response (41.4 months; 95% CI, 28.4–66.8) or partial response (12.9 months; 95% CI, 10.6–14.9) compared with nonresponders (3.7 months; 95% CI, 3.6–3.8; Fig. 3C). Best overall response In the cobimetinib plus vemurafenib arm, a best overall response of confirmed objective response was achieved in 172/247 patients (70%), with complete response in 52 patients (21%) and partial response in 120 patients (49%; Supplementary Table S3). In the placebo plus vemurafenib arm, 123/248 patients (50%) achieved confirmed objective response, with complete response in 32 patients (13%) and partial response in 91 (37%; Supplementary Table S3). In both treatment arms, the complete response rate improved with longer follow-up. In the cobimetinib plus vemurafenib arm, complete response rates improved from 10% at the primary analysis to 16% at the updated PFS analysis and 21% in the current analysis. In 100 80 60 40 20 0 Overall survival (%) Time (months) 012 24 36 48 7260 Patients at risk LDH normal LDH elevated LDH normal LDH elevated Censored ++16% 43% 46% 19% 50% 23% 29% 65% LDH normal n = 131 38.5 (28.0–NE) 14.8 (11.3–18.6) LDH elevated n = 112 Median OS, months (95% CI) 131 112 117 89 104 61 90 45 75 30 56 23 62 25 49 18 44 13 25 6 2 1 46 17 54 18 C 100 80 60 40 20 0 Overall survival (%) Time (months) 012 24 76% 53% 18% 68% 38% 14% 55% 29% 13% 61% 32% 14% 36 48 7260 Patients at risk Complete response Partial response 52 120 52 119 50 95 46 77 37 62 33 42 33 50 29 33 24 29 15 16 1 2 27 31 31 37 Nonresponders 75 39 24 16 10 8887288 Complete response n = 52 NR (41.2–NE) 26.5 (19.7–33.4) Partial response n = 120 9.7 (6.1–12.6) Nonresponders n = 75 Median OS, months (95% CI) D Figure 1. (Continued.)C, Overall survival in cobimetinib plus vemurafenib–treated patients with normal versus elevated LDH levels at baseline. D, Cobimetinib plus vemurafenib–treated patients who achieved complete response or partial response versus nonresponders. 5-Year Outcomes with Cobimetinib þVemurafenib in Melanoma AACRJournals.org Clin Cancer Res; 27(19) October 1, 2021 5229 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 the placebo plus vemurafenib arm, the complete response rate improved from 4% at the primary analysis to 11% at the updated PFS analysis and 13% at the current analysis. The median duration of response was 14.7 months (95% CI, 12.9–19.3) in the cobimetinib plus vemurafenib arm and 9.2 months (95% CI, 7.5–12.9) in the placebo plus vemurafenib arm. Safety At data cutoff, median duration of cobimetinib treatment was 275 days (range, 4–2,245) and median duration of vemurafenib treatment was 281 days (range, 9–2,246) for patients in the cobimetinib and vemurafenib arm; median duration of vemurafenib treatment for patients in the placebo plus vemurafenib arm was 175 days (range, 5– 2,268). Treatment-emergent AEs of any grade occurred in 246/248 patients (99%) in the cobimetinib plus vemurafenib arm and 240/245 patients (98%) in the placebo plus vemurafenib arm. AEs occurring in ≥20% patients in either arm are shown in Table 3. Grade ≥3 AEs occurred in 194/248 patients (78%) in the cobimetinib plus vemurafenib arm and 155/245 patients (63%) in the placebo plus vemurafenib arm. The difference in grade ≥3 AE rates between arms was largely attributable to laboratory abnormalities of gamma glutamyltransferase (GGT) increased (15% vs. 10%), alanine aminotransferase (ALT) increased (12% vs. 6%), and blood creatine phosphokinase (CPK) increased (12% vs. <1%; Table 3). Protocol-defined AEs of special interest (AESI) were actively monitored during the study. AESIs that were more common in the cobimetinib plus vemurafenib arm compared with the placebo plus 100 80 60 40 20 0 Overall survival (%) Time (months) 012 24 36 48 7260 Patients at risk LDH normal + SLD ≤45 mm LDH normal + SLD >45 mm 63 68 58 59 55 49 50 40 42 33 33 23 37 25 30 19 26 18 15 10 2 NE 27 19 32 22 LDH elevated ≤2× ULN + ECOG PS 0 62 55 40 33 22 1921 15 11 5 11415 LDH elevated ≤2× ULN + ECOG PS ≥1 16 12 9 6 6 33321NE33 LDH elevated >2× ULN 33 21 11 6 2 11 NE NENENENENE 58% 36% 26% 23% 52% 34% 22% 15% 61% 40% 33% 23% 3% 74% 57% 38% 38% 7% B ITT population N = 247 Baseline LDH abnormal n = 112 Baseline LDH >2× ULN n = 33 Baseline LDH >ULN to ≤2× ULN n = 79 Baseline LDH normal n = 131 SLD >45 mm n = 68 SLD ≤45 mm n = 63 ECOG PS ≥1 n = 16 ECOG PS 0 n = 62 A Figure 2. Overall survival outcomes by prognostic subgroups. A, Decision tree for prognostic subgroups identified by Hauschild et al. (10) in cobimetinib plus vemurafenib–treated patients. B, Kaplan–Meier curves of overall survival across prognostic subgroups identified by Hauschild et al. (10) in cobimetinib plus vemurafenib–treated patients. (Continued on the following page.) Ascierto et al. Clin Cancer Res; 27(19) October 1, 2021 CLINICAL CANCER RESEARCH 5230 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 vemurafenib arm were retinal detachment or central serous retinopathy (27% vs. 5%), grade ≥3 photosensitivity (4% vs. 0), grade ≥3 liver laboratory abnormalities (25% vs. 15%), grade ≥2 ejection fraction reduction (13% vs. 4%), and grade ≥3 CPK elevation (12% vs. 1%). Fewer patients in the cobimetinib plus vemurafenib arm had any cutaneous primary malignancy compared with the placebo plus vemurafenib arm (13% vs. 23%). Grade ≥3 rash (17% vs. 17%) and grade ≥3 QTc interval prolongation (2% vs. 2%) occurred in similar numbers of patients in each treatment arm. Serious AEs occurred in 105/248 patients (42%) with cobimetinib plus vemurafenib and 71/245 patients (29%) with placebo plus vemurafenib. Serious AEs occurring in ≥2% of patients in either arm were pyrexia (3% vs. 1%), pneumonia (2% vs. 1%), and dehydration (2% vs. 0). Grade 5 AEs occurred in 6/248 patients (2%) in the cobimetinib plus vemurafenib arm [cardiac arrest, pneumonia, death (unknown), coma, Clostridium difficile colitis, and myocardial infarction] and 5/245 patients (2%) in the placebo plus vemurafenib arm [cardiac failure, pulmonary embolism, atelectasis, death (unknown), and hemorrhagic stroke]. AEs leading to discontinuation of any study drug occurred in 67/248 patients (27%) in the cobimetinib plus vemurafenib arm and 30/245 patients (12%) in the placebo plus vemurafenib arm. AEs leading to discontinuation of cobimetinib or placebo in ≥2% of patients were aspartate aminotransferase (AST) increased (2% vs. <1%), ejection fraction decreased (2% vs. 1%), and rash (2% vs. <1%) in the cobimetinib plus vemurafenib arm versus the placebo plus vemurafenib arm. AEs leading to discontinuation of vemurafenib in ≥2% of patients were AST increased (2% vs. 1%), ALT increased (2% vs. 1%), GGT increased (2% vs. 2%), and rash (2% vs. <1%). ITT population N = 247 Baseline LDH abnormal n = 112 Baseline LDH >2× ULN n = 33 Baseline LDH >ULN to ≤2× ULN n = 79 Baseline LDH normal n = 131 ≥3 organ sites with metastasis n = 96 <3 organ sites with metastasis n = 35 ECOG PS ≥1 n = 16 ECOG PS 0 n = 62 100 80 60 40 20 0 Overall survival (%) Time (months) 012 24 36 48 7260 35 96 33 84 32 72 32 58 28 47 24 32 26 36 22 27 20 24 13 12 NE 2 21 25 23 31 62 55 40 33 22 1921 15 11 5 11415 16 12 9 6 6 33321NE33 33 21 11 6 2 11NENENENENENE Patients at risk LDH normal + <3 organ sites LDH normal + ≥3 organ sites LDH elevated ≤2× ULN + ECOG PS 0 LDH elevated ≤2× ULN + ECOG PS ≥1 LDH elevated >2× ULN 85% 57% 38% 38% 7% 78% 39% 33% 23% 3% 75% 35% 26% 23% 68% 33% 22% 15% D C Figure 2. (Continued.)C, Decision tree for prognostic subgroups identified by Long et al. (11) in cobimetinib plus vemurafenib–treated patients. D, Kaplan–Meier curves of overall survival across prognostic subgroups identified by Long et al. (11) in cobimetinib plus vemurafenib– treated patients. 5-Year Outcomes with Cobimetinib þVemurafenib in Melanoma AACRJournals.org Clin Cancer Res; 27(19) October 1, 2021 5231 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 100 80 60 40 20 0 Progression-free survival (%) Time (months) 012 24 36 48 7260 Patients at risk Cobimetinib + vemurafenib Placebo + vemurafenib Cobimetinib + vemurafenib Placebo + vemurafenib Censored ++ 10% 14% 17% 12% 23% 13% 16% 32% Cobimetinib + vemurafenib n = 247 12.6 (9.5–14.8) 7.2 (5.6–7.5) Placebo + vemurafenib n = 248 Median PFS, months (95% CI) 247 248 175 122 117 65 85 46 69 33 44 24 54 27 29 21 19 15 10 4 2 1 24 19 36 23 A 100 80 60 40 20 0 Progression-free survival (%) Time (months) 012 24 36 48 7260 Patients at risk LDH normal LDH elevated LDH normal LDH elevated Censored ++7% 18% 23% 8% 28% 14% 19% 40% LDH normal n = 131 15.0 (12.9–22.0) 8.6 (7.3–10.0) LDH elevated n = 112 Median PFS, months (95% CI) 131 112 100 71 74 39 54 27 46 19 29 12 35 16 20 7 11 6 6 3 1 1 15 7 25 8 B 100 80 60 40 20 0 Progression-free survival (%) Time (months) 012 24 36 48 7260 Patients at risk Complete response Partial response Complete response n = 52 41.4 (28.4–66.8) 12.9 (10.6–14.9) Partial response n = 120 3.7 (3.6–3.8) Nonresponders n = 75 Median PFS, months (95% CI) 52 120 51 108 46 64 38 42 33 33 23 20 27 26 16 12 9 9 6 3 1 1 13 10 18 17 Nonresponders 75 16 7 5 3 1111111 46% 12% 4% 39% 9% 4% 57% 19% 4% 68% 29% 6% C Figure 3. Progression-free survival. A, Kaplan–Meier curves of progression-free survival in the ITT population. B, Cobimetinib plus vemurafenib–treated patients with normal versus elevated LDH levels at baseline. C, Cobimetinib plus vemurafenib–treated patients who achieved complete response or partial response versus nonresponders. Ascierto et al. Clin Cancer Res; 27(19) October 1, 2021 CLINICAL CANCER RESEARCH 5232 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022 Discussion This extended follow-up of the phase III coBRIM study confirms both the long-term clinical benefit and the safety profile of cobimetinib plus vemurafenib in patients with BRAF V600 mutation–positive metastatic melanoma. With at least 5 years of follow-up since the last patient was randomized, results continue to demonstrate substantial PFS and OS benefits for cobimetinib plus vemurafenib compared with vemurafenib monotherapy. The safety profile was consistent with previously published reports (1, 8), with no new safety signals detected over extended follow-up. The 5-year OS rate of 31% for cobimetinib plus vemurafenib is consistent with that reported with the combination of dabrafenib plus trametinib (34%) in a pooled analysis of the COMBI-d and COMBI-v studies (5). Similar to the COMBI-d and COMBI-v pooled analysis, we observed a plateauing of both PFS and OS curves from approximately 3 years, suggesting favorable survival outcomes for a substantial proportion of patients treated with the combination. Moreover, the 5-year OS rates for cobimetinib plus vemurafenib in patients with normal and elevated LDH (43% and 16%, respectively) were identical to those achieved with dabrafenib plus trametinib in the pooled analysis of the COMBI-d and COMBI-v studies (5). Similar proportions of patients across these studies received subsequent anticancer treatment with immunotherapy or further targeted therapy. Although the extent to which long-term OS is influenced by subsequent treatment is unclear, recent analyses suggest that patients who progress following treatment with BRAF and/or MEK inhibitors derive an OS benefit from subsequent treatment with immunotherapy or additional targeted therapy (12). Identification of subgroups of patients likely to achieve long-term treatment benefit is important to inform treatment decisions in the management of patients with metastatic melanoma. Conventional prognostic factors for survival in patients with metastatic melanoma include disease stage, baseline LDH levels, and baseline ECOG PS (13, 14). Recent analyses suggest that LDH level at baseline remains the most important prognostic factor for survival in patients treated with targeted therapy or immunotherapy (10, 11, 15, 16). Consistent with these findings, we observed longer PFS and OS for cobimetinib plus vemurafenib–treated patients with normal LDH levels (below ULN) at baseline compared with those who had elevated LDH levels at baseline. In accordance with previous prognostic models in patients with metastatic melanoma treated with BRAF and MEK inhibitor combination therapy, long-term OS was most favorable in patients with normal LDH levels and low tumor burden (defined as either SLD ≤45 mm or <3 organ sites with metastasis; refs. 10, 11). The majority of these patients had long-term survival with cobimetinib Table 3. Most common AEs, a regardless of attribution to study treatment. Placebo þvemurafenib (n¼245) Cobimetinib þvemurafenib (n¼248) AEs, n(%) Any grade Grade ≥3 Any grade Grade ≥3 Diarrhea 81 (33) 3 (1) 152 (61) 17 (7) Nausea 65 (27) 2 (1) 108 (44) 3 (1) Rash 95 (39) 14 (6) 104 (42) 14 (6) Arthralgia 103 (42) 12 (5) 96 (39) 7 (3) Fatigue 83 (34) 8 (3) 93 (38) 11 (4) Blood CPK increased 7 (3) 1 (<1) 91 (37) 30 (12) Photosensitivity reaction 47 (19) 0 86 (35) 8 (3) Pyrexia 60 (24) 0 79 (32) 4 (2) Vomiting 34 (14) 2 (1) 69 (28) 4 (2) ALT increased 44 (18) 14 (6) 68 (27) 29 (12) AST increased 30 (12) 4 (2) 66 (27) 23 (9) GGT increased 43 (18) 25 (10) 59 (24) 38 (15) Decreased appetite 49 (20) 1 (<1) 55 (22) 0 Asthenia 43 (18) 3 (1) 52 (21) 5 (2) Anemia 22 (9) 8 (3) 51 (21) 10 (4) Hypertension 24 (10) 7 (3) 51 (21) 21 (8) Pruritus 47 (19) 1 (<1) 51 (21) 3 (1) Headache 40 (16) 4 (2) 50 (20) 2 (1) Blood alkaline phosphatase increased 25 (10) 4 (2) 47 (19) 14 (6) Alopecia 75 (31) 1 (<1) 42 (17) 1 (<1) Myalgia 31 (13) 6 (2) 42 (17) 1 (<1) Rash maculopapular 38 (16) 13 (5) 39 (16) 18 (7) Dermatitis acneiform 22 (9) 3 (1) 37 (15) 6 (2) Ejection fraction decreased 11 (4) 3 (1) 32 (13) 5 (2) Pain in extremity 39 (16) 6 (2) 32 (13) 3 (1) Hyperkeratosis 75 (31) 6 (2) 31 (13) 1 (<1) Basal cell carcinoma 6 (2) 6 (2) 16 (6) 15 (6) Hyponatremia 3 (1) 1 (<1) 13 (5) 7 (3) Dehydration 2 (1) 0 13 (5) 6 (2) Squamous cell carcinoma of skin 33 (13) 33 (13) 10 (4) 9 (4) Lipase increased 4 (2) 2 (1) 9 (4) 8 (3) Pneumonia 5 (2) 2 (1) 7 (3) 6 (2) Keratoacanthoma 23 (9) 23 (9) 5 (2) 5 (2) a AEs of any grade occurring in ≥20% of patients and AEs of grade ≥3 occurring in ≥2% of patients in either treatment arm. 5-Year Outcomes with Cobimetinib þVemurafenib in Melanoma AACRJournals.org Clin Cancer Res; 27(19) October 1, 2021 5233 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/19/5225/3197473/5225.pdf by guest on 24 October 2022