COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600–Mutant Melanoma

PURPOSE

Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600–mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453).

METHODS

Patients with locally advanced unresectable or metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned.

RESULTS

Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.

CONCLUSION

In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600–mutant melanoma.

INTRODUCTION

Approximately 50% of melanomas contain BRAF V600 mutations, which constitutively activate the mitogen-activated protein kinase pathway, driving cellular proliferation and disease progression.^1,2 Combination treatment with BRAF and MEK inhibitors (BRAFi and MEKi) is now the standard of care for treating BRAF V600–mutant locally advanced or metastatic melanoma. Currently, guidelines include three combinations of BRAFi + MEKi: encorafenib plus binimetinib, vemurafenib plus cobimetinib, and dabrafenib plus trametinib.^3-7

CONTEXT

• Key Objective

• Combination treatment of BRAF plus MEK inhibitors is now the standard of care for treating BRAF V600–mutant locally advanced or metastatic melanoma. In previously reported results of the COLUMBUS trial, encorafenib plus binimetinib extended progression-free survival and median overall survival, improved quality of life, and was well tolerated with a low discontinuation rate. This 5-year updated analysis assessed long-term efficacy and safety outcomes with encorafenib plus binimetinib in patients with unresectable or metastatic BRAF V600–mutant melanoma.

• Knowledge Generated

• Long-term results from the COLUMBUS trial indicate continuous benefits of encorafenib plus binimetinib and confirmed previous reports of prolonged progression-free survival and overall survival compared with vemurafenib monotherapy, consistent with those reported from other BRAF plus MEK inhibitor combinations. The burden of toxicity decreasing over time with long-term safety is consistent with previous observations.

• Relevance

• This 5-year update of COLUMBUS demonstrates the long-term benefits of encorafenib plus binimetinib in patients with unresectable or metastatic BRAF V600–mutant melanoma.

In phase III trials, vemurafenib plus cobimetinib and dabrafenib plus trametinib have demonstrated 5-year progression-free survival (PFS) rates of 14%-19% and overall survival (OS) rates of 31%-34%.^8,9 Encorafenib plus binimetinib was evaluated in a phase Ib/II trial (ClinicalTrials.gov identifier: NCT01543698) and in the phase III COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453).^10-12 Encorafenib is a highly selective ATP-competitive BRAFi.¹³ Its long dissociation half-life may allow for sustained target inhibition, enhanced antitumor activity, and reduced paradoxical activation of mitogen-activated protein kinase pathways in normal tissues.^13-16 Binimetinib is a potent, allosteric, ATP-uncompetitive, selective MEKi with a short half-life, which may help to rapidly resolve toxicity after dose interruption.^10,17

Previously, we reported results from part 1 of COLUMBUS, which compared encorafenib plus binimetinib with monotherapy with vemurafenib or encorafenib.^11,18-21 Compared with vemurafenib, encorafenib plus binimetinib extended PFS (14.9 v 7.3 months; hazard ratio [HR], 0.51; 95% CI, 0.39 to 0.67) and median OS (33.6 v 16.9 months; HR, 0.61; 95% CI, 0.48 to 0.79; median follow-up for OS, 48.8 months).²⁰ The combination was generally well tolerated; the rate of discontinuation was low (10% v 14% with vemurafenib); the burden of toxicity decreased with a longer treatment duration.²⁰ Encorafenib plus binimetinib treatment also improved quality of life; compared with vemurafenib, postbaseline scores were 3.03 points higher (P < .0001) for FACT-M and 5.28 points higher (P = .0042) for EORTC QLQ-C30.²¹ In this 5-year updated analysis of COLUMBUS part 1, we assessed long-term efficacy and safety outcomes with encorafenib plus binimetinib in patients with unresectable or metastatic BRAF V600–mutant melanoma.

METHODS

Study Design and Participants

The study design and patient eligibility criteria have been published.^11,18,19 Briefly, COLUMBUS (ClinicalTrials.gov identifier: NCT01909453) was a two-part, multicenter, randomized, open-label, phase III trial. Patients with locally advanced unresectable or metastatic BRAF V600–mutant melanoma who were untreated or whose cancer had progressed after first-line immunotherapy were enrolled between December 30, 2013, and April 10, 2015. In part 1 of COLUMBUS, patients were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. Random assignment was stratified by American Joint Committee on Cancer stage (IIIB, IIIC, IVM1a, IVM1b, or IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1), and BRAF mutation (V600E or V600K; before Protocol amendment 2 [December 20, 2013]) or use of previous first-line immunotherapy (yes or no; after Protocol amendment 2). Patients received study treatment until disease progression (assessed by central review), death, unacceptable toxic effects, or withdrawal of consent. Dose adjustments were based on tolerability and adverse events (AEs).¹¹ Independent ethics committees or review boards at each study site approved the study Protocol (online only) and amendments. Conduct of the study conformed with Good Clinical Practice guidelines and the ethical requirements outlined in the Declaration of Helsinki. Written informed consent was obtained from all patients before screening procedures were initiated.

Study End Points

Updated analyses were conducted 65 months after the last patient was randomly assigned (data cutoff: September 15, 2020) for outcomes of PFS, OS, objective response rate (ORR), poststudy anticancer therapy, safety, and tolerability. In addition, PFS and OS were analyzed in subgroups, including prognostic subgroups related to lactate dehydrogenase (LDH) levels and number of organs involved as identified previously by Long et al²² and Hauschild et al.²³ Outcome definitions and details of efficacy and safety assessments have been published.^11,18,19

Statistical Analysis

Efficacy end points were assessed in the intent-to-treat population (defined as randomly assigned patients). Median durations of follow-up for OS and PFS were estimated by reverse Kaplan-Meier analysis. The Kaplan-Meier method was used to estimate rates of OS and PFS. Subgroup analyses of baseline variables and potential prognostic factors, including previous immunotherapy, were also specified. Because of the hierarchical testing procedure used during this study, the analyses presented here are descriptive. HRs were estimated using Cox proportional hazard regression models and presented along with 95% CIs. Safety assessments and poststudy anticancer therapy data were summarized descriptively. The safety analysis set included all patients who received at least one dose of study treatment and had one postbaseline safety assessment.²⁰ Exposure-adjusted incidence rate (EAIR; per 100 patient-months of exposure to study treatment) was calculated for each AE as the number of patients experiencing the AE divided by the total exposure time at risk for the AE. Exposure time was the treatment duration for patients not experiencing the event and treatment duration up to the time of first onset of the AE for those experiencing the event.¹⁹ AEs of interest for encorafenib plus binimetinib were summarized by the time of onset (median and 95% CI). Detailed information on statistical analyses has been reported.^11,18

RESULTS

Patients

COLUMBUS part 1 randomly assigned 577 patients: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib (Appendix Fig A1, online only). Baseline characteristics were similar among treatment arms (Appendix Table A1, online only). Overall, 27% of patients had elevated LDH levels; 45% had ≥ 3 organs involved. At the time of data cutoff, treatment was ongoing in 41 patients (Table 1). Among patients treated with encorafenib plus binimetinib, 55% discontinued treatment primarily because of progressive disease; 12% discontinued primarily because of AEs.

TABLE 1.

Patient Disposition

Efficacy

The median follow-up for PFS was 40.8 months. Median PFS in all arms was consistent with previously reported values (Fig 1). The median PFS was 14.9 months (95% CI, 11.0 to 20.2) with encorafenib plus binimetinib and 7.3 months (95% CI, 5.6 to 7.9) with vemurafenib (HR, 0.51; 95% CI, 0.40 to 0.67). The median PFS with encorafenib was 9.6 months (95% CI, 7.4 to 14.8; encorafenib plus binimetinib v encorafenib: HR, 0.79; 95% CI, 0.61 to 1.02; encorafenib v vemurafenib: HR, 0.68; 95% CI, 0.52 to 0.88). PFS rates were highest with encorafenib plus binimetinib, followed by encorafenib, at each yearly landmark. At 5 years, the PFS rates were 23% with encorafenib plus binimetinib, 10% with vemurafenib, and 19% with encorafenib. The 5-year PFS rates were 31% for patients treated with encorafenib plus binimetinib with normal LDH and 39% for those with low tumor burden (ie, normal LDH levels and < 3 organs involved) at baseline.

FIG 1.

PFS in (A) all patients, (B) patients in the encorafenib plus binimetinib arm according to baseline LDH levels, and (C) patients in the encorafenib plus binimetinib arm who had a low tumor burden (ie, normal LDH levels and < 3 organs involved) at baseline. For (A), HR was analyzed using stratified Cox regression model. HR, hazard ratio; LDH, lactate dehydrogenase; NE, not evaluable; PFS, progression-free survival.

The median follow-up for OS was 70.4 months. Median OS for all arms was consistent with previously reported values (Fig 2). The median OS was 33.6 months (95% CI, 24.4 to 39.2) with encorafenib plus binimetinib and 16.9 months (95% CI, 14.0 to 24.5) with vemurafenib (HR, 0.64; 95% CI, 0.50 to 0.81). The median OS with encorafenib was 23.5 months (95% CI, 19.6 to 33.6; encorafenib plus binimetinib v encorafenib: HR, 0.93; 95% CI, 0.72 to 1.19; encorafenib v vemurafenib: HR, 0.71; 95% CI, 0.56 to 0.91). OS rates were highest in the encorafenib plus binimetinib arm, followed by the encorafenib arm, and were higher than the vemurafenib arm at each yearly landmark. Interestingly, at 1 and 5 years, the OS rates were nearly identical between the encorafenib plus binimetinib and encorafenib monotherapy arms. At 5 years, the OS rates were 35% with encorafenib plus binimetinib and encorafenib monotherapy and 21% with vemurafenib. The 5-year OS rates were 45% for patients treated with encorafenib plus binimetinib with normal LDH and 48% for those with low tumor burden at baseline.

FIG 2.

OS in (A) all patients, (B) patients in the encorafenib plus binimetinib arm according to baseline LDH levels, and (C) patients in the encorafenib plus binimetinib arm who had a low tumor burden (ie, normal LDH levels and < 3 organs involved) at baseline. For (A), HR was analyzed using a stratified Cox regression model. HR, hazard ratio; LDH, lactate dehydrogenase; NE, not evaluable; OS, overall survival.

OS subgroup analyses comparing encorafenib plus binimetinib and vemurafenib showed point estimates in favor of encorafenib plus binimetinib (Fig 3A). OS subgroup analyses comparing encorafenib plus binimetinib and encorafenib did not show clear trends toward either arm, except in patients with three organs involved at baseline who had a greater OS benefit with encorafenib plus binimetinib (Appendix Fig A2, online only). Patients who had long-term response (ie, ≥ 24 months) tended to have less advanced stage of cancer, better ECOG performance status, normal LDH, and fewer organs involved at baseline (Fig 3B). By central review, 92% of patients receiving combination treatment achieved disease control (Table 2); the median duration of response among responders was 18.6 months (95% CI, 12.7 to 27.6). Complete responses (CRs) were achieved in 14% of patients in the encorafenib plus binimetinib arm and 8% each in the vemurafenib arm and encorafenib arm. Most CRs or partial responses were achieved within 6 months of encorafenib plus binimetinib treatment; median PFS and OS were similar between those with and without a response at 6 months (Appendix Fig A3, online only).

FIG 3.

(A) OS in subgroups for encorafenib plus binimetinib versus vemurafenib. The Cox proportional hazards model is unstratified. (B) Proportion of patients treated with encorafenib plus binimetinib by duration of response. AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival.

TABLE 2.

Best Overall Response and Duration of Response by Central Review

Subsequent Therapy

After COLUMBUS study treatment, 50% of the encorafenib plus binimetinib arm, 69% of the vemurafenib arm, and 62% of the encorafenib arm received systemic treatments. The most common subsequent treatments in all arms were anti–cytotoxic T-cell lymphocyte-4 or anti-programmed cell death protein 1 (PD-1) as monotherapy or in combination (Table 3). Immunotherapies were the most common first subsequent therapy in all arms; however, similar numbers of patients in the monotherapy arms received targeted therapies as their first treatment after COLUMBUS. Thereafter, immunotherapies were the most common second treatment in the monotherapy arms.

TABLE 3.

Anticancer Therapy After Study Treatment Discontinuation

Safety

The safety profile observed with this 5-year follow-up was generally consistent with previous reports (Appendix Tables A2 and A3, online only). Grade 3/4 AEs occurred in 70%, 66%, and 70% of patients in the encorafenib plus binimetinib, vemurafenib, and encorafenib arms, respectively. For most AEs, EAIRs were lowest with encorafenib plus binimetinib. AEs led to dose adjustment or interruption in 56%, 62%, and 72% of patients in the encorafenib plus binimetinib, vemurafenib, and encorafenib arms, respectively; in the encorafenib plus binimetinib arm, these AEs were gastrointestinal disorders (17%), eye disorders (12%), pyrexia (6%), decreased ejection fraction (5%), and increased gamma-glutamyl transferase (5%). In each treatment arm, 16%-18% of patients experienced AEs, leading to study treatment discontinuation. AEs that led to discontinuation of encorafenib plus binimetinib treatment in more than one patient were increased alanine aminotransferase (n = 5; four were grade 3/4), aspartate aminotransferase (n = 4; two were grade 3/4), or blood creatinine (n = 2; one was grade 3/4); headache (n = 4; two were grade 3/4); or rash (n = 2; both were grade 3/4); three patients discontinued because of central nervous system metastases. There were 25 (13%), 20 (11%), and 16 (8%) on-treatment deaths in the encorafenib plus binimetinib, vemurafenib, and encorafenib arms, respectively; most were due to underlying disease.

The median time to onset for most AEs of interest was within 6 months of starting treatment with encorafenib plus binimetinib (Appendix Table A4, online only). The median time to onset of nausea, diarrhea, visual impairment, and increased transaminases was within 1 month of starting treatment with encorafenib plus binimetinib. As expected, ocular AEs related to MEKi occurred in the encorafenib plus binimetinib arm (Appendix Table A3); most were mild or moderate. Blurred vision occurred in 16%; retinal detachment, subretinal fluid, and macular edema were each reported in 7%. One patient discontinued because of reduced visual acuity and retinal disorder. In the encorafenib plus binimetinib arm, left ventricular dysfunction, consisting of the AEs of abnormal or decreased ejection fraction, cardiac failure, and left ventricular dysfunction, occurred in 7% of patients (excluding censored observations); the median time to first occurrence was approximately 3.5 months (range, 0 to approximately 21 months).

Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.²⁴

DISCUSSION

Long-term results from the randomized, phase III COLUMBUS trial indicate continuous benefits of encorafenib plus binimetinib for patients with unresectable or metastatic BRAF V600–mutant melanoma. Overall, the results suggest that preclinical and pharmacologic differences between BRAFi are clinically meaningful. This 5-year update confirmed previous reports of prolonged PFS and OS with encorafenib plus binimetinib treatment compared with vemurafenib treatment.²⁰ In patient subgroup analyses, the observed OS either favored or trended toward treatment with encorafenib plus binimetinib over vemurafenib. PFS and OS rates at each yearly landmark were higher in the encorafenib plus binimetinib arm than in the vemurafenib arm. Survival curves for encorafenib plus binimetinib began to plateau around 4 years. Similar plateaus have been observed with dabrafenib plus trametinib and vemurafenib plus cobimetinib and with immune checkpoint inhibitors in clinical trials of advanced melanoma.^8,25-27 Although direct comparisons cannot be made, 5-year PFS and OS rates with encorafenib plus binimetinib treatment in COLUMBUS were consistent with those observed with other BRAFi + MEKi combinations.^8,9

The 5-year OS rate was 35% for both the encorafenib plus binimetinib and encorafenib monotherapy arms; however, combination treatment demonstrated significantly longer PFS (median > 5 months) and numerically longer OS (median > 10 months). Compared with encorafenib monotherapy, the encorafenib plus binimetinib arm had numerically greater ORR, disease control rate, and duration of response. Furthermore, combination treatment improved tolerability; EAIRs for most AEs were lower with encorafenib plus binimetinib compared with encorafenib monotherapy. Patients in COLUMBUS part 1 treated with encorafenib plus binimetinib reported fewer (difference of 10% or more between arms) dermatologic AEs and arthralgia and myalgia events compared with those treated with encorafenib monotherapy. Although certain AEs occurred more commonly in the combination arm than in the encorafenib monotherapy arm (eg, diarrhea, increased blood creatine phosphokinase, and blurred vision), the rate of discontinuation because of AEs was similar between these arms. Previous studies have also shown that both efficacy and tolerability of BRAFi are improved with the addition of a MEKi.^9,28-30 The contribution of binimetinib to the encorafenib plus binimetinib combination was further evaluated in part 2 of the COLUMBUS trial, which compared encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily monotherapy.¹² Briefly, encorafenib plus binimetinib showed meaningful improvements in PFS by 5.5 months (HR, 0.57; 95% CI, 0.41 to 0.75) and ORR by 16%; furthermore, the combination was better tolerated than monotherapy, resulting in greater relative dose intensity, fewer grade 3/4 AEs, and fewer AEs leading to discontinuation.¹²

AEs with encorafenib plus binimetinib were generally manageable and consistent with previous reports; no new safety signals were observed after long-term follow-up. As reported previously in COLUMBUS and coBRIM, the overall burden of toxicity of combination treatment tends to decrease with time on treatment.^20,29,31 The most common AEs observed were class effects such as gastrointestinal AEs and arthralgia; first onset of these AEs occurred within 2 months of starting treatment. Since the 3-year analysis of COLUMBUS, the proportion of patients with a rash increased by 3.7%, 6.5%, and 5.2% in the encorafenib plus binimetinib, vemurafenib, and encorafenib arms, respectively. Of note, approximately half of the newer reports of rash with vemurafenib treatment were grade 3/4 events. There was also a notable increase in pruritus of 11.2% and 8.8% in the vemurafenib and encorafenib arms, respectively, but not in the encorafenib plus binimetinib arm. Ocular toxicities, a known AE of MEKi, were routinely evaluated in COLUMBUS. Most ocular disorders were asymptomatic and managed by adjustment or interruption of the encorafenib plus binimetinib dose; discontinuation because of ocular toxicity occurred in only one patient. MEK-associated retinopathy was reported in 29% of patients treated with vemurafenib plus cobimetinib in coBRIM; approximately half of the events were symptomatic.³² Finally, left ventricular dysfunction, consisting of the AEs of abnormal or decreased ejection fraction, cardiac failure, and left ventricular dysfunction, occurred in 7.3% of patients (excluding censored observations) treated with encorafenib plus binimetinib, typically 3-4 months after treatment; no new onset was recorded after 2 years.

Within the limits of cross-trial comparisons, encorafenib plus binimetinib treatment resulted in fewer AEs of pyrexia than dabrafenib plus trametinib treatment (21% v 53%); dose adjustments or interruptions because of pyrexia in the encorafenib plus binimetinib arm were uncommon, occurring in 6% of patients.⁸ Furthermore, treatment with encorafenib plus binimetinib resulted in fewer AEs of rash (20% v 42% with vemurafenib plus cobimetinib) and photosensitivity (4% v 35% with vemurafenib plus cobimetinib).⁹ These observations are in agreement with the findings of a recent pharmacovigilance study using data from the US Food and Drug Administration Adverse Event Reporting System.³³ Encorafenib plus binimetinib treatment was found to be associated with lower risks of dermatologic AEs and acute kidney injury compared with vemurafenib plus cobimetinib and lower risks of pyrexia and elevated C-reactive protein compared with dabrafenib plus trametinib.³³ The same study also reported a greater likelihood of colitis, renal impairment, and seizures with encorafenib plus binimetinib than with other BRAFi + MEKi combinations; in COLUMBUS, < 10% of patients treated with encorafenib plus binimetinib experienced these AEs.

Patients treated with encorafenib plus binimetinib in COLUMBUS most commonly received immunotherapy with anti–PD-1 or anti–cytotoxic T-cell lymphocyte-4 or both after study treatment. Treatment sequence is an active area of research, as is combining targeted treatments and immunotherapy; the STARBOARD trial (ClinicalTrials.gov identifier: NCT04657991) is underway to investigate encorafenib plus binimetinib in combination with anti–PD-1 immunotherapy (pembrolizumab) for the treatment of BRAF V600–mutant melanoma.

This 5-year analysis had some limitations: it is post hoc and descriptive. OS was not a primary end point; however, OS was a key efficacy end point. The trial was not powered for OS comparisons between the encorafenib plus binimetinib arm and the encorafenib arm or vemurafenib arm. In addition, few patients with metastatic brain metastases were enrolled in COLUMBUS (n = 20). Case studies of encorafenib plus binimetinib treatment in patients with brain metastases reported promising outcomes.^34-37 Patients with advanced BRAF V600–mutant melanoma and brain metastases have been enrolled in phase II trials evaluating encorafenib plus binimetinib (POLARIS [ClinicalTrials.gov identifier: NCT03911869], SWOG S2000 [ClinicalTrials.gov identifier: NCT04511013], and EBRAIN-MEL [ClinicalTrials.gov identifier: NCT03898908]).

In conclusion, 35% of patients with unresectable or metastatic BRAF V600–mutant melanoma treated with encorafenib plus binimetinib in COLUMBUS were alive after 5 years, with 23% remaining progression-free; 64% achieved CR/partial response. Among patients with normal LDH levels and < 3 organs involved at baseline, the 5-year PFS and OS rates were 39% and 48%, respectively. The safety profile observed with a longer follow-up was consistent with previous observations, and the burden of toxicity with encorafenib plus binimetinib treatment decreased over time. These data demonstrate the long-term benefits of encorafenib plus binimetinib in patients with unresectable or metastatic BRAF V600–mutant melanoma.

APPENDIX

FIG A1.

CONSORT diagram. ^aSome patients were ineligible for more than one reason. ^bPrimary reason. ^cOngoing at the time of data cutoff (September 15, 2020). AE, adverse event.

FIG A2.

OS in subgroups for encorafenib plus binimetinib versus encorafenib. The Cox proportional hazards model is unstratified. AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival.

FIG A3.

(A) PFS in the encorafenib plus binimetinib arm by response status at 6 months. (B) OS in the encorafenib plus binimetinib arm by response status at 6 months. Patients are classified on the basis of their response status at 6 months (the landmark time). The number of patients at risk at baseline excludes patients who had an event or were censored at 6 months. HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

TABLE A1.

Baseline Patient and Disease Characteristics

TABLE A2.

AEs Occurring in ≥10% of Patients in the Encorafenib Plus Binimetinib Arm by Incidence and EAIR

TABLE A3.

AEs of Interest

TABLE A4.

Median Time to First Occurrence of AEs of Interest in the Encorafenib Plus Binimetinib Arm (n = 192)

DATA SHARING STATEMENT

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

AUTHOR CONTRIBUTIONS

Conception and design: Reinhard Dummer, Keith T. Flaherty, Caroline Robert, Dirk Schadendorf, Paolo A. Ascierto

Provision of study materials or patients: Reinhard Dummer, Keith T. Flaherty, Caroline Robert, Ana Arance, Jan Willem B. de Groot, Claus Garbe, Helen J. Gogas, Ralf Gutzmer, Ivana Krajsová, Gabriella Liszkay, Carmen Loquai, Mario Mandalà, Dirk Schadendorf, Naoya Yamazaki, Paolo A. Ascierto

Collection and assembly of data: Keith T. Flaherty, Caroline Robert, Jan Willem B. de Groot, Claus Garbe, Helen J. Gogas, Ralf Gutzmer, Ivana Krajsová, Gabriella Liszkay, Carmen Loquai, Mario Mandalà, Dirk Schadendorf, Naoya Yamazaki, Paolo A. Ascierto

Data analysis and interpretation: Reinhard Dummer, Keith T. Flaherty, Caroline Robert, Ana Arance, Jan Willem B. de Groot, Claus Garbe, Helen J. Gogas, Ralf Gutzmer, Dirk Schadendorf, Alessandra di Pietro, Jean Cantey-Kiser, Michelle Edwards, Paolo A. Ascierto

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600–Mutant Melanoma

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