Encorafenib plus binimetinib versus dabrafenib plus trametinib for the first-line treatment of patients with BRAFV600E-mutant metastatic non-small cell lung cancer: a matching-adjusted indirect treatment comparison

D Planchard; J Mazières; JM Grouin; C Le Reun; H Luttenauer; M Boussahoua; B Macabeo

doi:10.1016/j.esmoop.2025.106051

. 2026 Jan 27;11(2):106051. doi: 10.1016/j.esmoop.2025.106051

Encorafenib plus binimetinib versus dabrafenib plus trametinib for the first-line treatment of patients with BRAF^V600E-mutant metastatic non-small cell lung cancer: a matching-adjusted indirect treatment comparison

D Planchard ¹, J Mazières ^2,³, JM Grouin ⁴, C Le Reun ⁵, H Luttenauer ⁶, M Boussahoua ⁷, B Macabeo ^7,^∗

PMCID: PMC12865620 PMID: 41604820

Abstract

Background

The first-line (1L) standard of care for B-Raf proto-oncogene (BRAF)^V600E-mutant metastatic non-small cell lung cancer is BRAF inhibitor dabrafenib with MEK inhibitor trametinib (D + T). Combination therapy with encorafenib and binimetinib (E + B) has recently demonstrated clinical benefit in this setting in the single-arm, phase II PHAROS trial. We evaluated the relative efficacy and safety of E + B versus D + T in 1L using an unanchored matching-adjusted indirect comparison.

Material and methods

Individual patient data for E + B from PHAROS were matched on validated adjustment factors to aggregate data for D + T from Study BRF113928. The relative efficacy and safety of E + B versus D + T were assessed using weighted Cox proportional hazards models for overall survival and progression-free survival (PFS) and logistic regression models for objective response rate, grade 3-4 adverse events, serious adverse events (SAEs) and treatment discontinuation.

Results

Compared with D + T, E + B was associated with a statistically significant improvement in PFS [hazard ratio (HR) = 0.47; 95% CI 0.26-0.85; P = 0.01] and non-significant improvements in overall survival (HR = 0.55; 95% CI 0.30-1.01; P = 0.06) and objective response rate [odds ratio (OR) = 1.81; 95% CI 0.71-4.59, P = 0.21]. E + B was also associated with a statistically significant reduction in SAEs versus D + T (OR = 0.35; 95% CI 0.14-0.85; P = 0.02); reductions in grade 3-4 adverse events (OR = 0.93; 95% CI 0.37-2.32; P = 0.87) and treatment discontinuations (OR = 0.71; 95% CI 0.24-2.06; P = 0.53) were not statistically significant. Unadjusted indirect treatment comparisons and sensitivity analysis results were consistent with matching-adjusted indirect comparison findings.

Conclusions

This analysis suggests that E + B was associated with statistically significantly longer PFS and fewer SAEs compared with D + T, and may offer an alternative option for the 1L treatment of BRAF^V600E-mutant metastatic non-small cell lung cancer.

Key words: BRAF-mutant non-small-cell lung cancer, matching-adjusted indirect treatment comparison, encorafenib-binimetinib, dabrafenib-trametinib

Highlights

•
Efficacy and safety of E + B versus D + T were assessed via unanchored matching-adjusted indirect treatment comparison.
•
E + B was associated with a statistically significant improvement in PFS and SAEs versus D + T.
•
Given the rarity of BRAF^V600E mutation, low sample size led to reduced statistical power to detect significant differences.
•
Improvements in OS, ORR and treatment discontinuation with E + B versus D + T were not statistically significant.

Introduction

Lung cancer is the most commonly diagnosed cancer (12.4% of total cases) and the leading cause of cancer death (18.7% of total cancer deaths) globally.¹ Non-small cell lung cancer (NSCLC) accounts for 80%-90% of all lung cancers.² A range of actionable mutations have been identified in NSCLC, including mutations in the proto-oncogene B-Raf (BRAF), present in 1%-5% of patients diagnosed with NSCLC.2, 3, 4, 5 BRAF^V600E is the most common of the BRAF point mutations and is observed in over 50% of BRAF-mutant NSCLC cases.⁵

The 2025 European Society for Medical Oncology (ESMO) guidelines for NSCLC recommend the BRAF inhibitor dabrafenib in combination with the mitogen-activated protein kinase enzyme (MEK) inhibitor trametinib (D + T) as a first-line (1L) treatment option for patients with advanced BRAF^V600E-mutant metastatic NSCLC (mNSCLC).⁶^,⁷ The current standard of care for 1L treatment of BRAF^V600E-mutant NSCLC varies between countries depending on the reimbursement status of D + T, however. For example, D + T is only reimbursed in the second line (2L) setting in France, whereas D + T is only reimbursed in the 1L setting in the United Kingdom (UK) and Norway.⁸^,⁹

The efficacy and safety of D + T for treatment of patients with stage IV BRAF^V600E-mutant mNSCLC was assessed in the pivotal single-arm phase II trial, Study BRF113928 (NCT01336634).¹⁰^,¹¹ At the final analysis point (data cut-off February 2021), D + T demonstrated clinically meaningful antitumour activity, with an objective response rate (ORR) of 63.9% [95% confidence interval (CI) 46.2-79.2] in 36 treatment-naïve patients with stage IV BRAF^V600E-mutant mNSCLC.¹¹ The most frequently observed adverse event in Study BRF113928 was pyrexia (56%), with a dose reduction of 11 patients (12%) and withdrawal in two patients (2%).¹¹ This safety profile is consistent with study findings for D + T in the melanoma setting.10, 11, 12, 13

Combination therapy with encorafenib, a selective adenosine 5′-triphosphate competitive BRAF inhibitor for BRAF^V600E-mutant cells, and binimetinib, a MEK inhibitor (E + B), was recently evaluated as a treatment of BRAF^V600E-mutant mNSCLC in the open-label, single-arm, multicentre, non-randomised phase II PHAROS study (NCT03915951).¹⁴ At the primary analysis data cut-off (September 2022), E + B showed meaningful clinical benefit, with an ORR of 75% (95% CI 62%-85%) in 59 treatment-naïve patients.¹⁴ Median progression-free survival (PFS) was not estimable (NE) (95% CI 15.7-NE) for this population at the primary analysis data cut-off.¹⁴ Results from a later data cut-off (April 2024) with an additional 18 months of follow-up provide more mature survival data (median PFS: 30.2 months in treatment-naïve patients), although median OS was NE.¹⁵ E + B was associated with a manageable safety profile at both data cut-offs.¹⁴^,¹⁵

Based on evidence from the PHAROS trial, E + B combination therapy was approved for use in adult patients with BRAF^V600E-mutant advanced or metastatic NSCLC by the US Food and Drug Administration in 2023 and the European Medicines Agency in 2024, following the existing approval in BRAF-mutant metastatic melanoma.14, 15, 16, 17 E + B was subsequently recommended as a treatment for stage IV BRAF^V600E-mutant mNSCLC in an update to the ESMO living guidelines, and the current ESMO guidelines include an ESMO-Magnitude of Clinical Benefit Scale score of three for E + B, an improvement from the ESMO- Magnitude of Clinical Benefit Scale score of two for D + T (after adjustment for toxicity).6, 7, 18, 19

Given the availability of two different combination BRAF and MEK-inhibitor therapies for BRAF^V600E-mutant mNSCLC, comparison of the efficacy and safety of D + T versus E + B is essential for evidence-based clinical decision-making. In the absence of head-to-head randomised clinical trials, indirect treatment comparisons can be used to inform comparative effectiveness estimates and are routinely accepted by national health technology assessment bodies when appraising new interventions for reimbursement.²⁰ Standard methods for indirect treatment comparisons involve the synthesis of data from multiple comparative trials via a common comparator, allowing for the estimation of relative treatment effects using anchored comparisons between the therapies of interest.²⁰^,²¹ In the absence of a common comparator between trials, as is the case when only single-arm trials are available, unanchored methods can also be used, including unanchored matching-adjusted indirect treatment comparison.²² Matching-adjusted indirect treatment comparison is a population adjustment method that compares therapies assessed in different trial populations when individual patient data (IPD) are available for one trial population but only aggregate data are available for the comparator trial population.²²

The objective of this study was to compare the efficacy and safety of E + B versus D + T for the 1L treatment of patients with BRAF^V600E-mutant mNSCLC. An unanchored matching-adjusted indirect treatment comparison approach was selected based on the results of a systematic literature review (SLR) and feasibility assessment.

Material and methods

Analysis overview

E + B was compared with D + T for treatment of BRAF^V600E-mutant mNSCLC using clinical trial data from PHAROS and Study BRF113928 in a matching-adjusted indirect treatment comparison, in which the PHAROS population was weighted to match the Study BRF113928 trial population. Unadjusted indirect treatment comparisons are reported alongside the main matching-adjusted indirect treatment comparison results for reference. These should only be interpreted in the context of the matching-adjusted indirect treatment comparison results, however, as they do not provide valid comparative data in isolation. The matching-adjusted indirect treatment comparison was conducted in line with the recommendations provided by the National Institute for Health and Care Excellence (NICE) Decision Support Unit in Technical Support Document (TSD) 18.²² All statistical analyses were conducted in R based on adapted code provided in NICE TSD18.²²

Evidence base

An SLR was conducted in October 2021 and updated in May 2023 and July 2023 to identify interventional trials and observational studies reporting efficacy and safety outcomes in patients with BRAF^V600E-mutant mNSCLC. Databases searched were Embase, Medline®, and the Cochrane Library. The SLR also sought to gather evidence on prognostic variables and treatment effect modifiers (TEMs) associated with OS and response in BRAF^V600E-mutant mNSCLC. The SLR was conducted according to Cochrane Collaboration and Centre for Reviews and Dissemination guidelines as well as the methodological requirements of the NICE and Preferred Reporting Items for Systematic Reviews and Meta-Analyses.23, 24, 25, 26

Potential comparator studies for D + T identified in the SLR were assessed for inclusion in an indirect treatment comparison with the PHAROS study based primarily on: availability of aggregate data on adjustment factors, reporting on outcomes of interest, differences in the enrolled populations, availability of data for treatment-naïve patients and methodological heterogeneity. Further details of the SLR and feasibility assessment methodology and results are provided within the Supplementary Materials (Supplementary Methods, supplemenary results, Table S1 and Figure S1), available at https://doi.org/10.1016/j.esmoop.2025.106051.

Study design

From the studies identified in the SLR, Study BRF113928 was identified as the only suitable comparator trial for inclusion in an indirect treatment comparison with PHAROS. No other studies of E + B were identified in the SLR. Quality assessment was conducted for both studies using the Effective Public Health Practice Project Quality Assessment Tool (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.106051).

An anchored comparison between PHAROS and Study BRF113928 could not be carried out as both trials were single-arm. An unanchored matching-adjusted indirect treatment comparison was therefore selected as the most appropriate approach to evaluate the relative efficacy and safety of E + B versus D + T; the matching-adjusted indirect treatment comparison methodology allows for comparison between therapies that have not been assessed within a head-to-head trial through population adjustment. This typically involves reweighting IPD from one study of interest so that the means of the selected adjustment factors in the reweighted IPD population match those reported in aggregate data for the comparator study. In this case, IPD for E + B from the PHAROS trial were reweighted to match the aggregate data for D + T from Study BRF11398.¹⁰^,¹¹^,¹⁴^,¹⁵

Outcomes

Efficacy outcomes included in the matching-adjusted indirect treatment comparison were OS, PFS, and ORR. Safety outcomes included grade 3-4 adverse events (AEs), serious adverse events (SAEs), and permanent discontinuation due to AEs. Further details on outcome definitions from each study are provided in the Supplementary Materials (Table S3), available at https://doi.org/10.1016/j.esmoop.2025.106051.

Patient populations

All patients in the PHAROS trial met the eligibility criteria for Study BRF113928 and were included in the analysis. While the enrolment criteria for Study BRF113928 were broader in terms of Eastern Cooperative Oncology Group Performance (ECOG) score, this was considered acceptable given that only one patient (representing 2.8% of the sample population) in Study BRF113928 had an ECOG score greater than the range specified in the eligibility criteria for PHAROS. Further details of the eligibility criteria for each study are provided in the Supplementary Materials (supplementary results), available at https://doi.org/10.1016/j.esmoop.2025.106051.

Adjustment factors and derivation of weights

Potential adjustment factors were identified in the SLR and validated by experts in the field. Of the identified adjustment factors, only a subset were reported in PHAROS and Study BRF113928 and ultimately included in the matching-adjusted indirect treatment comparison. These were: age, gender, race, ECOG performance status, smoking status, histology, and the presence of brain metastases. Further details on the identification of adjustment factors are provided in the Supplementary Materials (supplementary results), available at https://doi.org/10.1016/j.esmoop.2025.106051.

Weights for the PHAROS IPD were estimated using a logistic propensity score model, using the method developed by Signorovitch et al. (2012) and described in TSD 18.²²^,²⁷ Following weighting, the distribution of weights was examined to ensure that no individual observations had an undue influence on the entire matched population, by checking that there were no very large weights or weights close to or equal to zero. In addition, to ensure that propensity score weighting successfully generated a balanced reweighted IPD population for PHAROS, the distribution of adjustment variables in the reweighted pseudo-population was compared with the distribution of the adjustment variables in the aggregate data. To estimate the sample size of the pseudo-population of reweighted IPD, estimated sample size (ESS) was computed as the squared sum of the weights divided by the sum of the squared weights. ESS was then compared with the sample size in the original IPD population to ensure that a reasonable proportion of the original IPD population was represented in the reweighted pseudo-population for analysis.

Calculation of indirect estimates

Event probabilities were summarised using Kaplan–Meier (KM) curves. Published KM curves for D + T OS and PFS in Study BRF113928 were digitised and pseudo-IPD were recreated using the Guyot algorithm.¹¹^,²⁸ A Cox proportional hazards (PH) model was then used to estimate the relative treatment effect of E + B versus D + T [hazard ratios (HRs) and corresponding 95% CIs and P values generated using the Wald test] for OS and PFS. The PH assumption was assessed using visual inspection of log-log plots as well as Schoenfeld residual testing. ORR and safety outcomes were analysed using logistic regression models, fitted to estimate the odds ratio (OR) and corresponding 95% CIs comparing E + B with D + T. Nominal P values generated using the Wald test are also reported for these outcomes.

Sensitivity analysis

In line with TSD 18, uncertainty in estimated weights was assessed using the bootstrap method.²² In total, 1000 bootstrap samples (with replacement) were generated from the PHAROS study population and the indirect treatment effect was estimated on each bootstrap sample. The median treatment effect of this distribution was reported for each outcome of interest with its 95% bias-corrected accelerated (BCa) CIs.

Results

Variables for baseline characteristics matching

Before matching, the baseline characteristics of the populations enrolled in PHAROS and Study BRF113928 were relatively comparable, with some imbalances in gender, race, histology, ECOG performance status, and smoking status. After population reweighting on the selected adjustment factors (age, gender, race, ECOG performance status, smoking status, histology and the presence of brain metastases), PHAROS baseline characteristics were exactly aligned with the Study BRF113928 (Table 1).

Table 1.

Baseline characteristics

	D + T (Study BRF113928)¹⁰^,¹¹	E + B (PHAROS)¹⁴
	D + T (Study BRF113928)¹⁰^,¹¹	Before matching (N = 59)	After matching (ESS N = 44)
Median age (years)	67	68	67
Gender (% male)	39	44	39
ECOG status (% ECOG = 0)	36	32	36
Smoking status (% never smoked)	28	31	28
Race (% white)	83	90	83
Histology (% adenocarcinoma)	89	97	89
Brain metastases (% yes)	6	7	6

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D + T, dabrafenib-trametinib; E + B, encorafenib-binimetinib; ECOG, Eastern Cooperative Oncology Group score; ESS, effective sample size.

Population adjustment resulted in an ESS of 44 patients compared with the original 59 patients enrolled in PHAROS. Rescaled weights ranged from 0.48 to 3.32, with a median of 0.81, indicating that no observations contributed disproportionately to the analyses. Furthermore, the distributions of the reweighted pseudo-population and the aggregate data were identical, indicating that the population reweighting step was successful. Given the relatively high ESS compared with the original IPD population, as well as a reasonable range for rescaled weights, the matching was deemed appropriate for valid interpretation of matching-adjusted indirect treatment comparison results.

Efficacy outcomes

E + B was associated with an estimated 45% decrease in the risk of death compared with D + T in the matching-adjusted indirect treatment comparison (HR = 0.55; 95% CI 0.30-1.01; P = 0.06) and an estimated 40% decrease in the unadjusted indirect treatment comparison (HR = 0.60; 95% CI 0.34-1.07; P = 0.08; Table 2). The estimated reduction in the hazard of OS was not statistically significant at a 95% confidence level in either the matching-adjusted or unadjusted analysis. The KM curves for D + T and E + B (matching-adjusted and unadjusted) are presented in Figure 1. The PH assumption was tested and deemed reasonable.

Table 2.

Indirect treatment comparison results

Outcome	Unadjusted indirect treatment comparison	Matching-adjusted indirect treatment comparison
Efficacy outcomes
OS, HR (95% CI)	0.60 (0.34-1.07); P = 0.08	0.55 (0.30-1.01); P = 0.06
PFS, HR (95% CI)	0.48 (0.27-0.87); P = 0.01	0.47 (0.26-0.85); P = 0.01
ORR, OR (95% CI)	1.66 (0.68-4.07); P = 0.27	1.81 (0.71-4.59); P = 0.21
Safety outcomes
Grade 3-4 AEs, OR (95% CI)	1.00 (0.41-2.47); P = 0.996	0.93 (0.37-2.32); P = 0.87
SAEs, OR (95% CI)	0.45 (0.19-1.07); P = 0.07	0.35 (0.14-0.85); P = 0.02
Discontinuations due to AEs, OR (95% CI)	0.71 (0.25-2.02); P = 0.53	0.71 (0.24-2.06); P = 0.53

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AE, adverse event; CI, confidence interval; HR, hazard ratio; OS, overall survival; OR, odds ratio; ORR, objective response rate; PFS, progression-free survival; SAE, serious adverse event.

**Matching-adjusted and unadjustedOS KM curves for E + B and D + T**. KM, Kaplan−Meier; OS, overall survival.

E + B was associated with a statistically significant decrease of 53% in the risk of disease progression or death compared with D + T in the matching-adjusted indirect treatment comparison (HR = 0.47; 95% CI 0.26-0.85; P = 0.01) and a 52% decrease in risk of disease progression or death in the unadjusted indirect treatment comparison (HR = 0.48; 95% CI 0.27-0.87; P = 0.02; Table 2). In both analyses, the estimated decrease in the risk of disease progression or death was statistically significant at a 95% confidence level. The KM curves for D + T and E + B (matching-adjusted and unadjusted) are presented in Figure 2. The PH assumption was tested and deemed reasonable.

**Matching-adjusted and unadjustedPFS KM curves for E + B and D + T**. KM, Kaplan−Meier; PFS, progression-free survival.

The estimated difference in odds of objective response with E + B compared with D + T did not reach statistical significance at a 95% confidence level in either the matching-adjusted indirect treatment comparison (OR = 1.81; 95% CI 0.71-4.59; P = 0.21) or the unadjusted indirect treatment comparison (OR for ORR = 1.66; 95% CI 0.68-4.07; P = 0.27; Table 2).

Safety outcomes

In both the matching-adjusted indirect treatment comparison (OR = 0.93; 95% CI 0.37-2.32; P = 0.87) and the unadjusted indirect treatment comparison (OR = 1.00; 95% CI 0.41-2.47; P = 0.996), there was no difference in the odds of grade 3-4 AEs between E + B and D + T (Table 2). E + B was associated with a statistically significant reduction of 65% in the odds of SAEs compared with D + T in the matching-adjusted indirect treatment comparison (OR = 0.35; 95% CI 0.14-0.85; P = 0.02), but not in the unadjusted indirect treatment comparison (OR = 0.45; 95% CI 0.19-1.07; P = 0.07, Table 2). In both the matching-adjusted indirect treatment comparison (OR = 0.71; 95% CI 0.24-2.06; P = 0.53) and the unadjusted indirect treatment comparison (OR = 0.71; 95% CI 0.25-2.02, P = 0.53; Table 2), there was no statistically significant difference in the odds of discontinuation due to AEs between E + B and D + T.

Sensitivity analysis

The sensitivity analysis using the bootstrap method with 1000 iterations yielded consistent findings compared with the main matching-adjusted indirect treatment comparison analysis (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2025.106051). E + B was associated with a statistically significant decrease in the risk of death compared with D + T in the sensitivity analysis (bootstrap median HR = 0.57; 95% BCa CI 0.35-0.78), however, whereas the estimated decrease in the risk of death in the main matching-adjusted indirect treatment comparison analysis was not statistically significant. Relative treatment effects for all other efficacy and safety outcomes were consistent in terms of directionality and statistical significance between the sensitivity and main analyses.

Discussion

This study aimed to estimate the comparative efficacy and safety of E + B versus D + T for the 1L treatment of patients with BRAF^V600E-mutant mNSCLC using an unanchored matching-adjusted indirect treatment comparison.

This analysis demonstrated a statistically significant reduction in the risk of disease progression and in the risk of SAEs with E + B compared with D + T. The results of the bootstrapping sensitivity analysis were consistent with those in the main analysis, demonstrating the robustness of the main analysis results. For OS, E + B was associated with a statistically significant decrease in the risk of death compared with D + T in the bootstrapping sensitivity analysis but not the main analysis. This may be a result of the increased statistical power associated with the bootstrapping analysis compared with the main analysis (which had a small sample size as expected, given the rarity of BRAF^V600E-mutant mNSCLC), given that the confidence intervals for OS in the main analysis only narrowly cross the null value of one. Low sample size across treatment arms (ESS of 44 for PHAROS and 36 for Study BRF113928) also contributed to wide confidence intervals for the odds of objective response, risk of grade 3-4 AEs and discontinuation due to AEs.

This study has several strengths. Firstly, matching-adjusted indirect treatment comparison is a well-established approach to enable comparisons between treatments that have only been evaluated in single-arm trials, and this analysis was conducted in line with best practices for matching-adjusted indirect treatment comparison.²² In addition, the patient demographics and characteristics at baseline in PHAROS and Study BRF113928 are generally reflective of the patient population expected in clinical practice.¹⁰^,¹¹^,¹⁴^,¹⁵ Moreover, PHAROS and Study BRF113928 had similar inclusion and exclusion criteria, such that all patients included in PHAROS met the eligibility criteria of Study BRF113928 and were included in the analysis.¹⁰^,¹¹^,¹⁴^,¹⁵ Finally, the consistency of the sensitivity analysis results with the main results demonstrates the robustness of the analysis, suggesting that the estimated relative treatment effects were not unduly influenced by uncertainty introduced by estimating weights in the matching-adjusted indirect treatment comparison. Importantly, this study is the first to provide comparative effectiveness and safety evidence for E + B and D + T in treatment-naïve patients with BRAF^V600E-mutant mNSCLC, a patient population with limited treatment options.

There were also several limitations of the analysis. Firstly, there were some differences in the ORR and PFS outcomes from PHAROS versus Study BRF113928 used in the analysis; ORR and PFS data from PHAROS were based on independent radiology review, whereas the ORR and PFS outcomes from Study BRF113928 used in the matching-adjusted indirect treatment comparison were assessed by independent review committee (the primary endpoint in Study BRF113928 was investigator-assessed ORR). Secondly, tumour assessments were conducted at slightly different intervals in the two studies, which may affect the comparability of the PFS outcomes. These differences in outcome assessment method and interval could be potential sources of bias. The use of an unanchored matching-adjusted indirect treatment comparison also assumes that all prognostic variables and TEMs have been identified, measured similarly, and adjusted within the analysis. Certain adjustment factors identified in the SLR (concomitant mutation in the PI3K pathway, presence of metastases in the thoracic cavity, PD-L1 ≥1% expression, presence of liver metastases and presence of M1a metastases) were not reported for PHAROS and Study BRF113928 and therefore could not be adjusted for within the matching-adjusted indirect treatment comparison. This may have introduced bias into the comparison of E + B and D + T due to potential unmeasured differences in patient populations between trials. Input from experts in the field indicated that the importance of these adjustment factors was comparatively low versus the adjustment factors included in the analysis, however.

Other limitations included the fact that the inclusion criteria for Study BRF113928 were broader than the inclusion criteria for PHAROS; patients with a higher ECOG score (up to two in Study BRF11398 versus zero or one in PHAROS) were eligible for inclusion in Study BRF113928 compared with PHAROS. This difference cannot be accounted for in a matching-adjusted indirect treatment comparison; however, given that only one patient included in the 1L cohort of Study BRF113928 would not have been eligible for inclusion in PHAROS based on their ECOG score (2.8% of the sample population), the impact of this difference is expected to be minimal. The two studies were also not carried out over the same time period (the enrolment period for Study BRF113928 was 16 April 2014-28 December 2015, while the enrolment period for PHAROS was 4 June 2019-2 June 2022), meaning that molecular screening for BRAF^V600E mutation was not as well developed during Study BRF113928 as it was during PHAROS. Furthermore, there may have been differential access to specific treatments for BRAF^V600E-mutant mNSCLC during these periods, potentially leading to differences in the demographics of the populations recruited.¹⁰^,¹⁴ Finally, both PHAROS and Study BRF113928 were open-label, single-arm and non-randomised trials, making them less robust in their design compared with a randomised clinical trial.

The immaturity of the PHAROS OS data also contributes to some unavoidable uncertainty in the results. Longer term OS data would be valuable to further establish the effect of E + B on disease progression and survival. In the meantime, future research may consider additional efficacy and safety data with a longer duration of follow-up than the current analysis, such as further analyses of PHAROS or the ongoing ENCO-BRAF study. Based on the currently available data from the primary data cut-off point of the ENCO-BRAF study, E + B demonstrated substantial clinical activity in the treatment-naïve population, reporting ORR comparable with that of PHAROS (ORR = 66.7%; 95% CI 55.0%-78.3%) and PFS lower than that of PHAROS (median PFS = 11.1 months; 95% CI 7.1-16.7 months), with a median follow-up time of 18 months.²⁹ Given the immaturity of the survival data in the ENCO-BRAF study, this study was not included in the current analysis, however.

Treatment with E + B versus D + T in 2L or subsequent settings is an additional area of potential interest for future research. The 2025 ESMO guidelines for NSCLC recommend D + T or E + B as 2L treatment for patients with advanced BRAF^V600E-mutant mNSCLC who have not received D + T or E + B, respectively, as 1L treatment.⁶^,⁷ Data on the efficacy and safety of D + T and E + B in this setting are available from Study BRF113928 and PHAROS, both of which enrolled separate cohorts of treatment-naïve and previously-treated patients.¹⁰^,¹¹^,¹⁴^,¹⁵ It was not possible to conduct a matching-adjusted indirect treatment comparison of E + B versus D + T in the 2L setting as Study BRF113928 enrolled a much greater proportion of patients receiving treatment in the third line and later setting compared with PHAROS and did not report data separately for patients treated in the 2L setting.¹⁴^,¹⁵ As such, the difference between the trial populations was too substantial to be robustly adjusted for using matching-adjusted indirect treatment comparison.¹⁰^,¹¹ It would be valuable for future research to compare E + B with D + T in previously-treated patients, in order to support clinical decision-making in this setting.

Conclusions and implications

In the absence of direct head-to-head clinical trial evidence, this matching-adjusted indirect treatment comparison provides evidence for the comparative efficacy and safety of E + B compared with D + T in the 1L treatment of patients with BRAF^V600E-mutant mNSCLC.

The results of this analysis suggest that E + B provides a potential alternative to D + T in the 1L treatment of patients with BRAF^V600E-mutant mNSCLC, resulting in longer PFS and lower odds of SAEs. In the context of this rare cancer mutation, relatively small sample sizes contributed to wide confidence intervals for most outcomes considered, highlighting the need for further research in this area.

Acknowledgements

The authors thank Rachel Tao, MPH, Elizabeth Parke, MSc and Helen Bewicke-Copley, MSc, of Costello Medical, London, UK for providing medical writing support, which was sponsored by Pierre Fabre in accordance with Good Publication Practice guidelines.

Funding

This study was sponsored by Pierre Fabre.

Disclosure

DP: acted in consulting, advisory role or lectures for AstraZeneca, AbbVie, Bristol Myers Squibb, Bohringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre Fabre, Takeda, ArriVent, Mirati, Seagen and GlaxoSmithKline; acted as principal or co-investigator on clinical trials funded by AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, AbbVie, Janssen, Pierre Fabre, Takeda, ArriVent, Mirati and Seagen; received fees for travel, accommodation or expenses from AstraZeneca, Roche, Novartis and Pfizer.

JM: received personal fees from Roche, AstraZeneca, Pierre Fabre, Takeda, Bristol Myers Squibb, MSD, Pfizer, Jiangsu Hengrui, Blueprint, Daiichi Sankyo, Novartis and Amgen; received grant funding from Roche, AstraZeneca, Pierre Fabre, Bristol Myers Squibb and Illumina.

JMG: acted in consulting, advisory role for Beigene, Pierre Fabre, Chugai, Biocon and Janssen.

CLR: received consulting fees (from Clarivate) to feasibility assessment and analyses.

HL: received consulting fees (from Pierre Fabre) for the feasibility assessment and the analyses.

MB: employee of Pierre Fabre.

BM: employee of Pierre Fabre.

Supplementary data

Supplementary Materials

mmc1.docx^{(385.2KB, docx)}

References

1.Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
2.Planchard D., Popat S., Kerr K., et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;29:iv192–iv237. doi: 10.1093/annonc/mdy275. [DOI] [PubMed] [Google Scholar]
3.Dagogo-Jack I. Durable response to dabrafenib combined with trametinib in a patient with NSCLC harboring a BRAF G469A mutation. J Thorac Oncol. 2020;15:e174–e176. doi: 10.1016/j.jtho.2020.07.007. [DOI] [PubMed] [Google Scholar]
4.Frisone D., Friedlaender A., Malapelle U., Banna G., Addeo A. A BRAF new world. Crit Rev Oncol Hematol. 2020;152 doi: 10.1016/j.critrevonc.2020.103008. [DOI] [PubMed] [Google Scholar]
5.O’Leary C.G., Andelkovic V., Ladwa R., et al. Targeting BRAF mutations in non-small cell lung cancer. Transl Lung Cancer Res. 2019;8:1119–1124. doi: 10.21037/tlcr.2019.10.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.European Society for Medical Oncology (ESMO) 2025. ESMO oncogene-addicted metastatic non-small-cell lung cancer living guideline, v1.2 - January 2025. [Google Scholar]
7.Hendriks L.E.L., Cortiula F., Martins-Branco D., et al. Updated treatment recommendations for systemic treatment: from the ESMO oncogene-addicted metastatic NSCLC living guideline. Ann Oncol. 2025;36:1227–1231. doi: 10.1016/j.annonc.2025.06.007. [DOI] [PubMed] [Google Scholar]
8.National Institute for Health and Care Excellence (NICE) Dabrafenib plus trametinib for treating BRAF V600 mutation-positive advanced non-small-cell lung cancer. Technology appraisal guidance. 2023. https://www.nice.org.uk/guidance/TA898 Available at. [PubMed]
9.Haute Autorité De Santé (HAS) Opinion on drugs: tafinlar - meikinist (dabrafenib/trametinib) 2022. https://www.has-sante.fr/jcms/p_3381101/en/tafinlar-mekinist-dabrafenib/trametinib Available at.
10.Planchard D., Smit E.F., Groen H.J.M., et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–1316. doi: 10.1016/S1470-2045(17)30679-4. [DOI] [PubMed] [Google Scholar]
11.Planchard D., Besse B., Groen H.J.M., et al. Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis. J Thorac Oncol. 2022;17:103–115. doi: 10.1016/j.jtho.2021.08.011. [DOI] [PubMed] [Google Scholar]
12.Long G.V., Stroyakovskiy D., Gogas H., et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–451. doi: 10.1016/S0140-6736(15)60898-4. [DOI] [PubMed] [Google Scholar]
13.Robert C., Karaszewska B., Schachter J., et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–39. doi: 10.1056/NEJMoa1412690. [DOI] [PubMed] [Google Scholar]
14.Riely G.J., Smit E.F., Ahn M.J., et al. Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer. J Clin Oncol. 2023;41:3700–3711. doi: 10.1200/JCO.23.00774. [DOI] [PubMed] [Google Scholar]
15.Riely G.J., Ahn M.J., Clarke J.M., et al. Updated efficacy and safety from the phase 2 PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC—a brief report. J Thorac Oncol. 2025;20:1538–1547. doi: 10.1016/j.jtho.2025.05.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.European Medicines Agency (EMA) BRAFTOVI (encorafenib) Summary of Product Characteristics. 2024. https://www.ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf Available at.
17.Food and Drug Administration (FDA) BRAFTOVI (encorafenib) Highlights of Prescribing Information. 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation Available at.
18.European Society for Medical Oncology (ESMO) ESMO-MCBS scorecard: encorafenib. https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards?scorecard=405 Available at.
19.European Society for Medical Oncology (ESMO) ESMO-MCBS scorecard: dabrafenib + trametinib. https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards?scorecard=131 Available at.
20.Bucher H.C., Guyatt G.H., Griffith L.E., Walter S.D. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50:683–691. doi: 10.1016/s0895-4356(97)00049-8. [DOI] [PubMed] [Google Scholar]
21.Dias S, Welton N.J., Sutton A.J., Ades A.E. National Insitute for Health and Care Excellence (NICE) Decision Support Unit (DSU) Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials. 2016. https://sheffield.ac.uk/nice-dsu/tsds/evidence-synthesis Available at. [PubMed]
22.Phillippo D., Ades T., Dias S., Palmer S., Abrams K.R., Welton N. National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) Technical Support Document (TSD) 18: Methods for Population-Adjusted Indirect Comparisons in Submissions to NICE. https://sheffield.ac.uk/nice-dsu/tsds/population-adjusted Available at.
23.Higgins J., Thomas J., Chandler J., et al. Cochrane; 2022. Cochrane handbook for systematic reviews of interventions, version 6.3.https://training.cochrane.org/handbook Available at. [Google Scholar]
24.Centre for Reviews and Dissemination Systematic reviews CRD’s guidance for undertaking reviews in health care. 2009. https://www.york.ac.uk/media/crd/Systematic_Reviews.pdf Available at.
25.National Institutes of Health and Care Excellence (NICE) NICE Health Technology Evaluations: The Manual: Process and Methods [PMG36] 2022. https://www.nice.org.uk/process/pmg3 Available at.
26.Page M.J., McKenzie J.E., Bossuyt P.M., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Br Med J. 2021;372 doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Signorovitch J.E., Sikirica V., Erder M.H., et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15:940–947. doi: 10.1016/j.jval.2012.05.004. [DOI] [PubMed] [Google Scholar]
28.Guyot P., Ades A.E., Ouwens M.J.N.M., Welton N.J. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9. doi: 10.1186/1471-2288-12-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Planchard D., Mazieres J., Masceaux J., et al. 1259MO Encorafenib plus binimetinib in patients (pts) with previously untreated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): an open-label, multicenter phase II trial (IFCT-1904 ENCO-BRAF) Ann Oncol. 2024;(suppl 2):S806–S807. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

mmc1.docx^{(385.2KB, docx)}

[bib1] 1.Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]

[bib2] 2.Planchard D., Popat S., Kerr K., et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;29:iv192–iv237. doi: 10.1093/annonc/mdy275. [DOI] [PubMed] [Google Scholar]

[bib3] 3.Dagogo-Jack I. Durable response to dabrafenib combined with trametinib in a patient with NSCLC harboring a BRAF G469A mutation. J Thorac Oncol. 2020;15:e174–e176. doi: 10.1016/j.jtho.2020.07.007. [DOI] [PubMed] [Google Scholar]

[bib4] 4.Frisone D., Friedlaender A., Malapelle U., Banna G., Addeo A. A BRAF new world. Crit Rev Oncol Hematol. 2020;152 doi: 10.1016/j.critrevonc.2020.103008. [DOI] [PubMed] [Google Scholar]

[bib5] 5.O’Leary C.G., Andelkovic V., Ladwa R., et al. Targeting BRAF mutations in non-small cell lung cancer. Transl Lung Cancer Res. 2019;8:1119–1124. doi: 10.21037/tlcr.2019.10.22. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib20] 6.European Society for Medical Oncology (ESMO) 2025. ESMO oncogene-addicted metastatic non-small-cell lung cancer living guideline, v1.2 - January 2025. [Google Scholar]

[bib21] 7.Hendriks L.E.L., Cortiula F., Martins-Branco D., et al. Updated treatment recommendations for systemic treatment: from the ESMO oncogene-addicted metastatic NSCLC living guideline. Ann Oncol. 2025;36:1227–1231. doi: 10.1016/j.annonc.2025.06.007. [DOI] [PubMed] [Google Scholar]

[bib8] 8.National Institute for Health and Care Excellence (NICE) Dabrafenib plus trametinib for treating BRAF V600 mutation-positive advanced non-small-cell lung cancer. Technology appraisal guidance. 2023. https://www.nice.org.uk/guidance/TA898 Available at. [PubMed]

[bib9] 9.Haute Autorité De Santé (HAS) Opinion on drugs: tafinlar - meikinist (dabrafenib/trametinib) 2022. https://www.has-sante.fr/jcms/p_3381101/en/tafinlar-mekinist-dabrafenib/trametinib Available at.

[bib10] 10.Planchard D., Smit E.F., Groen H.J.M., et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–1316. doi: 10.1016/S1470-2045(17)30679-4. [DOI] [PubMed] [Google Scholar]

[bib11] 11.Planchard D., Besse B., Groen H.J.M., et al. Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis. J Thorac Oncol. 2022;17:103–115. doi: 10.1016/j.jtho.2021.08.011. [DOI] [PubMed] [Google Scholar]

[bib12] 12.Long G.V., Stroyakovskiy D., Gogas H., et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–451. doi: 10.1016/S0140-6736(15)60898-4. [DOI] [PubMed] [Google Scholar]

[bib13] 13.Robert C., Karaszewska B., Schachter J., et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–39. doi: 10.1056/NEJMoa1412690. [DOI] [PubMed] [Google Scholar]

[bib14] 14.Riely G.J., Smit E.F., Ahn M.J., et al. Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer. J Clin Oncol. 2023;41:3700–3711. doi: 10.1200/JCO.23.00774. [DOI] [PubMed] [Google Scholar]

[bib15] 15.Riely G.J., Ahn M.J., Clarke J.M., et al. Updated efficacy and safety from the phase 2 PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC—a brief report. J Thorac Oncol. 2025;20:1538–1547. doi: 10.1016/j.jtho.2025.05.023. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib16] 16.European Medicines Agency (EMA) BRAFTOVI (encorafenib) Summary of Product Characteristics. 2024. https://www.ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf Available at.

[bib17] 17.Food and Drug Administration (FDA) BRAFTOVI (encorafenib) Highlights of Prescribing Information. 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation Available at.

[bib18] 18.European Society for Medical Oncology (ESMO) ESMO-MCBS scorecard: encorafenib. https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards?scorecard=405 Available at.

[bib19] 19.European Society for Medical Oncology (ESMO) ESMO-MCBS scorecard: dabrafenib + trametinib. https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/esmo-mcbs-scorecards?scorecard=131 Available at.

[bib22] 20.Bucher H.C., Guyatt G.H., Griffith L.E., Walter S.D. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50:683–691. doi: 10.1016/s0895-4356(97)00049-8. [DOI] [PubMed] [Google Scholar]

[bib23] 21.Dias S, Welton N.J., Sutton A.J., Ades A.E. National Insitute for Health and Care Excellence (NICE) Decision Support Unit (DSU) Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials. 2016. https://sheffield.ac.uk/nice-dsu/tsds/evidence-synthesis Available at. [PubMed]

[bib24] 22.Phillippo D., Ades T., Dias S., Palmer S., Abrams K.R., Welton N. National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) Technical Support Document (TSD) 18: Methods for Population-Adjusted Indirect Comparisons in Submissions to NICE. https://sheffield.ac.uk/nice-dsu/tsds/population-adjusted Available at.

[bib25] 23.Higgins J., Thomas J., Chandler J., et al. Cochrane; 2022. Cochrane handbook for systematic reviews of interventions, version 6.3.https://training.cochrane.org/handbook Available at. [Google Scholar]

[bib26] 24.Centre for Reviews and Dissemination Systematic reviews CRD’s guidance for undertaking reviews in health care. 2009. https://www.york.ac.uk/media/crd/Systematic_Reviews.pdf Available at.

[bib27] 25.National Institutes of Health and Care Excellence (NICE) NICE Health Technology Evaluations: The Manual: Process and Methods [PMG36] 2022. https://www.nice.org.uk/process/pmg3 Available at.

[bib28] 26.Page M.J., McKenzie J.E., Bossuyt P.M., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Br Med J. 2021;372 doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib29] 27.Signorovitch J.E., Sikirica V., Erder M.H., et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15:940–947. doi: 10.1016/j.jval.2012.05.004. [DOI] [PubMed] [Google Scholar]

[bib30] 28.Guyot P., Ades A.E., Ouwens M.J.N.M., Welton N.J. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9. doi: 10.1186/1471-2288-12-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib31] 29.Planchard D., Mazieres J., Masceaux J., et al. 1259MO Encorafenib plus binimetinib in patients (pts) with previously untreated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): an open-label, multicenter phase II trial (IFCT-1904 ENCO-BRAF) Ann Oncol. 2024;(suppl 2):S806–S807. [Google Scholar]

PERMALINK

Encorafenib plus binimetinib versus dabrafenib plus trametinib for the first-line treatment of patients with BRAFV600E-mutant metastatic non-small cell lung cancer: a matching-adjusted indirect treatment comparison

D Planchard

J Mazières

JM Grouin

C Le Reun

H Luttenauer

M Boussahoua

B Macabeo

Abstract

Background

Material and methods

Results

Conclusions

Highlights

Introduction

Material and methods

Analysis overview

Evidence base

Study design

Outcomes

Patient populations

Adjustment factors and derivation of weights

Calculation of indirect estimates

Sensitivity analysis

Results

Variables for baseline characteristics matching

Table 1.

Efficacy outcomes

Table 2.

Figure 1.

Figure 2.

Safety outcomes

Sensitivity analysis

Discussion

Conclusions and implications

Acknowledgements

Funding

Disclosure

Supplementary data

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Encorafenib plus binimetinib versus dabrafenib plus trametinib for the first-line treatment of patients with BRAF^V600E-mutant metastatic non-small cell lung cancer: a matching-adjusted indirect treatment comparison