EGFR inhibitors plus dabrafenib and trametinib in patients with EGFR-mutant lung cancer and resistance mediated by BRAF^V600E mutation: a multi-center real-world experience in China

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide (1). Although significant advances have been made in the treatment of non-small cell lung cancer (NSCLC) over the past 30 years by identifying driver gene mutations and developing targeted therapies, lung cancer remains a significant public health problem due to its high incidence. The best-known oncogenic drivers of NSCLC involve activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene, with the most frequent mutations being the exon 19 deletion and the exon 21 L858R substitution (2). The two most common EGFR alterations represent approximately 85–90% of all EGFR alterations in NSCLC and both result in activation of the tyrosine kinase domain and are associated with sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKIs) (3). However, whether it is 9.5 months of progression-free survival (PFS) in the IPASS trial, 11.1 months of PFS in the LUX-Lung 3 trial, or 18.9 months of PFS in the FLAURA trial, acquired patient resistance to EGFR-TKIs remains an area that needs further exploration (4-6). The currently known acquired resistance mechanisms to EGFR TKIs can be broadly categorized into on-target mechanisms, such as the EGFR^T790M/EGFR^C797S mutation and EGFR amplification, as well as off-target mechanisms, including Rat sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway aberrations, bypass signaling activation, and histologic or phenotypic transformation (7-9).

RAS-MAPK pathway aberrations that are known to confer resistance to osimertinib include B-Raf proto-oncogene (BRAF), neuroblastoma RAS viral oncogene homolog (NRAS), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. BRAF mutations are found in 2–5% of NSCLC cases, with approximately 50% being the BRAF^V600E variant (10). Although the frequency of this mutation as a secondary targetable alteration in osimertinib-resistant patients is much lower, studies have confirmed that new driver gene alterations in EGFR-mutated lung cancer can serve as a mechanism of resistance to osimertinib (11,12). Non-V600 BRAF mutations, such as G469A, have also been reported as an acquired resistance mechanism to osimertinib (13). Based on the data from the clinical trial BRF113928 (NCT01336634) [dabrafenib and trametinib combination group—objective response rate (ORR): 63%, median progression free survival (mPFS): 10.2 months, median overall survival (mOS): 18.2 months], the combination of BRAF inhibitor dabrafenib and mitogen-activated protein kinase kinase (MEK) inhibitor trametinib was approved by the Food and Drug Administration (FDA) in June, 2017 for the treatment of BRAF^V600E mutation-positive NSCLC (14). Despite the excellent efficacy demonstrated by the combination of dabrafenib and trametinib in patients initially identified with BRAF^V600E mutations, the absence of data from large-scale clinical studies on patients who develop BRAF mutations following resistance to EGFR-TKIs remains a major obstacle in selecting treatment options for these patients.

In this study, we reviewed the treatment histories of 14 patients with newly acquired BRAF^V600E mutation among 1,288 patients who developed EGFR-TKI resistance. Based on the studied population of patients, we estimated the median PFS for the triple therapy regimen of EGFR-TKI plus dabrafenib and trametinib. Our subgroup analysis can also help identify potential factors influencing treatment outcomes and promote clinical decision-making. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-803/rc).

Methods

Study design and patients enrollment

We reviewed the medical records of 1,861 patients who were treated with EGFR-TKI targeted drugs at three major medical centers in Shanghai between June 2015 and August 2024. Among 1,288 patients who developed disease progression, we identified 14 patients who were diagnosed with NSCLC with either EGFR^19del or EGFR^L858R mutations and after treatment with 1^st/2^nd/3^rd generation of EGFR-TKI, then blood or tissue-based next-generation sequencing (NGS) was performed to identify BRAF^V600E mutation as potential resistance mechanisms. Data were cut-off on August 1, 2024. Patients who did not complete tumor response assessments were excluded from the study.

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and the protocol was reviewed and approved by the institutional review board of Ruijin Hospital (No. 2024-164), the Ethics Committee of Fudan University Shanghai Cancer Center (No. 1612167-18) and the Ethics Committee of Shanghai Pulmonary Hospital (No. L22-407). Individual consent for this retrospective analysis was waived.

Effectiveness and safety evaluation

Effectiveness was assessed by PFS, overall survival (OS), ORR, and disease control rate (DCR). PFS was defined as the time from initiation of dabrafenib plus trametinib therapy to the disease progression or death. OS was defined as the time from using dabrafenib plus trametinib therapy to death due to any cause. DCR was defined as the proportion of patients achieving complete response (CR), partial response (PR) or stable disease (SD). ORR was defined as the proportion of patients achieving CR or PR. Tumor response was initially evaluated after 1 month of treatment with dabrafenib and trametinib, and subsequently every 2 months, based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Adverse events (AEs) were monitored monthly in accordance with the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Survival outcomes and disease progression data were acquired through medical record review and telephone interviews conducted by trained staff members. In cases the patients or their family members were unreachable at the scheduled follow-up date, the date and survival information were censored according to the last follow-up.

Statistical analysis

Categorical variables were summarized by frequency and percentage, while continuous variables were described using medians and ranges. PFS and OS were estimated using the Kaplan-Meier method, accompanied by hazard ratios (HRs). All outcome measures were reported with 95% confidence intervals (CIs), estimated through the log-rank proportional hazards model. Due to the limited sample size and inability to satisfy the proportional hazards assumption of Cox regression, exploratory univariate analyses were conducted using the log-rank test. AEs were summarized by frequency counts and percentages.

All P values were two-sided, with statistical significance set at P<0.05. Analyses were performed using IBM^® SPSS^® Statistics version 26 and R version 4.0.2, with graphs created in R version 4.0.2.

Results

Patient baseline characteristics

Fourteen patients with newly acquired BRAF^V600E mutation after EGFR-TKI resistance at three major medical centers in Shanghai between June 2015 and August 2024 were included in the study (Figure 1). A total of 1,124 patients underwent NGS testing after developing resistance to EGFR-TKIs, revealing a BRAF^V600E incidence rate of 1.25% in this setting and the incidence rates in the respective groups were 1.65% and 1.32%. The baseline characteristics of the patients at the start of dabrafenib plus trametinib therapy are outlined in Table 1. The median age of the patients was 60 years (range, 53 to 70 years); 57.1% (8 out of 14) were female, and 64.3% (9 out of 14) were never-smokers. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) score of 1 and were stage IV disease at baseline of dabrafenib plus trametinib therapy; 42.9% (6/14) of patients had a surgical history at the time of initial diagnosis of lung cancer.

Figure 1 Flowchart of the patient selection process. NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; NGS, next-generation sequencing; D+T + EGFR-TKI, dabrafenib and trametinib plus epidermal growth factor receptor-tyrosine kinase inhibitor.

Most patients (11/14, 78.6%) had distant metastasis at baseline of dabrafenib plus trametinib therapy, with the most common sites being contralateral lung (35.7%), bone (21.4%) and brain (21.4%). In the initial genetic analysis, all patients were found to harbor EGFR-sensitive mutations, with 71.4% exhibiting deletions in exon 19 and 21.4% showing the L858R mutation in exon 21. Additionally, one patient displayed both the exon 19 deletion and the exon 21 L858R mutation concurrently. As for first-line therapy, 42.9% of patients received first-generation EGFR-TKIs, 14.2% received second-generation, and 42.9% received third-generation. Eight patients (57.1%) took the primary lesion progression as the progression way of the first line treatment, while the rest of the patients developed the new lesions.

Treatment history

The key findings of 14 patients are summarized in Table 2. Eight patients used first or second-generation EGFR-TKIs as first-line, then switched to osimertinib; six patients chose osimertinib directly as first-line. In all these cases, following treatment with osimertinib, NGS of blood or tissue samples was conducted to detect resistance mechanisms.

The second NGS testing results revealed that all cases retained their initial EGFR mutations and additionally acquired new BRAF^V600E mutations. It is noteworthy that half of the cases (7/14) showed additional mutations in the second NGS testing, apart from BRAF^V600E mutations, including EGFR^T790M/C797S mutations, TP53 mutations and MET amplification. As of today, there is no therapeutic strategy to simultaneously inhibit both the EGFR and BRAF/MEK pathways. Therefore, the combination of EGFR-TKI osimertinib, BRAF inhibitor dabrafenib, and MEK inhibitor trametinib represents a rational and feasible treatment approach.

Tumor responses

Tumor responses are shown in Table 3. One patient (7.1%) achieved CR, 4 patients (28.6%) achieved PR and 6 patients (42.9%) had SD, leading to an ORR of 35.7% (95% CI: 14.0–64.4%) and a DCR of 78.6% (95% CI: 52.4–92.4%). Three patients (21.4%) were reported progressive disease (PD) as the best response.

A swimmer plot (Figure 2) was generated to facilitate comparison of the duration and therapeutic response across each line of treatment targeting secondary acquired driver alterations in EGFR-mutated NSCLC patients. Time 0 is defined as the initiation of first-line targeted therapy following the identification of the EGFR mutation. The yellow bars indicate the treatment duration with first- or second-generation EGFR-TKIs, the purple bars represent the treatment duration with third-generation TKIs, and the blue bars denote the treatment duration with the addition of BRAF inhibitor dabrafenib and MEK inhibitor trametinib following the second NGS test.

Figure 2 Swimmer plot of the duration and therapeutic response for patients in each line treatment. EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; D+T, dabrafenib plus trametinib; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Clinical outcomes

At the time of the data cutoff (August 1, 2024), the estimated median PFS was 6.7 months (95% CI: 2.5–NE) and 11 (11/14, 78.6%) patients developed disease progression (Figure 3A).

Figure 3 The clinical response of triple regimen, EGFR-TKI plus dabrafenib and trametinib. (A) Kaplan-Meier curve PFS of triple regimen in all 14 patients with newly acquired BRAF^V600E mutation after EGFR-TKI resistance. (B) Kaplan-Meier curve PFS of triple regimen treatment in patients receiving different EGFR-TKIs options. (C) Kaplan-Meier curve PFS of triple regimen treatment in patients with different gene mutation backgrounds. (D-F) Kaplan-Meier curve PFS of triple regimen treatment in patients with different surgical history, smoking history and the mode of progression after first-line EGFR-TKI treatment. PFS, progression-free survival; CI, confidence interval; NE, not evaluated; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; D+T, dabrafenib plus trametinib; HR, hazard ratio.

Death occurred in 6 patients (6/14, 42.9%) in all cases. The median OS was not reached in these patients.

Subgroup analysis and potential influencing factors

To explore whether the sequence of EGFR-TKI administration affects patients’ PFS and OS, patients were divided into two groups: one receiving third-generation TKI after first-/second-generation EGFR-TKIs (8 patients) and the other receiving third-generation TKI as first-line treatment (6 patients). The median PFS was 8.35 months in the former group and 6.9 months in the latter, with no significant difference in PFS between the two groups (HR: 1.107; 95% CI: 0.318–3.854; P=0.85) (Figure 3B).

Next, we stratified patients to investigate factors affecting the efficacy of dabrafenib plus trametinib treatment. The presence of additional mutations (e.g., EGFR^T790M/C797S, TP53 mutations and MET amplification), after resistance to osimertinib, potentially influenced treatment efficacy. In seven patients with complex mutation profiles, all experienced disease progression, with a median PFS of 2.5 months. However, in seven patients with only BRAF mutations, four of them progressed with a median PFS of 15.9 months (HR: 3.538; 95% CI: 1.008–12.422; P=0.02) (Figure 3C). PFS was not significantly influenced by surgical history (P=0.90, Figure 3D), smoking history (P=0.79, Figure 3E) or the mode of progression after first-line EGFR-TKI treatment (P=0.94, Figure 3F).

The pie chart (Figure 4) visually demonstrated that the group with a complex background, characterized by multiple mutations, showed a significant disadvantage in response with the triple therapy regimen. This highlights that a complex genetic mutation background and individual heterogeneity contribute to the uncertainty of drug efficacy and the early onset of resistance.

Figure 4 Disadvantages in response and early onset of resistance to the triple therapy regimen for patients with complex genetic mutation backgrounds. PD, progressive disease; SD, stable disease; PFS, progression-free survival; CR, complete response; PR, partial response.

Safety

AEs of any grade occurred in 13 patients (93%) and of grade 3 or worse were noted in 4 patients (29%) (Table 4). No unexpected AEs and grade 5 AEs were observed. Pyrexia (8/14, 57%) was the most commonly reported. Apart from pyrexia, gastrointestinal-related adverse reactions (including nausea, diarrhea, weight loss, and decreased appetite) and skin-related adverse reactions (including dry skin, pruritus, and rash) warrant close attention. One patient experienced a dose interruption due to a grade 3 rash. Two patients discontinued dabrafenib plus trametinib because of grade 4 diarrhea and one patient discontinued because of grade 4 pyrexia. Based on the current data, the combination of the three drugs did not lead to fatal adverse reactions and the safety profile was considered manageable.

Discussion

This retrospective study represents the largest investigation to date on the use of a triple therapy regimen comprising an EGFR-TKI plus dabrafenib and trametinib in patients with advanced NSCLC who developed BRAF^V600E mutations after progressing on osimertinib. The study aimed to explore the effectiveness and safety of this triple therapy approach, as well as potential influencing factors that may affect its efficacy including the sequential use of first-, second-, and third-generation EGFR-TKIs, complex genetic mutation backgrounds, history of radical surgery, smoking history, and the progression pattern of first-line therapy.

Newly concomitant BRAF^V600E mutations, as a mechanism of resistance to third-generation EGFR-TKIs, pose a significant challenge in the treatment of advanced NSCLC. Because secondary BRAF drivers identified after progression on EGFR-TKIs are rare, and molecular alterations and associated therapies are highly heterogeneous, no prospective trials have yet reported the efficacy of this approach. Consequently, treatment decisions must currently be guided by case reports and case series. Giustini et al. (15) described in their case series of 8 patients that all of them retained their original EGFR mutations at the time of post-progression NGS, consistent with the cases we have observed in clinical practice, explaining why osimertinib is recommended to combine with the dabrafenib and trametinib regimen.

Given that all patients in our study exhibited BRAF^V600E mutations after osimertinib failure, this underscores the importance of utilizing NGS to identify resistance mechanisms following osimertinib failure. However, in clinical practice, it is important to note that the accuracy and reliability of NGS results are influenced by multiple factors including sample source, quality, the sequencing platform and so on (16,17). The case report by Chimbangu et al. (18) highlighted that a patient developed resistance to Gefitinib and no actionable driver mutations were detected in the peripheral blood. Consequently, the treatment was switched to chemotherapy and a subsequent liver biopsy revealed a BRAF mutation. This highlights the importance of high-quality biopsy samples and appropriate timing of testing for NGS results, which directly impact patient treatment decisions.

In previous research conducted by Wei et al. (19), it was demonstrated that the median PFS for 5 patients treated with a combination of EGFR and BRAF inhibitors [vemurafenib (n=4); dabrafenib plus trametinib (n=1)] was 7.8 months, whereas it was only 5.0 months for 17 patients receiving chemotherapy. In our study, the median PFS for 14 patients with acquired BRAF^V600E mutations undergoing simultaneous EGFR and BRAF inhibition was 6.7 months. Several studies (20,21) have indicated that for patients with EGFR-TKI resistance, the efficacy of immunotherapy combined with chemotherapy does not surpass that of chemotherapy alone. However, adding anti-angiogenic agents to the immunotherapy-chemotherapy combination, as demonstrated by the ORIENT-31 and ATTLAS trials (22,23), suggests that a four-drug regimen enhance PFS benefits. Nonetheless, the associated tolerability and safety concerns of the four-drug regimen pose new challenges. Therefore, as a precision treatment strategy, the triple regimen of EGFR-TKI plus dabrafenib and trametinib can be considered as an alternative option before resorting to cytotoxic chemotherapy regimens for such patients. An interesting finding we observed is that BRAF^V600E mutation was not detected after patients developed resistance to first- or second-generation EGFR-TKIs, but after resistance to osimertinib, so it remains unclear whether patients treated with osimertinib are more prone to developing acquired BRAF mutations compared to those treated with other EGFR-TKIs. Additionally, the use of multiple EGFR-TKIs does not significantly impact the PFS of the triple regimen after progression.

The phenomenon of resistance to EGFR-TKI therapy and its underlying mechanisms have been extensively studied and discussed. Feldt et al. (24) and Michels et al. (25) focused on how MET amplification impacts the efficacy of EGFR inhibitors and explored how concurrent mutations further diminish therapeutic effectiveness. Hernández Borrero and El-Deiry (26) and Stiewe and Haran (27) have reviewed how the p53 pathway functions as a complex cellular stress response network that interacts with the genome to promote tumorigenesis and drug resistance. Based on our study cohort, MET amplification, TP53 mutations, and the T790M mutation are identified as key factors contributing to the increased genetic complexity in patients with EGFR resistance who subsequently develop BRAF^V600E mutations. Although the statistical significance has not yet reached, this may be a potential reason why patients with complex genetic mutation backgrounds exhibit poorer efficacy and survival outcomes. This finding could provide valuable insights for future clinical diagnosis and treatment.

Furthermore, the safety profile of the triple regimen is a crucial consideration and a prerequisite for its potential adoption. In addition to pyrexia, which has been identified as the most frequent AE in multiple studies (28,29), attention should also be given to gastrointestinal and dermatological adverse effects. Notably, based on the current research data, the combination of these three drugs does not lead to an additive effect in terms of AEs when compared to their individual use. The incidence of grade ≥3 AEs is comparable to those observed with standard therapies and no unexpected toxicities are identified, indicating an overall manageable safety profile.

There are several limitations in this study, including its retrospective nature, the inconsistency in sources and methodologies for secondary or tertiary NGS samples, and the small sample size due to the rarity of BRAF mutations.

Conclusions

In conclusion, the triple therapy regimen of EGFR-TKI plus dabrafenib and trametinib was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with newly concomitant BRAF^V600E mutations after osimertinib failure. However, the presence of a complex background with multiple genetic mutations may potentially reduce the efficacy of this regimen.

Acknowledgments

Funding: This work was supported by Shanghai Municipal Health Commission (No. 2020CXJQ02), Shanghai Anti-Cancer Association (No. SACA-AX202210), Shanghai Municipal Science and Technology Commission (No. 22Y31920405), Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases (No. 20dz2261100), Shanghai Municipal Key Clinical Specialty (No. shslczdzk02202) and Beijing Life Oasis Public Service Center (No. CPHCF-ZLKY-2023016).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-803/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-803/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-803/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-803/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and the protocol was reviewed and approved by the institutional review board of Ruijin Hospital (No. 2024-164), the Ethics Committee of Fudan University Shanghai Cancer Center (No. 1612167-18) and the Ethics Committee of Shanghai Pulmonary Hospital (No. L22-407). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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