Efficacy, safety, and quality of life of dabrafenib plus trametinib treatment in Chinese patients with BRAF^V600E mutation-positive metastatic non-small cell lung cancer

Introduction

Lung cancer is the most frequently diagnosed cancer in China, with an estimated 870,982 new cases and it was becoming the leading cause of cancer-related deaths in 2020 (1). Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. Genomic studies have identified BRAF (B-Raf proto-oncogene) mutations in about 1.4–1.8% of Chinese patients with NSCLC (2,3).

Studies have shown that patients with metastatic NSCLC and BRAF^V600E mutations have poorer outcomes and lower response rates to first-line chemotherapy compared with targeted therapies (4,5). The combination of dabrafenib, a BRAF kinase inhibitor selective for the BRAF^V600 mutation, and trametinib, a potent MEK (mitogen-activated protein kinase) inhibitor, has shown substantial antitumor activity in patients with previously treated BRAF^V600E mutation positive metastatic NSCLC. Dabrafenib plus trametinib (Dab + Tram) has been approved in many countries, including the USA, Europe, and most recently in China (March 2022), for the treatment of patients with metastatic NSCLC and BRAF^V600 mutation (6).

For patients with cancer and their caregivers, survival improvement and maintaining quality of life (QoL) are important factors. Here, we report the primary analysis of the study, evaluating the efficacy, safety, and QoL of Dab + Tram treatment in Chinese patients with BRAF^V600E mutation-positive metastatic NSCLC. The study is the first to report QoL data in this set of patients. We present this article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-494/rc).

Methods

Study design and patients

This was a single-arm, non-randomized, open-label, multicenter, phase II study (NCT04452877) conducted in Chinese patients with BRAF^V600E mutation-positive metastatic NSCLC, across seven centres in China, and was initiated on August 19, 2020. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki (as revised in 2013) and the Good Clinical Practice guidelines of the International Council for Harmonisation. The initial study protocol and all subsequent amendments were reviewed and approved by the independent ethics committee or institutional review board of each centre (the list is available upon request). All patients provided written informed consent.

Patients aged ≥18 years with histologically or cytologically confirmed BRAF^V600E mutation-positive, stage IV NSCLC according to the 8^th edition of the American Joint Committee on Cancer (AJCC) Staging Manual were included in this study. The BRAF^V600E mutation was detected by a tissue-based local/central qualified assay (approved by China health authorities). Other key inclusion criteria included measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST 1.1) (7), previously treated or untreated for metastatic NSCLC, with life expectancy of ≥3 months and Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Patients must have demonstrated disease progression while undergoing or after platinum-based doublet chemotherapy or immune checkpoint inhibitor and should have received no more than 3 lines of systemic therapies, including at least one prior platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation who had previously received therapy with EGFR or ALK inhibitor(s), respectively, were also eligible. Patients with brain metastases were excluded if the lesions were symptomatic or treated but not stable 3 weeks after local therapy or asymptomatic and untreated but >1 cm in diameter. Patients who had previously received a BRAF inhibitor or a MEK inhibitor or had a history of another malignancy within 3 years of treatment start or any malignancy with confirmed activating RAS (rat sarcoma virus) mutation were also excluded.

Treatment

All the patients received dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily until disease progression, unacceptable adverse events (AEs), withdrawal of consent, or death. Study treatment could also be discontinued for any of the following reasons: pregnancy, patient request, investigator discretion, start of a new anti-neoplastic therapy, loss to follow-up, or if the study is closed or terminated.

Patient-reported outcomes (PROs)

The European Organization for Research and Treatment of Cancer core Quality of Life Questionnaire (EORTC QLQ-C30) (8), and its lung cancer specific module (EORTC QLQ-LC13) (9) were the PROs used to assess the impact of Dab + Tram treatment on QoL, disease and treatment-related symptoms and impacts. All QoL data were recorded electronically prior to any other assessments before enrollment, and at every study visit until 12 weeks after end of treatment or treatment discontinuation. Patients were asked to rate the frequency, severity, and interference of symptoms on functioning as well as their health and QoL in the past week, on a scale of 1–4 (1= not at all, 2= a little, 3= quite a bit, and 4= very much). Post hoc analyses of response trends for 19 of the most patient-relevant items for patients with NSCLC covering physical and role function, health status/QoL, pain, and shortness of breath (12 items from the QLQ-C30) as well as dyspnea, coughing, and pain in chest, arms or shoulders, or other body parts (7 items from QLQ-LC13) were conducted. Patients’ response patterns were categorized into four mutually exclusive groups for each item: remained asymptomatic (a response of 1 for that item at baseline and all post-baseline assessments); improved (a baseline response >1, with the last three post-baseline responses of lower severity/interference); worse (the last two post-baseline responses were of higher severity/interference); and stable (all other trends that fit none of the above definitions).

Assessments and statistical analysis

The primary endpoint was overall response rate (ORR), which was defined as the percentage of patients who have a partial response (PR) or complete response (CR) to therapy as assessed by independent central review based on RECIST 1.1 criteria. Secondary endpoints included ORR by investigator assessment, progression-free survival (PFS), duration of response (DOR), overall survival (OS), safety and tolerability, and QoL. The PFS was defined as time from the start of study treatment until disease progression or death from any cause, whereas OS was defined as time from first dose until death from any cause. Median PFS and OS were calculated using the Kaplan-Meier method.

Patients’ experience on QoL while receiving Dab + Tram treatment was assessed by evaluating the mean and absolute change from baseline in QLQ-C30 and QLQ-LC13 scores at baseline, every 3 weeks thereafter, and at the end of week 12. Full Analysis Set (FAS) comprising patients with at least one study drug dose from enrollment up to cut-off date, was used for baseline characteristics, efficacy, safety, and QoL analysis.

Results

Of the 34 Chinese patients with NSCLC screened, 20 met the inclusion criteria and were included in the analysis. Of these 20 subjects, 10 subjects had not received prior systemic anti-cancer therapy for metastatic disease (first line) and the additional 10 subjects had relapsed or progressed on at least one prior anti-cancer treatment regimen, but no more than three prior systemic therapies (second line plus). The sample size of 20 was deemed to be adequate to assess the efficacy, safety, and tolerability of dabrafenib in combination with trametinib in the treatment of Chinese patients with stage IV BRAF^V600E mutation-positive metastatic NSCLC.

At data cut-off (March 11, 2021), 18 of 20 enrolled patients were still receiving treatment. Two patients discontinued treatment: one due to AE and one due to progressive disease (PD). Median age of the patients was 64 years (range, 46–77 years). Majority of the patients were female (55%) and had ≥3 metastatic sites (70%). Eleven patients (55%) had no smoking history, while 9 patients (45%) had a smoking history. The common metastatic sites were bone (65%) and anterior mediastinal lymph nodes (60%). The predominant histologic subtype was adenocarcinoma (95%). Patient characteristics are summarized in Table 1.

Efficacy

The ORR was 75% [95% confidence interval (CI): 50.9–91.3%] by both, central independent review as well as investigator assessment. Overall, 14 (70%) patients achieved PR and one (5%) achieved CR per central independent review. Overall disease control rate (DCR) by central independent review was 95% (95% CI: 75.1–99.9%). The best overall responses reported in the patients were 1 CR, 14 PR, 2 stable disease (SD), and 2 non-CR/non-PD. The best percentage change from baseline demonstrated a decrease in size of the target lesions for 18 patients by central independent review (Figure 1A). For 2 patients, no target lesions were identified at baseline. One patient who achieved a CR had complete disappearance of target lesions. One patient was evaluated as having PD following identification of a new lesion, despite a significant decrease in the target lesion size.

Figure 1 Efficacy of dabrafenib plus trametinib in Chinese patients. (A) Waterfall plot for best percentage change from baseline in sum of longest diameters based on central independent review; (B) Kaplan-Meier estimates of PFS; (C) Kaplan-Meier estimates of OS. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UNK, unknown; NE, not estimable; PFS, progression free survival; OS, overall survival.

The median DOR, PFS, and OS were not reached/estimable due to the short follow-up period (median of 5 months at the data cut-off; Figure 1B,1C). At 4 months, 90.0% (95% CI: 47.3–98.5%) of patients showed response with trametinib and dabrafenib treatment and 91.7% (95% CI: 53.9–98.8%) of patients achieved PFS. None of the patients died at the time of data cut off and the 6-month OS rate was 100%.

Safety

The median (Q1–Q3) duration of treatment for trametinib and dabrafenib was 4.11 months (3.61–5.70 months) and 4.39 months (3.71–5.70 months), respectively. All patients had at least one AE, of which 18 patients (90%) had treatment-related AEs (TRAEs all grades; Table 2). The most common TRAEs (in ≥30% of patients) were pyrexia (45%), aspartate aminotransferase (AST) increased (35%), neutrophil count decreased (30%), and white blood cell (WBC) count decreased (30%). All reported pyrexia, AST increased, neutrophil count decreased, and WBC count decreased were TRAEs. Grade ≥3 AEs were reported in 11 patients (55%), of which 8 were TRAEs. The most common TRAEs were hyponatremia (15%), neutrophil count decreased (10%), blood creatinine increased (5%), and pyrexia (5%; Table 3). Serious AEs were reported in 8 patients (40%), with no grade 5 SAEs. Twelve patients (60%) had AEs that led to dose adjustment and/or interruption and all 20 patients received additional therapy to treat AEs. TRAEs led to permanent discontinuation of dabrafenib and/or trametinib in 2 patients; one discontinued both dabrafenib and trametinib treatment due to blood creatinine increased (grade 2), and another patient discontinued trametinib only due to hyponatremia (grade 3). No deaths were reported in this study.

PROs

Nineteen key NSCLC items from the EORTC-QLQ-C30 and EORTC-QLQ-LC13 were examined to assess patterns of change from baseline to last visit and one visit prior to last visit for all patients (N=20). In 5 out of 19 key NSCLC-related items, more than 50% of patients remained at the highest ratings possible during the treatment period (‘Remained asymptomatic’; Figure 2). Patients had stable or improved scores (no worsening) in 7 of 19 items (no worsening in C30 items 3–7, LC13 items 3 and 11) Furthermore, in all 19 items, at least 85% of the patients remained stable or better (Figure 2).

Figure 2 Patterns of trends change from baseline to last two visits for selected questions from QLQ-C30 and QLQ-LC13. “Worse” = item scores for last 2 post-baseline assessments were higher on severity/interference items as compared to baseline (BL); “Stable” = those with scores/trends NOT meeting definitions for ‘Worse’, ‘Improved’ or ‘Remained Asymptomatic’; “Improved” = item scores at baseline >1 AND last 3 post-baseline item assessments were lower on severity/interference items as compared to baseline; “Remained asymptomatic” = items scores at baseline AND all post-baseline assessments =1; note easier to worsen than to improve or remain stable with these definitions, as must have 3 post-baseline assessments improved to improve vs. 2 post-baseline assessments worsened to worsen. QLQ, quality of life questionnaire.

Single item analysis of the “physical function” questions (items C30 1–5) indicated that patients remained asymptomatic, improved, or stable during the treatment period. Of those who reported no interference in physical function items, the majority (75% never needed “help with eating, dressing, washing themselves, or using toilet”; 55% of patients had no trouble at all “taking a short walk”) remained in perfect functioning of those items throughout all cycles. Single item analysis of the “role function” questions (items C30 6–7) indicated that patients who reported interference at baseline improved or remained stable (50% of patients reported no limitation with working or daily activities, until their last assessment, another 50% of patients remained stable pursuing their hobbies or other leisure time activities; Figure 2).

Among the lung cancer related symptoms (items LC13 1, 3–5, 10–12) evaluated, majority of patients were stable or improved. Of the patients who were asymptomatic for dyspnea (when rested) and asymptomatic for chest pain at baseline, 50% remained asymptomatic throughout. Of those who were not asymptomatic, up to 45% of patients remained stable. Only 1 patient (5%) reported worsening of chest pain.

Discussion

The combination of Dab + Tram has been approved recently by the China National Drug Authority for patients with previously treated BRAF^V600+ mutation-positive metastatic NSCLC (6). The approval is based on the substantial efficacy observed in global phase II trials (10,11). The evaluation of efficacy, safety, and QoL of Dab + Tram in a Chinese patient population is therefore warranted to inform its optimal use in this specific population.

Overall, in the present study, Dab + Tram showed substantial clinical benefit in Chinese population (ORR: 75%, 95% CI: 50.9–91.3%). The median PFS and median DOR were not reached due to the relatively short follow-up period (median follow-up: 5 months). No patient had died at the time of primary cut-off, while the event-free OS rate was 100% at 6 months. The efficacy observed in the present study, although from a small sample size and the single-arm design, was in line with that reported in the global phase II study (NCT01336634) (10,11). In previously treated patients (N=36), treatment with Dab + Tram resulted in an ORR of 63.2% (95% CI: 49.3–75.6%), and DCR of 78.9% (95% CI: 66.1–88.6%), and median PFS was 9.7 months (10). In treatment-naïve patients (N=23), Dab + Tram was associated with an ORR of 64% (95% CI: 46–79%) and DCR of 75% (95% CI: 58–88%). Median PFS and OS were 14.6 and 24.6 months, respectively (11). Interestingly, similar results were observed with another BRAF inhibitor encorafenib plus binimetinib for BRAF^v600E NSCLC where the ORR was 75% in treatment naïve patients (N=59) and 46% in previously treated patients (N=39) respectively with manageable safety profile (12). The safety profile of Dab + Tram in this study was also consistent with that reported in the global phase II study, with no new safety signals observed (10,11). Notably, less than half of the patients also reported grade ≥3 AEs. Overall, the substantial clinical benefit of Dab + Tram treatment in patients with BRAF^V600E-mutant metastatic NSCLC (10,11) and BRAF^V600-mutant melanoma (13) indicates that AEs with grade 3 or higher can be effectively managed by dose reduction/interruption or concomitant medication.

Patient reported outcome data can help clinicians better understand the disease and treatment-related symptoms experienced by patients and can facilitate shared and informed decision-making as well as assessment of overall risk/benefit profiles for possible treatment options. The QoL results can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients. Our study reports for the first time the QoL data in patients with BRAF^V600E mutation-positive metastatic NSCLC, treated with a combination of Dab + Tram. Overall, the QoL data suggest a trend of stable and improving QoL from baseline to data cut-off, with the majority having no deterioration in health-related QoL with Dab + Tram treatment. Given the small sample size and the 19 items analyzed, the magnitude of changes observed cannot be used to determine clinically-relevant improvements or declines in QoL.

Conclusions

In conclusion, this phase II study demonstrated that the efficacy and safety profile of Dab + Tram in Chinese patients with BRAF^V600 mutation-positive metastatic NSCLC was consistent with that observed in previous global studies. In addition, this study highlighted that the majority of patients had stable or improved QoL during the treatment period. Taken together, these data emphasize the need for clinicians and patients to consider the clinical benefit of efficacy, safety, and QoL offered by Dab + Tram when deciding between treatment options.

Acknowledgments

Dabrafenib + trametinib was originally developed by Incyte and was in-licensed by Novartis as of 24 November 2009. The authors thank the patients, their families and caregivers, the participating clinical sites, and their teams. The authors acknowledge the contributions of Stefanie Knoll (Novartis Pharmaceuticals Corporation), Kendra Jin (*Novartis Pharmaceuticals Corporation, HEOR, Beijing, China), and Lindsay Petrenchik (*Novartis Pharmaceuticals Corporation, PCO Fellow) toward the discussions related to analyses, interpretation, and value of PRO data in this manuscript. Scientific writing assistance was provided by Sashi Kiran Goteti (Novartis Healthcare Pvt Ltd.). The authors would like to acknowledge that the abstract titled “Safety and efficacy of dabrafenib plus trametinib in Chinese patients with BRAF^V600E-mutation positive metastatic NSCLC” (Abstract number: EP08.02-052) was previously published in the IASLC 2022 World Conference on Lung Cancer (WCLC 2022) Abstract Book.

Funding: This study was funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) and partially supported by The National Natural Science Foundation of China (NSFC) (Nos. 82272789 and 82241232).

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-494/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-494/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-494/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-494/coif). J.Z. received speaker honorarium from Roche, Lily, MSD, AstraZeneca, Hengrui, Pfizer, Bristol-Myers Squibb, Novartis, Innovent Biologics, BeiGene; and served on data safety monitoring board for BeiGene. T.Z., H.L. and D.B.M. are employed by Novartis. V.Q.P. is employed by Novartis and also owns stocks in Novartis. L.Z. received speaker honorarium from AstraZeneca, BeiGene, HengRui Pharm., Innovent Biologics, Roche; and served as consulting or advisory board of AstraZeneca, Innovent Biologics. He also received research funding from AstraZeneca, Akeso Biopharma, Bristol-Myers Squibb, Chia Tai Tianqing Pharmaceutical Group, Junshi Pharmaceuticals, QiLu Pharmaceutical and Pfizer. The other 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 ethical principles of the Declaration of Helsinki (as revised in 2013) and the Good Clinical Practice guidelines of the International Council for Harmonisation. The initial study protocol and all subsequent amendments were reviewed and approved by the independent ethics committee or institutional review board of each centre (the list is available upon request). All patients provided written informed consent.

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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