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Patients with advanced metastases with multiple metastases are desperate to find a "first-line" life, and dabrafenib + trametinib dual-target therapy brings rapid relief
With the continuous progress in precision therapy in the field of rare targets, rare targets such as BRAF V600 mutation have gradually entered the field of vision of clinicians. As a rare target for non-small cell lung cancer (NSCLC), patients with BRAF V600 mutations are not sensitive to chemotherapy and immunotherapy, and face the dilemma of long-term lack of targeted drugs. In March 2022, the dual-target treatment regimen of dabrafenib + trametinib was approved for lung cancer indication in China, opening a new chapter in treatment and bringing hope for long-term survival to this special group of patients.
In this issue, we will share a case of advanced NSCLC with multiple metastatic BRAF V600 mutations, who received dabrafenib + trametinib in the first line, maintained CR (complete response) for a long time, and achieved progression-free survival (PFS) of up to 28 months. The case was provided by Dr. Wang Tao of the Fifth People's Hospital of Fuyang City, and Professor Wang Yong of the Fifth People's Hospital of Fuyang City was invited to comment.
Case Profile
➤ Basic information
Basic information: Female, 66 years old
Date of initial visit: November 2, 2021
Initial complaint: irritating cough for more than 1 month
Anamnesis: Previous history of hypertension for more than 10 years, denial of diabetes, heart disease, surgical trauma, etc
Personal history: denial of history of tobacco and alcohol, history of penicillin allergy
Admission:
- Chest CT: right hilar mass, central lung cancer with mediastinal and right hilar lymph node metastases, multiple nodules and pleural nodules in both lungs, pulmonary metastases and pleural metastases, multiple inflammatory lesions in both lungs, and a small amount of right pleural effusion.
- Whole-body lymph node color ultrasound: multiple lymphadenopathy in the right neck and right supraclavicular bone, consider that metastases may be large, please combine clinical and other examinations
Figure 1. Chest CT on November 5, 2021
- Right supraclavicular lymph node biopsy results: metastatic poorly differentiated adenocarcinoma from the lung. Immunohistochemistry results: P40 (-), P63 (-), TTF-1 (+), NapsinA (+), CK7 (+), Ki-67 (+, about 30%)
- Cranial MRI showed multiple ischemic foci in both frontoparietal lobes, lateral paraventricles and basal ganglia, left ventricular anterior horn and left temporal lobe malacia, white matter demyelination changes, and senile brain changes
- Abdominal CT showed abnormal enhancement of the top of the liver, considering abnormal perfusion, metastasis is not excluded, re-examination is recommended, right hilar lymph node metastasis, multiple hyperdense shadows in both lungs, considering the possibility of inflammation, metastasis is not excluded, and right pleural effusion
- Whole-body bone scintigraphy: no abnormalities
- Next-generation sequencing (NGS) gene detection: BRAF V600E gene mutation was found, with a frequency of 29.0%
Clinical diagnosis: adenocarcinoma of the right lung [cT4N3M1c (both lung, pleura, liver metastases) stage IVB BRAF V600E mutation PS: 0 points]
Treatment
From November 23, 2021 to the present, the first-line treatment has been treated with a dual-target regimen of dabrafenib 150mg twice a day combined with trametinib 2mg qd, and achieved partial response (PR) after one month of treatment and CR after 2 months. Follow-up patients received regular follow-up reexaminations, efficacy evaluation: CR was maintained, and the last re-examination on February 26, 2024, the patient's PFS had reached 28 months, and the patient was still on medication.
Safety: Good, no obvious adverse reactions (such as fever, nausea, vomiting, etc.).
Fig.2 Baseline comparison of imaging examinations after 1 and 2 months of dual-target therapy
Fig.3 Imaging examination during first-line dual-target therapy (continuous CR)
Expert commentary
Prof. Yong Wang: For patients with BRAF V600 mutation multiple metastatic advanced lung adenocarcinoma, first-line dabrafenib + trametinib has brought sustained benefits for more than 28 months
In recent years, there has been a lot of good news for NSCLC patients with positive driver genes, and a variety of new drugs for common and rare targets have been continuously developed and successfully marketed, which has greatly prolonged the survival of patients. Although BRAF V600 mutation is a rare target, there is still a need for precision therapy for the huge lung cancer base in mainland China. The amazing efficacy and good safety profile of dabrafenib + trametinib dual-target therapy regimen have completely changed the status of "no drug available" for such patients.
The approval of the dual-target regimen is based on the results of the BRF113928 study, which showed that the objective response rate (ORR) of dabrafenib + trametinib in the first-line treatment of patients with advanced NSCLC with BRAF V600 mutation was 63.9%, the median duration of response (DoR) was 15.2 months, the median PFS was 14.6 months, and the median overall survival (OS) was 24.6 months, with more than half of the patients achieving 2-year survival benefit and more than one-fifth of the patients achieving 5-year long survival. In the second-line setting, dabrafenib + trametinib therapy has a rapid onset of action, can effectively control tumor progression, and has a long response time: the median time to first response is 6 weeks, the ORR is 68.4%, the median DoR is 9.8 months, the median PFS is 10.2 months, and the median OS is 18.2 months, and about one-fifth of patients achieve long-term survival at five years [1-3].
In real-world studies, the "D+T" dual-target regimen has also shown amazing efficacy. In a study of 40 patients with BRAF V600E-mutant NSCLC, dabrafenib + trametinib resulted in median PFS of 16.8 months and median OS of 21.8 months [4]. In addition, at the 2021 European Society for Medical Oncology (ESMO) Annual Meeting, a real-world study was presented that analyzed 140 patients with BRAF V600 mutations comparing different first-line treatment regimens. The results showed that patients who received "D+T" dual-target therapy had the best OS of up to 29.3 months [5], which was nearly 1 year longer than immunotherapy combined with chemotherapy and more than 1.5 years longer than immune monotherapy.
This protocol presented data from patients with advanced NSCLC with BRAF V600 mutations in China at the 2022 World Conference on Lung Cancer (WCLC), which showed positive results consistent with those obtained globally [6]. Moreover, regardless of first- and second-line treatments, the ORR assessed by the Independent Review Committee (IRC) was as high as 75%, and the disease control rate (DCR) reached 95%, suggesting that the regimen may have a better benefit trend in the Chinese population.
The above-mentioned cases were newly diagnosed patients with stage IVB multiple metastases, with BRAF V600 mutations detected by genetic testing, and rapid and complete remission 2 months after first-line dual-target therapy, and PFS for up to 28 months, and controllable adverse reactions during maintenance therapy, with good overall tolerability. The treatment process of this case once again verified the efficacy advantages of dabrafenib + trametinib treatment, and further consolidated the benefits of dual-target therapy.
This case also reminds us that in the treatment of lung cancer, the concept of "targeting and targeting first" should be implemented, so as to improve the survival of patients. The combination of efficacy, safety, and accessibility ultimately determines the survival of patients. It is expected that more studies in the future can bring more treatment options to patients and help more patients achieve long-term survival and chronic disease management.
Review Expert Profile
Professor Wang Yong
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Chief Physician, Director of the Department of Respiratory and Critical Care Medicine
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The second Yinghuai Famous Doctor, Anhui Province Anti-epidemic Advanced Individual
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Academic and Technical Leader of Fuyang Respiratory Disease (Level 2)
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The third batch of professional and technical top-notch talents in Yingquan District
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Member of the Interstitial Disease Group of the Respiratory Disease Branch of Anhui Medical Association
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Member of the Respiratory Disease Committee of Anhui Provincial General Medical Association
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Member of the Tumor Immunology and Targeted Therapy Committee of Anhui Anti-Cancer Association
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Member of the Sleep Medicine Committee of Anhui Medical Doctor Association
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Member of the Respiratory Rehabilitation Committee of Anhui Rehabilitation Medical Association
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Member of the Standing Committee of the Respiratory Disease Branch of Fuyang Medical Association
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Vice Chairman of the Antimicrobial Branch of Fuyang Medical Association
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Member of the Tuberculosis Branch of Fuyang Medical Association
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Director of the Oncology Branch of Fuyang Medical Association
Specialist profiles are provided with cases
Dr. Wang Tao
- The Fifth People's Hospital of Fuyang City
- Attending physician, Master of Medicine
- Department of Respiratory and Critical Care Medicine, Fuyang Fifth People's Hospital
- Graduated from the Department of Clinical Medicine of Bengbu Medical College
- Member of Fuyang Branch of Chinese Medical Association
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Bibliography:
[1] Planchard D,et al. J Thorac Oncol.2022 Jan; 17(1):103-115.
[2] Planchard D.et al. Lancet, Oncol 2017; 18:1307–16.
[3] Planchard D, et al. Lancet Oncol. 2016;17:984-993.
[4] Auliac J B , Bayle S , Do P , et al. Efficacy of Dabrafenib Plus Trametinib Combination in Patients with BRAF V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019. [J]. Cancers, 2020(12).
[5] Melosky B, Knoll S M, Souef I S, et al. 1260P Clinical outcomes of patients with BRAFv600-mutated metastatic NSCLC (mNSCLC) receiving first-line (1L) dabrafenib-trametinib vs other standard of care in real-world practice[J]. Annals of Oncology, 2021, 32: S988.
[9] Fan Yun, et al. EP08.02-052. WCLC 2022.
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The effective date of the material is 2024.03.21, and the expiration date of the material is 2025.03.21
* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform