*For medical professionals only
Patients with BRAF mutations received "D+T" dual-target therapy in the later line, and the efficacy was remarkable.
GLOBOCAN cancer statistics show that lung cancer remains the leading cause of cancer death [1], while non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, with a low proportion of BRAF mutations, but the number of deaths due to it each year worldwide is still staggering. Treatment options for BRAF mutations have been developed, with targeted therapy being one of the main treatment options. In targeted therapy, the treatment regimen of the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib is listed as a Level I recommendation in the 2023 Chinese Society of Clinical Oncology (CSCO) clinical diagnosis and treatment guidelines[2].
In this issue, we will share the diagnosis and treatment process of a patient with BRAF V600 mutant NSCLC. After receiving radiotherapy, chemotherapy, and immunotherapy, the patient was treated with a dual-target regimen of dabrafenib + trametinib, and his progression-free survival (PFS) reached 50 months and continued benefit. The case was provided by Dr. Zhang Xiaofei from Fudan University Cancer Hospital, and commented by Professor Zhao Weixin from Fudan University Cancer Hospital.
Case Profile
➤ Basic information
Basic information: The patient is a 60-year-old male
History of present illness: The patient was diagnosed with stage IIIB lung cancer of the left lower lobe of the left lung at Shanghai Pulmonary Hospital on November 15, 2017 T1CN3M0 and underwent mediastinal 4R+7 group ultrasound bronchoscopy (EBUS) puncture pathology showed non-small cell lung cancer. EBUS enzyme marker: adenocarcinoma. Histogenetic testing: negative for EGFR and KRAS, positive for BRAF V600E. He was admitted to our hospital for further diagnosis and treatment.
Anamnesis: hypertension
Admissions Investigations:
1. Chest CT on January 23, 2018: Lung cancer of the lower lobe of the left lung may be accompanied by obstructive pneumonia of the left lung, with enlargement of mediastinal and hilar lymph nodes, which is smaller than that of the lower lobe of the left lung on November 1, 2017. Left-sided pleural effusion. Enlargement of the adrenal glands on both sides.
2. CT of the head (outer) cranial CT: no obvious mass was found in the skull.
3. (Outer Hospital) B-ultrasound on January 23, 2018: left supraclavicular lymph node enlargement, size 14.6mm×10.4mm.
4. Negative bone scan on 24 January 2018.
5. CT in June 2018: The lung cancer reading of the lower lobe of the left lung was similar to that of the CT in April 2018 in the hospital.
6. (Our Hospital) June 11, 2018 Left Neck Mass Puncture: Malignant Tumor Cells, Predisposition to Carcinoma (Adenocarcinoma).
Clinical diagnosis: adenocarcinoma of the left lower lobe of the lung with BRAF V600E mutation.
Treatment
1. Chemotherapy + anti-angiogenic therapy
The patient was diagnosed with BRAF V600E mutant lung adenocarcinoma in the hospital, and underwent two rounds of chemotherapy in January 2018 with unknown schedule. From February 6, 2018 to March 21, 2018, he underwent chest radiotherapy in an external hospital: the dose was 60 GY/30 f, no chemotherapy.
On April 13, 2018, gemcitabine + cisplatin (GP) + bevacizumab chemotherapy was performed in the hospital.
In June 2018, the patient underwent CT examination in our hospital.
Fig.1 CT of the lungs in June 2018
On June 11, 2018, a left neck mass puncture was performed at our hospital, and the results showed malignant tumor cells and carcinoma (adenocarcinoma). The patient received GP+bevacizumab chemotherapy and developed IV thrombocytopenia, so a drug switch of pemetrexed + cisplatin + bevacizumab was considered.
On November 2, 2018, the results of radiotherapy to the left lower lobe were similar to before, and the patient received pemetrexed + bevacizumab maintenance therapy.
On June 29, 2019, the patient developed hemoptysis, and on July 22, 2019, CT examination showed that after radiotherapy of the left lower lobe, the left lower lobe was dense with distal obstructive inflammation, and the anti-infection treatment in the local hospital was continued.
On August 29, 2019, the group discussed that the patient's left lower hilar mass was larger than before, and a comprehensive genetic test was obtained again, and the results showed BRAF V600E mutation.
2. Switching to immunotherapy, the effect is not good
On October 12, 2019, he was treated with a PD-1 inhibitor.
On October 31, 2019, the follow-up CT showed that the inflammation in the two lungs was more obvious than before, and there were small nodules in the lower lobe of the right lung, which metastasized in the lungs. Suspension of immunotherapy.
3. Dual-target therapy leads to long-term PFS benefits
On November 16, 2019, the patient started taking dabrafenib (150 mg bid) + trametinib (2 mg once a day).
CT scan on December 11, 2019 showed that the mass in the lower lobe of the left lung was accompanied by distal obstructive inflammation, and the extent was smaller than before; There are many small nodular shadows in both lungs, and some of them are smaller than before.
On July 23, 2021, CT scan showed that there was a slight inflammation in the two lungs, a small nodule in the right lung, and a smaller dense shadow in the left lower lung.
CT on December 18, 2023: Left lung cancer reexamination, soft tissue shadow of the lower lobe of the left lung with distal obstructive inflammation, similar to before. left hilar lymph node; A small amount of pericardial effusion, all as before. A small pleural effusion on both sides.
On December 18, 2023, B-ultrasound: heterogeneous changes in the liver area (possible for chronic liver disease), and there was no obvious abnormality in the remainder.
MRI January 4, 2024: Scattered small lacunar cerebral infarction in the brain, similar to before.
During the treatment, the patient did not have grade 3/4 adverse reactions. At present, after 50 months of follow-up, the patient still continues to take dabrafenib + trametinib for long-term benefits.
Fig.2 Chest CT results during dabrafenib + trametinib treatment
Expert commentary
Prof. Weixin Zhao: Patients with advanced lung cancer with BRAF V600 mutation can be treated with PFS for up to 50 months
In 2020, the number of lung cancer deaths worldwide was approximately 1.8 million [1], and BRAF as a poor prognostic factor for lung cancer cannot be ignored. CONVENTIONAL CHEMOTHERAPY HAS LIMITED EFFICACY IN PATIENTS WITH BRAF MUTATIONS, AND RESULTS FROM THE EUROPEAN IMMUNOTARGET STUDY SHOWED AN OBJECTIVE RESPONSE RATE (ORR) OF ONLY 24 PERCENT AND A MEDIAN PFS OF ONLY 3.1 MONTHS IN PATIENTS WITH BRAF WHO RECEIVED IMMUNOTHERAPY [3]. With the development of genetic testing technology and the advancement of precision drug therapy, targeted drugs have gradually become a new choice for patients with BRAF mutations.
For patients with BRAF V600 mutation NSCLC, the dual-target treatment regimen of dabrafenib + trametinib has attracted much attention. Among them, dabrafenib is an inhibitor of BRAF kinase activity, and trametinib is an inhibitor of MEK1 and MEK2 kinase activity, and the combination of the two can inhibit both BRAF and MEK targets at the same time, and synergistically exert a stronger inhibitory effect.
In the BRF113928 study, dabrafenib + trametinib resulted in an ORR of 63.9% (95% CI: 46.2%-79.2%), a median duration of response (DoR) of 15.2 months (95% CI: 7.8-23.5), and a median overall survival (OS) of 24.6 months (95% CI: 7.8-23.5) and median overall survival (OS) of 24.6 months (95% CI: 12.3 to inestimable), ORR was as high as 68.4% (95% CI: 54.8% to 80.1%), median DoR was 9.8 months (95% CI: 6.9-18.3), and the 5-year OS rate was as high as 19%. Data from this trial suggest that dabrafenib plus trametinib is superior in efficacy, regardless of whether the patient has been previously treated or not[4]. In addition, the results of the Chinese lung cancer registration clinical study showed that the ORR assessed by the independent review committee (BIRC) was as high as 75% and the disease control rate (DCR) reached 95% in both treatment-naïve and treatment-experienced patients with BRAF-mutated NSCLC [5].
Currently, the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and CSCO guidelines all recommend dabrafenib + trametinib in patients with BRAF V600-mutant NSCLC [2,6,7].
In the above cases, after the progression of chemoradiotherapy and immunotherapy, the patient switched to the dual-target regimen of dabrafenib + trametinib and obtained PFS for up to 50 months, and is still being followed up. This case once again validates the efficacy of "D+T" dual-target therapy, and shows that the efficacy of this treatment regimen is still very impressive even in the later line of therapy. Moreover, the patients did not have grade 3/4 adverse reactions during the treatment, which confirmed the good safety of the dual-target regimen. At present, dabrafenib + trametinib has been included in the medical insurance, which fundamentally improves the accessibility of the drug, which will benefit more patients with advanced NSCLC with BRAF V600 mutation.
It is worth mentioning that although the efficacy of this treatment regimen is amazing, for targeted therapy, drug resistance is still unavoidable. Therefore, we still need to continue to conduct in-depth research and explore new treatment strategies to provide more efficient and low-toxicity treatment options for cancer patients.
Review Expert Profile
Professor Zhao Weixin
Fudan University Cancer Hospital
Chief Physician of the Department of Radiation Oncology, Fudan University Cancer Hospital
He is a member of the Lung Oncology Professional Committee of the Chinese Medical Education Association
He is a member of the Tumor Immunotherapy Professional Committee of the Chinese Medical Education Association
He is a member of the Lung Cancer Molecular Targeting and Immunotherapy Professional Committee of Shanghai Anti-Cancer Association
Member of the Brain Metastases Committee of Shanghai Anti-Cancer Association
Member of the CSCO Expert Committee on Vascular Targeted Therapy
He is a member of the Molecular Oncology and Immunotherapy Professional Committee of the Chinese Association of Research Hospitals
He is a member of the Stereotactic Radiotherapy Professional Committee of the National Minimally Invasive Tumor Treatment Industry Technology Innovation Strategic Alliance
Specialist profiles are provided with cases
Prof. Xiaofei Zhang
Fudan University Cancer Hospital
Deputy Chief Physician of the Radiation Therapy Center of Fudan University Cancer Hospital
Ph.D. in Oncology, Fudan University
Clinical interests: radiation therapy and multidisciplinary diagnosis and treatment of thoracic tumors such as lung cancer and esophageal cancer
He has published more than 10 SCI papers as the first and corresponding author, and presided over scientific research projects such as the National Natural Science Foundation of China
Won the first prize in the national finals of the National Target Delineation Competition of Tumor Radiotherapy of the Chinese Anti-Cancer Association
Youth member of the Radiotherapy Youth Committee of Shanghai Anti-Cancer Association
She is a member of the Association of Women Lung Cancer Physicians of Shanghai Anti-Cancer Association
Long press the identification QR code or click to read the original article, and wonderful information is waiting for you
Bibliography:
[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] Chinese Society of Clinical Oncology (CSCO) Guidelines for the diagnosis and treatment of NSCLC.2023
[3] J Mazieres et al. Ann Oncol. 2019 Aug 1; 30(8):1321-1328.
[4] PLANCHARD D, BESSE B, GROEN H J M, et al. Dabrafenib plus trametinib in patients with previously treated BRAF (V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial［J］. Lancet Oncol, 2016, 17(7): 984-993.
[5] Fan Yun, et al. EP08.02-052. WCLC 2022
[6] NCCN Clinical practice guidelines in oncology (NCCN Guidelines®) non-small cell lung cancer. Version 5. 2021 ［M］. Pennsylvania, NCCN.org; 2021.
[7] PLANCHARD D, POPAT S, KERR K, et al. Metastatic nonsmall cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up［J］. Ann Oncol, 2018, 29(Suppl 4): iv192-iv237
MCC码TML0020502-51463;
The effective date of the material is 2024.04.17, and the expiration date of the material is 2025.04.17
* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform