Editor’s Note:
The World Conference on Lung Cancer (WCLC), a significant academic exchange event in the global lung cancer field, was successfully held in Singapore from September 9 to 12, 2023. The conference revealed many important research findings, bringing about a new era of treatment in clinical practice. Among them, the EGFR Exon20 insertion mutation (EGFR exon20ins) as the third major EGFR mutation has garnered widespread attention. In recent years, novel treatments for this mutation have continuously emerged. At the WCLC, the phase 1b results of the FAVOUR study on the treatment of EGFR exon20ins-positive advanced non-small cell lung cancer (NSCLC) with furmonertinib were reported. “ Oncology Frontier ” had the privilege of interviewing Dr. Caicun Zhou, a leading figure in the field of lung cancer treatment at Shanghai Pulmonary Hospital and Tongji University School of Medicine. Dr. Zhou shared the latest treatments of EGFR exon20ins-positive NSCLC.
Dr. Caicun Zhou
Chief Physician, Professor, Doctoral Supervisor
Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine
IASLC President-Elect
01
Oncology Frontier: The exploration of new drugs in the EGFR exon20ins mutation field is in full swing. As an expert with extensive clinical experience in the global EGFR exon20ins field, could you provide a comprehensive evaluation of the current treatment status in the EGFR exon20ins field and the impact of current first-line treatment exploration on global clinical practice?
Dr. Caicun Zhou: The EGFR Exon20ins mutation is the third most common category of EGFR mutations, accounting for approximately 5%-12% of all EGFR mutation-positive NSCLC[1]. EGFR Exon20ins, as an insertion mutation, has a wide variety of mutation subtypes, with about 120 identified subtypes, high heterogeneity, and differences in sensitivity to treatment among different subtypes. Currently, there are two approved drugs for Exon20ins insertion mutations in China, but they are both second-line treatments, and first-line targeted drug therapy remains a gap. Patients with EGFR Exon20ins-positive NSCLC face significant challenges in treatment. Over the long term, chemotherapy, EGFR TKIs, immunotherapy, and other approaches have shown limited benefits, leading to poor patient outcomes. There is an urgent need for new targeted drugs to meet the unmet clinical needs of this population.
The FAVOUR study’s phase 1b results on the third-generation TKI furmonertinib for treating Exon20ins-type advanced NSCLC are very encouraging, with a first-line objective response rate (ORR) of 78.6% and a median duration of response (DoR) of 15.2 months[2]. International multicenter phase III trials will be conducted globally. Currently, several first-line studies targeting EGFR exon20ins mutations are being explored, and we hope that future breakthroughs in first-line treatment will further improve survival benefits, leading the global treatment of EGFR exon20ins mutations in NSCLC to new heights and guiding the global wave of EGFR exon20ins-targeted therapy!
02
Oncology Frontier: Based on the achievements in the EGFR exon20ins mutation field so far, what do you think are the future directions for exploration?
Dr. Caicun Zhou: With numerous subtypes of EGFR exon20ins, precise testing is a prerequisite for targeted therapy, and the accurate identification of specific sequence subtypes is particularly important. The most commonly used testing methods include polymerase chain reaction (PCR) and next-generation sequencing (NGS). However, PCR is prone to false negatives and requires relatively large tissue samples, usually used to identify the most common genetic variations. NGS, as a diagnostic tool for identifying molecular heterogeneity sequence changes, not only provides rapid test results but can also simultaneously perform thousands of gene tests using a single tissue sample, offering higher sensitivity and reliability. Therefore, it is more valuable.
Due to the differences in efficacy among different mutation subtypes, several phase III clinical trials are currently underway for EGFR exon20ins mutations in NSCLC. Furmonertinib has been approved for the treatment of exon20ins mutation lung cancer and is undergoing phase III clinical trials. In the future, targeted drugs for EGFR exon20ins mutations are expected to become first-line treatments, further extending the survival of patients.
In addition, as lung cancer has not been completely cured to date, the issue of drug resistance often exists. To address this problem, a deep understanding of the molecular mechanisms of drug resistance is needed. Identifying the molecular mechanisms of resistance helps develop the next generation of targeted drugs; otherwise, clinical research will stagnate. Here, I call on pharmaceutical companies not to overlook the importance of translational research in clinical studies, actively obtain patients’ plasma and tumor tissue samples, better understand the mechanisms of lung cancer drug resistance, improve the level of translational research, address crucial clinical issues, and provide more effective treatment strategies for patients.
03
Oncology Frontier: What are your expectations and prospects for the treatment of EGFR exon20ins mutation combined with brain metastasis using furmonertinib in the future?
Dr. Caicun Zhou: Furmonertinib is a targeted drug, and its ability to penetrate the blood-brain barrier is one of its main advantages. This makes furmonertinib show good efficacy in treating lung cancer patients with brain metastases. When evaluating the efficacy of drugs, especially for targeted drugs, the treatment effect on brain metastases is an important consideration. As EGFR mutation patients experience extended survival after targeted drug therapy, the incidence of brain metastasis also increases. Therefore, this feature of furmonertinib is particularly suitable for managing this situation effectively. It can inhibit the development of brain metastases, providing EGFR mutation lung cancer patients with a longer chance of survival.
04
Oncology Frontier: EGFR exon20ins mutation has high heterogeneity. How do you view the clinical testing methods for such mutations and the exploration of biomarkers for current novel treatment drugs?
Dr. Caicun Zhou: EGFR exon20ins mutation has more than 120 subtypes, and understanding its molecular epidemiological characteristics and treatment response heterogeneity is crucial. Gene testing is crucial in NSCLC treatment management, and the selection of suitable test kits is particularly important. Multi-gene combined testing kits are a reliable choice, with NGS products potentially being more suitable. Test kits that have not been clinically validated or NGS certified may have defects, and this should be noted in clinical use. It should be ensured that the selected test kit can find various EGFR exon20ins mutations. If only one or two mutations can be found, it is not recommended to use it. It is better to choose a test kit that is more suitable.
Currently, the field of EGFR exon20ins mutations is still in the exploration stage. Targeted drugs with initial efficacy mainly include large molecule monoclonal antibodies and small molecule TKIs. Exploring more precise biomarkers for new types of targeted drugs with different types/mechanisms of action will be an important direction for further implementing personalized diagnosis and treatment.
References:
- Xue Yang, et al. Advances in Treatment of Non-small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations[J]. Chinese Journal of Lung Cancer. 2022;25(5):337-350.
- Baohui Han, et al. FAVOUR: A phase 1b study of furmonertinib, an oral, selective EGFR inhibitor, in patients with advanced NSCLC with EGFR Exon 20 insertions. WCLC2023 OA03.04.
TAG: WCLC 2023, GFR exon20ins, NSCLC
