The 24th World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer (IASLC), took place from September 9th to 12th, 2023, in Singapore. As one of the most prestigious academic gatherings in the field of lung cancer, WCLC brings together scholars from all over the world to discuss the latest cutting-edge advances in lung cancer. With the continuous development of precision therapy, the EGFR ex20ins mutation has garnered increasing attention, and clinical research in this area has progressed rapidly. At the WCLC, Dr. Baohui Han presented updated data from the phase Ib FAVOUR study. Furmonertinib has amazing efficacy and better safety in patients with untreated and previously treated advanced non-small cell lung cancer (NSCLC) with EGFR ex20ins mutations, with first-line ORR as high as 78.6%. In this discussion for “ Oncology Frontier”, Dr. Baohui Han of Shanghai Chest Hospital and Dr. Roy Herbst of Yale University jointly interpreted the current state, research progress, and future directions in the treatment of EGFR ex20ins mutations.
Dr. Baohui Han
Professor, Ph.D. Supervisor
Honorary Director of Respiratory Medicine, Shanghai Chest Hospital
Roy S. Herbst, MD, PhD
Deputy Director, Yale Cancer Center;
Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital
01
EGFR Ex20ins Mutation Treatment Landscape — Current Status in China and the United States
Dr. Roy Herbst: The global attention to EGFR Ex20ins mutations has been growing. The occurrence rate of EGFR Ex20ins mutations is approximately 3% to 4%, and effective treatments are lacking, as the efficacy of third-generation EGFR-TKIs is limited in these mutations. In the United States, first-line treatment options include platinum-containing chemotherapy, which is not highly satisfactory. For advanced-stage patients with EGFR Ex20ins mutations in later lines of treatment, two drugs, amivantamab and mobocertinib, have been approved in the United States. This field is worth exploring, and we need to help these patients obtain better treatment. At this year’s WCLC conference, several studies in this field showed very encouraging results.
Dr. Baohui Han: TKIs targeting the important EGFR signaling pathway have been in clinical use for over 20 years. Since 2003, with the introduction of the first-generation targeted drugs such as gefitinib, followed by the second and third generations of EGFR-TKIs, we have gradually gained knowledge about classic mutations, non-classic mutations, and resistance mutations. Today’s discussion focuses on EGFR Ex20ins mutations — “resistant” mutations among non-classic mutations, which are characterized by difficult treatment, poor prognosis, and relatively high malignancy. So far, drugs approved in the United States and China are for second-line treatment. Mobocertinib and savolitinib are two drugs available in China, and there is still room for improvement in terms of drug efficacy and median progression-free survival (PFS). In the FAVOUR study presented at this year’s WCLC conference, the first-line treatment with 240mg of famitinib for patients with EGFR Ex20ins mutant advanced NSCLC achieved an ORR of 78.6%, with a median duration of response (DoR) reaching 15.2 months. This is a very promising result, and we expect the median PFS to exceed 10 months, surpassing the efficacy of standard platinum-based doublet chemotherapy. Famitinib’s combination therapy strategies also include combination with chemotherapy and anti-angiogenic drugs, providing ample exploration space and worthy of further research in the first-line setting. Only through continuous progress and improvement can we greatly meet clinical needs.
02
Initial Exploration of Results in First-line Treatment, Famitinib’s Preliminary Results Shine at WCLC
Dr. Roy Herbst: In the field of first-line treatment, various drugs are currently being explored. The Phase III study results comparing mobocertinib with chemotherapy in the first line were negative, but the results have not been formally disclosed yet. On the other hand, the Phase III study results of amivantamab in combination with chemotherapy versus chemotherapy in first-line treatment were positive, and there are more explorations ongoing. At this year’s WCLC conference, the preliminary results of famitinib were encouraging, with an updated ORR of 78.6%. I believe the increased dosage played a significant role. In more difficult-to-treat mutation types, better efficacy was achieved with higher doses. The efficacy in first-line treatment was also explored (see Table 1), and the Phase III FURMO-004 clinical study is currently underway. The results presented by Professor Han are impressive, with few Grade ≥3 treatment-related adverse events (see Table 2). It is crucial to address adverse events early in clinical practice. Several clinical study results on EGFR Ex20ins mutations were announced at recent academic conferences, and I am particularly interested in the treatment of EGFR Ex20ins mutations with famitinib. In China, the incidence of EGFR Ex20ins mutations is approximately 3-4%, and given the large number of lung cancer patients in China, it is predicted that the next clinical trials can proceed smoothly. We look forward to the results in the coming years and anticipate collaborating with everyone.
Dr. Baohui Han: Famitinib is a domestically developed third-generation EGFR-TKI. Since the Phase I study, famitinib has attracted international attention. Its structural features, high activity of metabolites, and high selectivity have given it a significant advantage in the early stages of clinical development, demonstrating high efficacy and relatively low toxicity. Famitinib’s two studies in the second-line treatment of EGFR T790M mutation and first-line treatment of EGFR-sensitive mutation advanced NSCLC have both been published in “The Lancet Respiratory Medicine” and have been highly recognized by international peers. Famitinib’s wide therapeutic window — from the initial dose of 20mg to 240mg during the dose-escalation phase — did not encounter dose-limiting toxicity (DLT) or maximum tolerated dose (MTD). This means that famitinib remains safe even when used at three times the conventional dose (80mg qd). The increase in dosage has resulted in better efficacy in difficult-to-treat mutation types, including EGFR Ex20ins mutations.
In the Phase Ib study we reported, famitinib at 3 times and 2 times the conventional dose was used in patients with EGFR Ex20ins mutant advanced NSCLC. The results confirm that famitinib as a first-line treatment shows outstanding efficacy and good safety. We look forward to further expanding clinical trials based on this and allowing famitinib to achieve better results in the first-line setting to meet clinical needs and improve patient survival.
03
Application and Experience of Clinically Available Drugs for EGFR Ex20ins Mutations in China and the United States
Dr. Roy Herbst: For patients with EGFR Ex20ins mutations, in current clinical practice, clinicians are exploring personalized treatment strategies and hoping to validate results through clinical trials. In addition to clinical trials, in clinical practice, I would still choose chemotherapy as the first-line therapy. Amivantamab and mobocertinib are the current second-line treatment options in the United States, with an ORR of less than 50%, and some Grade 3 or 4 adverse events occurring. Even though they are currently being used clinically, they are not the optimal recommendation. Savolitinib from China, as revealed in the WU-KONG6 results presented at this year’s ASCO meeting, is impressive, and I might consider using it in later lines of treatment. At this year’s conference, we saw the updated results of the Phase Ib famitinib, and further attention to the updated results is needed. Based on the efficacy of famitinib compared to chemotherapy, it has great potential and hope for future application. It can also be explored in combination with chemotherapy. Famitinib is very worth researchers’ attention, as it is challenging to find drugs with high response rates and low toxicity in EGFR Ex20ins mutant patients. I am very much looking forward to the results of further research.
Dr. Baohui Han: This study is a small-sample study, including 90 patients, but this small-sample study has brought us satisfactory efficacy and commendable safety. EGFR Ex20ins mutations have various subtypes, with about 200 different mutation types, broadly classified into near-loop, distant-loop, and other types. Different types may require different strategies. In our exploration, famitinib at three times the dose showed equal efficacy in patients with near-loop, distant-loop, and other types. This means that famitinib will play a very good control role in various complex subtypes in future clinical studies. Regarding the two drugs already on the market in China, mobocertinib and savolitinib, clinicians may have accumulated more data and experience in the clinical treatment of different subtypes. The efficacy of amivantamab in patients with different subtypes is commendable, and its first-line treatment clinical trial is still ongoing. We hope that more drugs can join the treatment of this challenging mutation type. For different effective drugs, their adverse reactions may differ. The more weapons we have, the more precise the treatment, and the more assured the safety.
04
Strengthening Cooperation to Serve Patients, Extensive Development Space in the EGFR Treatment Field
Dr. Roy Herbst: Firstly, teamwork and conducting clinical trials internationally are crucial. EGFR is more common in Asia. In the United States, there are advocates who can serve patients and seek methods globally to provide them with treatment. We have entered the era of personalized medicine, such as EGFR precision treatment, and it is further individualized based on EGFR Ex20ins mutations and even more precise characteristics of EGFR mutations. In the future, having more weapons in our hands can better serve patients. In the EGFR Ex20ins field, current drugs include small molecule TKIs and large molecule antibodies. In the future, amivantamab may be widely used because antibodies may be better tolerated, and excellent small molecule TKIs also have great prospects. Secondly, understanding why patients are sensitive or resistant to a certain treatment plan and providing more precise treatment after resistance are needed. Looking forward to continuing collaboration with Professor Han’s team.
Dr. Baohui Han: Firstly, in the treatment of EGFR Ex20ins mutant NSCLC, there are already multiple targeted drugs approved for second-line treatment, and the next main battleground is first-line treatment. Because the current standard first-line treatment is still platinum-containing chemotherapy, and resistance to targeted therapy is still sensitive after chemotherapy. If targeted drugs enter the first line, the current second-line treatment may be “useless” due to low efficacy. It is crucial to race against time. The drug that reaches the first line first will have a leading market share and clinical application advantage, seizing the initiative. Secondly, to improve the efficacy of first-line treatment, famitinib’s first-line treatment ORR reached 78.6%, and PFS of approximately 10 months is favorable. However, it still has a long way to go compared to the PFS of third-generation EGFR-TKIs for classic EGFR mutations, reaching 20.8 months. Therefore, we need to consider combination with anti-angiogenic drugs, chemotherapy, or other therapies. Patients in first-line treatment usually have better performance status (PS) and can tolerate stronger treatment intensity. We hope to achieve deeper response depth, thereby converting ORR into PFS advantages and further into OS advantages. Thirdly, innovation is needed. In the future, antibody-drug conjugates (ADCs) with “precision targeting” may be one of the important directions to solve the treatment pattern of EGFR Ex20ins mutations. In this regard, joint operations are still needed because ADCs have advantages and disadvantages. Combined with classical targeted therapy, it may be possible to create more treatment patterns on the existing basis and ultimately improve patient survival.
05
Meeting Different Patient Needs, More “Weapons” to Improve Treatment Levels Together
Dr. Baohui Han: We hope to have more targeted treatment options, and we hope to have more weapons at our disposal. In terms of targeted therapy, there is a diverse landscape in China, with multiple manufacturers developing drugs targeting the same pathway, which is both an advantage and a manifestation of redundancy. If “me too” or similar drugs do not have significant characteristics, they will not have a positive impact on the market. Research data becomes chaotic and does not form an advantage. We hope to find targeted therapeutic drugs with excellent efficacy through natural selection and gradually bring these outstanding drugs to clinical use for widespread application.
Dr. Roy Herbst: Having multiple choices is never a problem; on the contrary, it is exciting and encouraging. We need to participate in academic conferences like the World Lung Cancer Congress to better access the latest research data and possibly integrate it into clinical practice. From the U.S. perspective, I would encourage patients or doctors to participate in clinical trials of osimertinib. The current state of this field has improved a lot but is still not sufficient. We are constantly exploring how to raise standards, searching for better drugs, and conducting clinical trials. We look forward to further publication of research data on osimertinib and hope for more interpretations at similar conferences to further establish better treatment standards. Currently, the services we provide to patients transcend time and space; we can collaboratively decide on treatment strategies with international doctors, understand different choices and toxicity profiles, which is an important part of modern medicine.
TAG: WCLC, Live interview, EGFR ex20ins, NSCLC
