Professor Wang Jie: The clinical diagnosis and treatment pattern of NSCLC with EGFR Ex20ins mutation may undergo significant changes
EGFR Ex20ins mutation is the third largest mutation in EGFR. In the Chinese population, EGFR Ex20ins mutation accounts for 4-12% of EGFR gene mutations and 3% of NSCLC. The EGFR EX20ins mutation has the characteristics of high heterogeneity, refractory nature, poor prognosis, and high malignancy. In recent years, more and more new drugs targeting this mutation have emerged, but the recommendation of targeted therapy in first-line treatment still lacks evidence. NSCLC carrying EGFR Ex20ins urgently needs new therapies. At present, several small molecule drugs have entered the clinical trial stage. Taking this opportunity, Professor Wang Jie from the Cancer Hospital of the Chinese Academy of Medical Sciences is invited by [Tumor Information] to interpret the current clinical treatment status and the most important breakthrough progress in first-line treatment of EGFR EX20ins mutant NSCLC, in order to inspire clinical practice.
Chief Physician of Internal Medicine, the Cancer Hospital of the Chinese Academy of Medical Sciences
Winner of the 2021 Science, Technology and Progress Award of Ho Leung Ho Lee Foundation
Winner of the National “Outstanding Youth” Fund
Leader of the Innovation Team of the Ministry of Education
Winner of the 7th China Young Female Scientist Award
Selected as a national talent project with millions of talents and awarded the title of young and middle-aged expert with outstanding contributions
Vice Chairman of the Chinese Society of Clinical Oncology (CSCO)
Vice Chairman of CSCO Small Cell Lung Cancer Expert Committee
Candidate Chairman of CSCO NSCLC Expert Committee
Chairman of the Multidisciplinary Committee on Oncology of the Chinese Medical Association
Vice Chairman of the Lung Cancer Professional Committee of the China Anti- Cancer Association
Vice Chairman of the Cancer Branch of Beijing Medical Association
Vice President of Beijing Chronic Disease Prevention and Health Education Research Association
The clinical treatment status of NSCLC with EGFR Ex20ins mutation is facing difficulties, eagerly anticipating new treatment opportunities to break through the encirclement
The clinical treatment status of NSCLC with EGFR Ex20ins mutation is facing difficulties, eagerly anticipating new treatment opportunities to break through the encirclement
Professor Wang Jie: EGFR mutations have been studied for about twenty years at both global and domestic levels. At present, EGFR mutations are classified into classic mutations in clinical practice, including common mutations such as EGFR Ex19del and EGFR Ex21 point mutation; and another common category, the EGFR Ex20ins mutation is the third most common mutation in EGFR after the loss of EGFR Ex19del and the L858R Ex21 point mutation. Among these mutations, the treatment of patients with EGFR Ex20ins mutations is the most challenging, mainly due to the many subtypes of mutations, strong heterogeneity, and poor prognosis of these patients. Moreover, due to the spatial steric hindrance relationship in the structure after Ex20ins, it is not sensitive to the existing first to third-generation EGFR TKIs, the efficacy of platinum standard chemotherapy, even platinum combined with anti-vascular drugs, and platinum combined with immunotherapy is not ideal. Therefore, patients with EGFR Ex20ins face significant challenges in treatment.
Currently, both drugs approved in China and the United States are used for second-line treatment, and the drugs listed in China mainly include Mobocertinib and Sunvozertinib. There is currently no approved drug for first-line treatment of NSCLC with EGFR Ex20ins mutation. It is reported that recently, due to unsatisfactory results in first-line treatment, Mobocertinib has been delisted globally for previously approved second-line indications. Generally, we still face significant challenges in the clinical diagnosis and treatment of patients with EGFR Ex20ins.
Deep analysis of the limited therapeutic mechanism of traditional EGFR TKI against EGFR Ex20ins mutant NSCLC induced by backlighting
Professor Wang Jie: The therapeutic effect of traditional EGFR TKI on NSCLC with EGFR Ex20ins mutation is very limited. The main reason is that the EGFR Ex20ins mutation causes a change in the spatial hindrance relationship in the structure. In the top international journal in the field of pharmaceutical chemistry, EJMC, Puhe Biopharma (Suzhou Puhe Biopharma Co., Ltd.) published a paper this year analyzing the difficulties in the development of EGFR Ex20ins mutation drugs, Discussed the design concept and mode of action of YK-029A [1]. Generally, EGFR Ex20ins mutation results in a wide variety of subtypes and strong heterogeneity depending on the specific location of the mutation and the different insertion amino acids. Currently, more than 100 mutation subtypes have been discovered worldwide. Therefore, designing a drug molecule that can simultaneously bind and overcome so many mutant subtypes is a huge challenge for the development of new drugs. At the same time, we also know that kinase inhibitors generally generate kinase inhibitory activity through direct competition between small molecules and ATP. The forms of EGFR Ex20ins mutation are very diverse, whether inserted from the front or from the back, the vast majority still maintain a strong affinity for ATP. This affinity is much stronger than other mutations, such as EGFR Ex19del deletion mutation, Ex21 point mutation, and other common EGFR mutations, which pose a great challenge to the development of EGFR Ex20ins mutation inhibitors. Moreover, this steric hindrance effect prevents the first to third-generation EGFR TKIs from entering this active conformational domain to exert therapeutic effects, thereby reducing their affinity for EGFR Ex20ins. This is also the reason why the EGFR Ex20ins mutation mentioned above has unsatisfactory therapeutic effects on the first to third-generation EGFR TKIs.
Interpreting the breakthrough progress in first-line treatment of EGFR EX20ins mutant NSCLC, with the expectation of rewriting the clinical practice of EGFR EX20ins NSCLC
Professor Wang Jie: For patients with EGFR Ex20ins mutations, the challenge they face is not only to have drugs to treat them, but also to gradually expand the application of new drugs from the rear line to the front line. Any good drug is expected to be pushed to the first-line treatment, but so far, for the treatment of patients with EGFR Ex20ins, although drugs like Sunvozertinib and Mobocertinib have shown some efficacy in second line treatment. But pushing it to the first line of treatment, like the final delisting of Mobocertinib, is also due to its negative results in first-line treatment. For patients with EGFR Ex20ins mutations, exploring drug study in the field of first-line treatment is very important.
Recently, the International Multicenter Phase 3 Study PAPILLON, led by Chinese scholars, published in the New England Journal of Medicine (NEJM) evaluated the efficacy and safety of amivantamab as a dual antibody combination chemotherapy targeting both EGFR and MET compared with chemotherapy alone in untreated patients with advanced or metastatic NSCLC with EGFR Ex20ins mutations. The data currently displayed is very good and it is a very promising combination therapy regimen. The results showed that the median PFS of the amivantamab+ chemotherapy group was 11.4 months, and the objective response rate (ORR) also reached 73% [2]. The PAPILLON study demonstrated that the combination of amivantamab dual antibody and chemotherapy is superior to chemotherapy in terms of efficacy, but the study control group chose chemotherapy alone. Generally, the above plans provide excellent treatment options for this type of patient. In addition, dual antibody drugs also have certain adverse reactions, after all, it is intravenous infusion, especially when used in combination with chemotherapy, which poses certain challenges.
In fact, we are more looking forward to using more convenient oral medications, such as YK-029A from Puhe Biopharma (Suzhou Puhe Biopharma Co., Ltd.). The early efficacy and safety data were published by our team in the top issue JTO of lung cancer. The confirmed independent imaging evaluation committee assessed an ORR of 73.1% and a DCR of 92.3%; The median progression free survival (mPFS) evaluated by the researchers was 11.1 months, with a 9-month PFS rate of 69.7% and a 1-year overall survival (OS) rate of 83.1% [3,4]. Treatment response was observed in all assessable subgroups, including patients with brain metastases and patients with different EGFR Ex20ins mutation subtypes. Although this study is a preliminary clinical study with a small sample size, YK-029A has been awarded a breakthrough therapeutic designation (BTD) by the China National Medical Products Administration's Center for Drug Evaluation (CDE) in 2022 due to its excellent efficacy and safety in its Phase I study, becoming the first breakthrough therapeutic drug in the field of EGFR Ex20ins lung cancer to date, This is also the only small molecule targeted drug in the field that has been recognized as a breakthrough therapy by CDE, and the only one that has published relatively complete Phase I clinical results in top international journals for first-line treatment. At present, a Phase III multicenter clinical study of YK-029A for first-line treatment has been initiated, and we look forward to obtaining positive results from this study
References
1. B. Liu, F. Gao, H. Zhao, S. Yuan, X. Peng, P. Zhang, J. Wang, T. Zhang, M. Duan, Y. Guo, Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790M and exon 20 insertion mutations, as a treatment for NSCLC, European Journal of Medicinal Chemistry (2023), doi: https://doi.org/10.1016/j.ejmech.2023.115590.
2. Zhou C, Tang K-J, Cho BC, et al., for the PAPILLON Investigators*, Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023 Oct 21. doi: 10.1056/NEJMoa2306441.
3. Duan J, Wu L, Yang K, Zhao J, Zhao Y, Dai X, Li M, Xie Y, Yao Y, Zhao M, Zhou C, Ren X, Liu Z, Pan Y, Li Y, Liu B, Cheng Y, Miao L, Yu Q, Zhang Z, Liu X, Cui J, Zhang Y, Zhang L, Li X, Li X, Shen B, Chen B, Zeng S, Li B, Hu Y, Li L, Wu R, Song Q, Wang J, Safety, tolerability, pharmacokinetics, and preliminary efficacy of YK-029A in treatment-naïve patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations: A phase I trial, Journal of Thoracic Oncology (2023), doi: https://doi.org/10.1016/j.jtho.2023.09.1449.
4. Jianchun Duan, et al. Safety and preliminary efficacy of YK-029A, a novel EGFR TKI, in patients with advanced NSCLC harboring ex20ins, T790M or rare mutations. J Clin Oncol 41, 2023 (suppl 16; abstr 9014)（Poster Bd #2）
Professor Duan Jianchun: Breakthrough therapy innovative drug YK-029A brings benefits to first-line treatment of EGFR Ex20ins mutant NSCLC
With the continuous deepening of the diagnosis and treatment of lung cancer, the association between different driver gene mutations and the efficacy of EGFR-TKI has been discovered. NSCLC patients with EGFR Ex20ins are generally insensitive to first, second, and third-generation EGFR-TKI therapy, and there are currently no good first-line treatment targeted drugs available.
Professor Duan Jianchun from the Cancer Hospital of the Chinese Academy of Medical Sciences, representing Professor Wang Jie's Research Team, taking the study data of the third generation EGFR-TKI——YK-029A, presented the study data "Safety and preliminary efficacy of YK-029A, a novel EGFR TKI, in patients with advanced NSCLC harboring Ex20ins, T790M or rare mutations" as a poster at 2023 American Society of Clinical Oncology (ASCO). Recently, he also presented a report titled "Safety, tolerability, pharmacokinetics, and preliminary efficacy of YK-029A in treatment-naïve patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations: a Phase I trial" is published in the Journal of Thoracic Oncology. This drug has been recognized as a breakthrough therapy for EGFR Ex20ins NSCLC initial treatment. On this occasion, Professor Duan Jianchun was invited by [Tumor Information] to provide a wonderful interpretation of the current diagnosis and treatment status and new breakthroughs of EGFR Ex20ins NSCLC.
Department of Internal Medicine, the Cancer Hospital of the Chinese Academy of Medical Sciences
Director of Internal Medicine, Shanxi Hospital, the Cancer Hospital of the Chinese Academy of Medical Sciences
Director of CSCO
Vice Chairman of CSCO Sarcoma Expert Committee
Member of CSCO Non-Small Cell Lung Cancer Expert Committee
Member of the CSCO Immunotherapy Expert Committee
Member of CSCO Youth Expert Committee
Vice Chairman of the National Youth Expert Committee for Clinical Application Monitoring of Antitumor Drugs
Vice Chairman of the Lung Cancer Medical Youth Expert Committee of the Beijing Medical Award Foundation
Executive Committee Member of the Lung Cancer Professional Committee of the China Primary Health Care Foundation
Standing Committee Member of the Lung Cancer Professional Committee of the Beijing Cancer Society
Standing Committee Member of the Lung Cancer Immunotherapy Professional Committee of the Beijing Cancer Prevention and Treatment Society
Member of the Youth Committee of the Oncology Branch of the Beijing Medical Association
Backbone members of the "Innovation Team" of the Ministry of Education
National Natural Science Youth Fund, recipient of National Natural Science General Project
Received the "First Prize for Science and Technology Progress of the Ministry of Education", "Second Prize for National Science and Technology Progress", and "2021 Mao Yisheng Science and Technology Award - Beijing Youth Science and Technology Award"
Long term commitment to standardized and individualized multidisciplinary comprehensive treatment and transformation research for chest tumors, mainly lung cancer.
EGFR Ex20ins mutation urgently needs to break through the first-line treatment dilemma of NSCLC
Professor Duan Jianchun: EGFR Ex20ins mutation is a common mutation in NSCLC, especially in lung adenocarcinoma. The incidence of EGFR Ex20ins mutation in EGFR mutation is lower than that of EGFR Ex19del deletion and L858R Ex21 substitution mutation, which are two classic mutations, making it the third largest type of mutation. The proportion of lung cancer patients with EGFR mutations in the Chinese population is very high. The incidence rate of patients with EGFR Ex20ins mutations may not be lower than that of patients with ALK fusion, ROS1 fusion and other mutations. Based on comprehensive estimation, the number of patients with EGFR Ex20ins mutations should not be underestimated.
In our previous study on NSCLC with EGFR Ex20ins mutations, our team found that EGFR Ex20ins mutations are less sensitive to traditional first to third-generation EGFR TKIs and differ from the two types of sensitive mutations mentioned earlier. Generally, NSCLC patients with EGFR Ex20ins mutation have the characteristics of high malignancy, strong heterogeneity, and poor prognosis.
In clinical practice, the overall efficacy of EGFR Ex20ins mutation NSCLC patients is not satisfactory, whether it is first-generation/second-generation TKI or traditional platinum-containing dual drug chemotherapy (including platinum-containing dual drug chemotherapy combined with immunotherapy or combined with anti-angiogenic therapy). The median progression free survival (PFS) for first-line treatment of such patients is generally between 4 and 6 months, which is far from meeting clinical treatment needs, and there are still significant challenges in clinical diagnosis and treatment.
Currently approved is Mobocertinib, also known as TAK-788, which is a second-line targeted drug. Due to the negative results of the first-line Phase III clinical study of TAK-788, Takeda has withdrawn the FDA's indication for the EGFR Ex20ins mutation. From this, it can be seen that the treatment for this type of patient is very difficult. Another drug is Sunvozertinib, which has been approved as a second-line indication in China, but in reality, it still cannot meet the treatment needs. In clinical practice, innovative drugs with high efficiency and low toxicity targeting EGFR Ex20ins mutations are an urgent need for every physician and patient to strive for.
In this study, YK-029A was also the third-generation EGFR TKI. Preclinical studies explored its efficacy and safety in treating EGFR T790M mutations, including rare EGFR mutations, as well as EGFR Ex20ins mutations and other different types of mutations. Surprisingly, YK-029A showed excellent therapeutic potential in EGFR Ex20ins mutated cell lines and clinical patients, which is expected to fill the gap in the treatment plan for EGFR Ex20ins mutated NSCLC. Especially from queue studies, it was found that the EGFR Ex20ins mutant NSCLC queue receiving YK-029A on the first line showed very good results in terms of efficacy, duration of remission, PFS, and safety.
The Phase I clinical study results of YK-029A are exciting
Professor Duan Jianchun: The clinical treatment of NSCLC patients with EGFR Ex20ins mutation is far from meeting the needs. Currently, the approved Mobocertinib and Sunvozertinib on the market have only been approved as indications for second-line treatment. In addition, Mobocertinib has withdrawn its corresponding indications due to the negative results of first-line treatment. At present, clinical treatment strategies for patients with EGFR Ex20ins mutations are recommended by domestic and foreign guidelines to refer to the treatment of driver gene negative NSCLC.
The innovation of this study lies in the first exploration of the efficacy, safety, tolerability, and pharmacokinetics of YK-029A for patients with different types of EGFR mutations in Phase IA and Phase IB studies. Preliminary results have shown that YK-029A exhibits impressive safety, tolerability, pharmacokinetics, and initial efficacy in untreated patients with EGFR Ex20ins mutations. In the safety analysis, no dose limited toxicity of YK-029A was observed, and the maximum tolerable dose was not reached, indicating that it has a wide safety window and shows very good therapeutic effect at a certain dose. Based on this, the optimal biological therapy dose was selected and corresponding treatment was performed in patients with EGFR Ex20ins mutation.
The phenotype of EGFR Ex20ins mutation differs from that of previous sensitive EGFR mutations, therefore, drug concentrations with higher EGFR Ex20ins mutations are more effective. But if the drug has weak selectivity for EGFR Ex20ins mutation, excessive drug concentration will affect the safety of patients. For Osimertinib, its IC50 value for EGFR 20ins mutant cell lines is relatively higher and closer to wild-type EGFR, so its efficacy for EGFR Ex20ins mutant patients does not seem to be ideal. For YK-029A, there is a significant difference in IC50 values for wild-type EGFR and EGFR Ex20ins mutations, indicating that YK-029A exhibits excellent therapeutic effects on EGFR Ex20ins mutation patients.
In the initial treatment cohort study, the efficacy of YK-029A can be preliminarily observed in patients with EGFR Ex20ins mutation. It has been confirmed that the objective response rate (ORR) evaluated by the independent imaging evaluation committee is as high as 73.1%, and the DCR is 92.3% [1,2]. Compared with previous studies, YK-029A has a significant therapeutic effect on this more difficult to treat mutation site. In addition, for median PFS, the efficacy evaluated by existing researchers can reach 11.1 months. Compared with the traditional treatment regimen of 4-6 months for median PFS, YK-029A has a significant benefit in first-line treatment of EGFR Ex20ins mutant NSCLC.
YK-029A in this study is an orally administered, irreversible, highly selective EGFR TKI targeting multiple EGFR mutant subtypes. With its excellent efficacy and safety in Phase I study, it has been recognized as a breakthrough therapy (BTD) in China in 2022, becoming the first breakthrough therapy new drug in the field of EGFR Ex20ins lung cancer for initial treatment. At present, study on other drugs is underway in this field, and a Phase III study on first-line treatment of YK-029A is being conducted. Compared with traditional chemotherapy, this study aims to further validate the drug's efficacy in a larger population and bring more hope to this type of patient.
YK-029A brings new hope to EGFR Ex20ins for the initial treatment of lung cancer, and multi-level exploration opens up continuous benefits and improvement
Professor Duan Jianchun: The clinical challenges brought by EGFR Ex20ins mutation NSCLC still exist.
Firstly, clinical detection of EGFR Ex20ins mutations. Previous studies have shown that different types of EGFR Ex20ins mutations, whether they are secondary or primary, may also have certain differences in efficacy. At present, most hospitals in clinical practice may use PCR to detect EGFR Ex20ins mutations. However, it can only detect patients with EGFR Ex20ins. The specific type of mutation, whether it is a near loop or far loop mutation, cannot be accurately diagnosed with this method. In addition, the accuracy of EGFR Ex20ins mutation detection and the development of detection method standards are equally important.
Secondly, the EGFR Ex20ins mutation in NSCLC exhibits strong heterogeneity, and the efficacy of targeted therapy varies among patients. The efficacy of YK-029A is not yet clear for patients with strong heterogeneity and specific metastatic sites (such as those with combined liver and brain metastases), and further clinical practice is needed to verify it.
Thirdly, management of adverse reactions. Small molecule targeted drugs often have varying degrees of mild to moderate adverse reactions. YK-029A also has its corresponding adverse reactions, and more data needs to be obtained in a large-scale population. Oral targeted drugs are mainly taken by patients at home, and early detection, control, and management of drug related adverse reactions are crucial to ensure long-term drug tolerance for patients.
Fourthly, can combined chemotherapy, like third-generation EGFR TKI, further improve the efficacy of first-line treatment and bring more benefits to patients? The exploration of efficacy optimization is endless, and it is hoped that patients can achieve better PFS, higher quality of life, and longer remission in first-line treatment. Further in-depth exploration is still needed.
Lastly, exploring the mechanism of drug resistance. Regardless of the era of chemotherapy drugs, targeted drugs, or immunotherapy, patients may experience varying degrees of primary or secondary resistance at different stages of treatment. Further exploration of drug resistance mechanisms, including the development of new drugs to overcome these mechanisms, has always been a direction of effort.
The above are all key issues that need to be paid attention to in the future!
References
1. Duan J, Wu L, Yang K, Zhao J, Zhao Y, Dai X, Li M, Xie Y, Yao Y, Zhao M, Zhou C, Ren X, Liu Z, Pan Y, Li Y, Liu B, Cheng Y, Miao L, Yu Q, Zhang Z, Liu X, Cui J, Zhang Y, Zhang L, Li X, Li X, Shen B, Chen B, Zeng S, Li B, Hu Y, Li L, Wu R, Song Q, Wang J, Safety, tolerability, pharmacokinetics, and preliminary efficacy of YK-029A in treatment-naïve patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations: A phase I trial, Journal of Thoracic Oncology (2023), doi: https://doi.org/10.1016/j.jtho.2023.09.1449.
2. Jianchun Duan, , et al. Safety and preliminary efficacy of YK-029A, a novel EGFR TKI, in patients with advanced NSCLC harboring ex20ins, T790M or rare mutations. J Clin Oncol 41, 2023 (suppl 16; abstr 9014)
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