BEST features of third-generation EGFR-TKIs

*For medical professionals only for reference (NSCLC) has been a year of great progress in clinical research and clinical practice
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Interpretation of the "Three Kingdoms" to achieve breakthroughs In March 2021, the national first-class new drug fumetinib mesylate (commonly known as "Fu drug" in China) was approved for the treatment of diseases that occurred during or after previous EGFR-TKI treatment Adult patients with locally advanced or metastatic NSCLC who have progressed and have EGFR T790M mutation-positive NSCLC
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Both fumetinib and another Chinese original third-generation EGFR-TKI (almetinib mesylate) have been recommended by China's authoritative lung cancer diagnosis and treatment guidelines for the treatment of EGFR T790M mutation-positive advanced NSCLC
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Targeted therapy for advanced lung cancer recommended in the "Chinese Medical Association Oncology Society Lung Cancer Clinical Diagnosis and Treatment Guidelines (2021 Edition)" [1] Table 1: Recommendations for the treatment of EGFR-mutated NSCLC in the 2021 edition of the "CSCO Non-Small Cell Lung Cancer Diagnosis and Treatment Guidelines" June 2021 In January, the results of a phase III clinical study of almetinib in the first-line treatment of advanced NSCLC with sensitive EGFR mutations in China showed that the disease progression-free survival was 19.
3 months, and the risk of disease progression was reduced by 54% [2]
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In December 2021, the Phase III clinical study of fumetinib in the first-line treatment of EGFR-sensitive mutated advanced NSCLC successfully obtained positive results.
The group can bring significantly longer progression-free survival (PFS) benefits, PFS is expected to exceed 20 months, and the reduction in the risk of disease progression is expected to achieve new breakthroughs
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In December 2021, almetinib was approved in China for the first-line treatment of advanced NSCLC with sensitive EGFR mutations
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In the same month, as a third-generation EGFR-TKI included in the National Medical Insurance Reimbursement Catalog, the price of the drug was reduced from 15,000 yuan to 3,300 yuan per month
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If calculated according to the 70% medical insurance reimbursement ratio, the annual treatment cost of the patient's own pocket is only 26,000 yuan, and the monthly purchase cost is about 2,200 yuan
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In 2022, the treatment of EGFR mutation-positive advanced NSCLC will have three third-generation EGFR-TKIs "competing on the same stage", and all three drugs have entered the national medical insurance reimbursement catalog through price negotiation
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How to choose a drug will be an issue for clinicians in 2022
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The trend of clinical application of third-generation EGFR-TKIs.
When talking with Professor Han Baohui, Department of Respiratory Medicine, Shanghai Chest Hospital, the platform talked with Professor Han about the treatment needs of EGFR mutation-positive NSCLC (including early and mid-stage) and the development of EGFR-TKI drugs.
Trend, and its content inspires how to select third-generation EGFR-TKI drugs
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Share wonderful views here for readers
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Medical Tumor Channel: With the continuous iterative update of drugs targeting EGFR/ALK driver genes, the survival of EGFR/ALK mutation-positive advanced NSCLC patients is getting longer and longer
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In this context, what challenges remain for treatment? Professor Han Baohui: In the 16 years since the first EGFR-TKI drug was approved in China for the treatment of advanced NSCLC in 2005, the first-generation, second-generation and third-generation EGFR-targeted targeted therapy drugs have compared Platinum chemotherapy significantly improves progression-free survival, and turning advanced lung cancer into a chronic disease has become a reality for some patients
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Although targeted therapy cannot completely remove tumors and cure advanced lung cancer, they allow some lung cancer patients to survive with tumors
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However, in the process of transforming lung cancer into a chronic disease, the biggest obstacle to be overcome is the metastasis of cancer cells to important organs
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Among the important organ metastases, brain metastases should bear the brunt, because nearly half of the advanced stage IV non-small cell lung cancers will have brain metastases of different degrees or different manifestations, and such brain metastases will eventually constitute the greatest risk to patients.
existential threat
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Medical Tumor Channel: The results of the Phase IIa clinical study of fumetinib announced at the 2020 World Lung Cancer Congress found that the intracranial effective rate of 160 mg of fumetinib in the treatment of patients with brain metastases was 84.
6%, higher than 80 mg 60% of the treatment effective rate, and did not significantly increase serious adverse reactions
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Does the treatment of lung cancer CNS metastases often require increased drug doses? Professor Han Baohui: Compared with the first-generation EGFR-TKI, the third-generation EGFR-TKI can penetrate the blood-brain barrier and enter the brain better.
However, in clinical practice, treating brain metastases or meningeal metastases is like treating rare or rare mutations of EGFR.
The dose of the drug is often increased to ensure adequate drug concentrations in the cerebrospinal fluid and brain
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But whether the dose can be increased is closely related to the safety and tolerability of the drug
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The dose intensity of antitumor drugs is positively correlated with the reduction of tumor burden and tumor downstaging
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That is to say, within a certain limit, increasing the drug dose can enhance the energy efficiency of killing tumors or reducing tumor burden
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The therapeutic window of chemotherapeutic drugs is narrow because it has a dose-limiting toxicity, while the therapeutic window of targeted therapy drugs is wider, which lays a safe foundation for us to overcome drug resistance and the problem of metastases in special organs
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But to increase the dose of drugs, our biggest concern is the safety hazard brought by high doses
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Such safety concerns include organ toxicity, such as liver failure, severe diarrhea and interstitial pneumonia
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If the therapeutic effect of increasing the dose is far greater than its toxicity, especially if we double the dose, or even triple the dose, and the drug safety data is similar to the recommended dose, I think for lung cancer brain metastases, and rare Or rare EGFR-mutant NSCLC, would be a very good treatment strategy
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Medical Oncology Channel: Results of the FAVOUR study announced at ESMO 2021 show that the use of three times the usual dose (240 mg) of fumetinib in the treatment of EGFR exon 20 insertion (ex20 ins) mutant advanced NSCLC did not cause serious adverse reactions
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Why was this dose chosen? Prof.
Baohui Han: In the phase I dose escalation trial of fumetinib, no dose-limiting toxicity was observed and the maximum tolerated dose was not obtained when the dose was escalated from 20 mg/d to 240 mg/d
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Among the 130 patients in the phase I dose escalation trial and the phase I-II dose expansion trial, 18 patients received 240 mg/d treatment, and there was no increase in grade ≥3 adverse events/treatment-related adverse events compared with the 80 mg/d patient group.
Exhibits good security
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Preliminary results from the FAVOUR study show that 240 mg fumetinib treatment still has a good safety record, with the exception of a relatively more increase in diarrhea, there is no significant increase in the incidence of liver toxicity and interstitial pneumonia
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Medical Oncology Channel: Why is the fumetinib dose safety window so wide? Professor Han Baohui: Fumetinib innovatively introduced the trifluoroethoxypyridine structure, so that its prototype drug and its main metabolites have high anti-tumor activity, and both have highly selective tumor-inhibiting effects
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In fact, other three-generation EGFR-TKIs are also highly specific for the selection of EGFR mutation targets, but the metabolites after entering the human body lose high selectivity, or can inhibit both EGFR sensitive mutations and EGFR wild-type.
lead to more adverse reactions
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Medical Tumor Channel: Currently, there are three third-generation EGFR-TKI drugs approved for the treatment of advanced lung cancer in China
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In clinical practice, if a patient is intolerant to a drug, will it be considered to switch to another third-generation EGFR-TKI drug? Professor Han Baohui: The multiple drugs of the first-generation, second-generation and third-generation EGFR-TKIs provide our clinicians with a very good variety of options, bringing flexibility to doctors for more effective and safe treatments
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For example, when a third-generation EGFR-TKI causes severe interstitial pneumonia and has to be discontinued, or when the patient cannot tolerate continued treatment because of severe diarrhea, we can consider other third-generation EGFR-type drugs
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I think fumetinib, as a relatively safe and relatively low toxic and side effect, is such an excellent third-generation EGFR TKI therapeutic drug, or it can "stand alone" in the case of intolerable toxicity of other drugs, because it Its efficacy and safety have been verified in clinical research and clinical practice
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Medical Tumor Channel: At present, three generations of EGFR-TKI targeted drugs have been approved in China for postoperative adjuvant treatment of patients with early and mid-stage NSCLC
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Is the safety of targeted therapy drugs more important for postoperative adjuvant therapy? Professor Han Baohui: Drug adjuvant therapy for early and mid-stage lung cancer after R0 resection is basically an intervention without tumor burden, and it is a preventive treatment, so the requirements for safety are much higher than those without surgery.
Advanced lung cancer that can only receive medical palliative care
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And in general, the course of adjuvant therapy is longer than that of advanced lung cancer
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At present, although China's drug approval and regulatory authorities have approved the third-generation EGFR-TKI for postoperative adjuvant treatment of patients with stage IB-IIIA NSCLC based on the results of large-scale phase III clinical studies in the world, we still need to use the third-generation EGFR-TKI for Evidence-based medicine for adjuvant therapy in the Chinese population to better guide our clinical practice
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Because whether it is chemotherapy, targeted therapy, or immunotherapy that is currently in full swing, there are significant differences in therapeutic efficacy and safety between Caucasians and other ethnic groups, such as Chinese people
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Therefore, although large-scale clinical studies have been conducted abroad, if the sample size in China is not enough, I think it is necessary for our Chinese companies and Chinese experts to take the lead in conducting large-scale Phase III confirmatory clinical trials for Chinese patients.
trials to understand the efficacy and safety of treating Chinese patients
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The randomized, double-blind, placebo-controlled, multicenter Phase III registrational clinical study (FORWARD) of fumetinib as adjuvant therapy in patients with EGFR mutation-positive stage II-IIIA NSCLC after curative resection with or without adjuvant chemotherapy has been conducted.
Launched this year
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The study compared the efficacy and safety of fumetinib with placebo adjuvant therapy for 3 years
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We hope FORWARD research will fill this gap
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Compared with osimertinib and almetinib, the third-generation EGFR-TKI of BEST, fumetinib is a latecomer
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However, fumetinib in the treatment of lung cancer, especially lung cancer brain metastases (Brain), has demonstrated excellent efficacy (Efficacy) in clinical research and clinical practice, and its safety (Safety) clinical research data and in clinical practice.
Tolerability is impressive
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In 2022, fumetinib, which has entered the national medical insurance reimbursement catalogue, is bound to gain wider clinical application, and only during this process can doctors spy, discover, and perceive what the young Chinese "forbidden medicine" can show.
Characteristics of BEST's third-generation EGFR-TKI
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 Expert Profile Professor Han Baohui Director, Chief Physician, Doctoral Supervisor of Department of Respiratory Medicine, Shanghai Chest Hospital Executive Dean of China Lung Cancer College Postdoctoral supervisor Director of Shanghai Chest Hospital Drug Clinical Research Institute Director of Asia Pacific Medical Immunology Society Oncology Branch Chairman Member of the National Cancer Clinic Executive Committee of the China Anti-Cancer Association, Vice Chairman of the Chinese Anti-Cancer Association Cancer Precision Diagnosis and Treatment Committee, and a member of the Standing Committee of the Respiratory Branch of the Chinese Medical Doctor Association Reference materials: [1] Oncologists Branch of the Chinese Medical Doctor Association, China Medical and Healthcare International Exchange Promotion Association Branch of Internal Medicine.
Chinese Treatment Guidelines for Stage IV Primary Lung Cancer (2021 Edition) [J].
Chinese Journal of Oncology 2021, 43(1): 39-59, DOI: 10.
3760/cma.
j.
cn112152-20201009-00884.
[2 ]Lu S,et al.
Randomized phaseⅢtrial of aumolertinib(HS-10296,Au)versus gefitinib(G)as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer(NSCLC)and EGFR exon 19 del or L858R mutations(EGFRm).
ASCO 2021.
Abstr 9013*This article is only for providing scientific information to medical professionals and does not represent the views of this platform