Professor Zhou Caicun: The safety and tolerability of the third-generation EGFR-TKI treatment of lung cancer will determine the outcome

*For reference by medical professionals only.
Vometinib and its metabolites have anti-tumor "dual activity" and are highly selective
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Vometinib mesylate is the third representative skin growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug originally developed in China
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In March of this year, vomitinib mesylate (hereinafter referred to as vomitinib) was approved for use in previous EGFR TKI treatment or after treatment, and the presence of locally advanced or metastatic EGFR T790M mutations was confirmed by testing.
For the treatment of adult patients with NSCLC, the recommended daily dose is 80 mg
.

Vometinib mesylate was approved in March this year for the treatment of advanced lung cancer.
At the just-opened European Medical Oncology Conference (September 16-September 21), vometinib was used to treat epidermal growth factor receptor (EGFR).
) The Phase Ib clinical study (FAVOUR) of advanced non-small cell lung cancer (NSCLC) with exon 20 insertion (ex20 ins) mutations announced the results of the first-line treatment cohort (Abstract #1325) [1]
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The results showed that 10 patients who received 240 mg of vomitinib daily for first-line treatment all had different degrees of tumor target lesion reduction, with a median shrinkage of -51.
8%, and a disease control rate of 100%; among them, the tumors of 6 patients reached Based on the objective remission standard, the confirmed ORR was 60% [1]
.

In the first-line treatment of vormetinib for advanced NSCLC with EGFR 20ins mutation, all patients showed different degrees of tumor target lesion reduction.
[1] In terms of safety, 9 patients in the group had treatment-related adverse reactions, and the most common treatment-related adverse reactions The reaction was diarrhea; 1 case was interrupted for 6 days due to diarrhea, and then continued to be treated with 240 mg vomitinib daily; however, no adverse reactions of grade 3 or higher have been observed in this cohort [1]
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The safety of vomitinib in the first-line treatment of advanced NSCLC with EGFR 20ins mutation [1] Increasing the dose of third-generation EGFR-TKI to treat EGFR ex 20 ins mutant NSCLC is not without precedent
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For example, after the 160mg/d dose of osimertinib, the ORR of the line treatment of advanced NSCLC with EGFR Ex20ins mutation was 24%, the median PFS reached 9.
6 months, but the ≥3 grade adverse events reached 45% [2]
.

Although the sample size of the FAVOUR study was small, three times the conventional dose of vomitinib treatment (median drug exposure time 4.
1 [2.
7-5.
4] months) did not bring about a case of ≥ grade 3 adverse reactions, and the overall suggestion of vomitinib It is a third-generation EGFR-TKI with good safety
.

The results of the Phase IIa clinical study of vometinib announced at the World Lung Cancer Congress in 2020 found that the intracranial effective rate of vomitinib at a daily dose of 160m was 84.
6% in patients with brain metastases, while the effective rate of 80 mg treatment was 60%; And compared to taking 80 mg daily, taking 160 mg daily did not significantly increase serious adverse reactions [3]
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The efficacy data of a phase IIa clinical study of vomitinib in the treatment of CNS metastasis [3] The safety of vomitinib must be derived from its high selectivity in inhibiting mutant EGFR
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But what is the reason behind the high degree of selectivity? What are the advantages of vomitinib for the treatment of advanced EGFR mutation-positive NSCLC, and the adjuvant treatment of early and mid-stage NSCLC? How important is the long-term safety of the third-generation EGFR-TKI to make lung cancer a chronic disease? Recently, this platform interviewed Professor Zhou Caicun, Director of the Department of Oncology, Shanghai Pulmonary Hospital Affiliated to Tongji University, and conducted in-depth communication on these issues
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▎Medical Oncology Channel: In the era when EGFR-mutated advanced NSCLC is gradually becoming a chronic disease, is the safety of targeted therapy drugs particularly prominent? Professor Zhou Caicun: EGFR-TKI drugs have completely changed the treatment pattern of advanced NSCLC with EGFR sensitive mutations, and the patient’s survival period has also been significantly prolonged.
The median OS has been extended from about 12 months in the chemotherapy era to the third-generation EGFR-TKI era.
In 38.
6 months, this type of lung cancer has gradually become a controllable chronic disease
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However, this also puts forward higher requirements for the safety and tolerability of the third-generation EGFR-TKI drugs
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Because the patient can tolerate "short pain" such as diarrhea and skin rash, but if it is "long pain", it will affect the patient's quality of life, and the patient may not be able to tolerate the treatment for a long time
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▎Medical Tumor Channel: The central nervous system is the most common distant metastasis site of advanced lung cancer
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Does the treatment of lung cancer CNS metastasis often need to increase the drug dose? Professor Zhou Caicun: With the prolonged survival of patients, the incidence of brain metastases from lung cancer will also be higher than in the chemotherapy era
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About 50% of patients will have CNS metastasis within three years
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Therefore, to evaluate the efficacy of a lung cancer targeted drug, the effectiveness of the treatment of brain metastasis is a very important dimension, because it means that the survival of the patient will also take a step forward
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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, the treatment of brain metastasis or meningeal metastasis is like the treatment of rare or rare EGFR mutations, and often needs to be increased.
The dosage of the drug to ensure that there is sufficient drug concentration in the cerebrospinal fluid and brain
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However, whether the dose can be increased is closely related to the safety and tolerability of the drug
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In fact, in clinical practice, we have many examples of the need to increase the dose of drugs
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For example, patients taking 80 mg of osimertinib had meningeal metastases.
We increased the dose of the drug to 160 mg and found that the symptoms of meningeal metastases were under control, but the patients could not bear it because the side effects such as rash and diarrhea came out or worsened; that is to say, increased Drug dosage can effectively control brain metastasis or meningeal metastasis, but whether the dosage can be increased depends on how wide the safety window of drug dosage is
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▎Medical Oncology Channel: Why can the safety window of vomitinib be so wide? Professor Zhou Caicun: Vometinib innovatively introduces the trifluoroethoxypyridine structure, so that its prototype drug and its main metabolites have high anti-tumor activity, and their anti-tumor effects are highly selective
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In fact, the other three generations of EGFR-TKIs are also very specific for the selection of EGFR mutation targets, but the metabolites after entering the human body lose high selectivity, and can inhibit EGFR sensitive mutations and EGFR wild-type.
Will cause more adverse reactions
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▎Medical Cancer Channel: At present, EGFR-TKI targeted drugs have been approved for the adjuvant treatment of early and mid-stage NSCLC patients in China
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For postoperative adjuvant therapy, is the safety of targeted therapy drugs more important? Targeted drugs are used in the adjuvant treatment of early and mid-stage lung cancer patients.
The safety of the drug determines the success or failure of the final treatment
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Why is security important? The main reason is that patients receiving postoperative adjuvant therapy need to insist on taking the medicine for a long time.
If the safety and tolerability are good, then disease recurrence-free survival (DFS) will definitely be long, and if DFS is long, OS will naturally grow; on the contrary, if it is not possible If you have an adverse reaction, you can't adhere to the treatment, and the DFS will naturally be short
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So this point deserves our focus
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For the postoperative adjuvant treatment of early lung cancer, in addition to skin rash and diarrhea, we must also pay attention to other uncommon side effects, such as liver function damage, interstitial pneumonia, and gastrointestinal adverse reactions, such as anorexia and stomatitis and so on
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If these adverse events accumulate and leave each patient "left behind", the efficacy will naturally be compromised
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A randomized, double-blind, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, led by He Jianxing, Dean of the First Affiliated Hospital of Guangzhou Medical University.
The placebo-controlled, multi-center Phase III registered clinical study (FORWARD) was launched this year
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The study compares the efficacy and safety of vomitinib and placebo in adjuvant treatment for 3 years
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I think from the current safety data of vometinib, the chance of vometinib winning is still quite large
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▎Medical Oncology Channel: Currently, the imported third-generation EGFR-TKI osimertinib has been approved in China for postoperative adjuvant treatment of patients with stage IB-IIIA NSCLC
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What is the significance of FORWARD research on vometinib? Medical Oncology Channel: The third-generation EGFR-TKI is used for postoperative adjuvant treatment of early and mid-term patients.
We still need more high-level evidence-based medical evidence for the treatment of the Chinese population
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The ethnic differences between the East and the West and the differences in derived cultures may cause the drugs to show different efficacy and safety
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For example, the process of metabolizing drugs between the East and the West may be different, and the size and structure of the human body are also different between the East and the West
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Therefore, the dosage of drugs used for Westerners may not be suitable for Easterners
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In addition, the different dietary cultures of the Eastern and Western people lead to different dietary structures.
For example, Asians eat more vegetables, fruits, and fish, while Western people mainly eat meat
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This may affect the metabolism, absorption, and efficacy of drugs, as well as the toxic and side effects of these drugs
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Therefore, the dosage of drugs used by foreigners may not be the same as that used by Chinese people
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This is why we must carry out clinical research on the Chinese population and observe the safety of the drug, especially the long-term safety, because white people and yellow people may also show completely different long-term adverse reaction profiles
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Therefore, clinical research on Chinese is the most valuable for guiding the clinical practice of domestic doctors
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At present, we have the results of the Chinese population data of the first generation of EGFR-TKI used in the postoperative adjuvant treatment of patients with stage II-IIIA lung cancer, but the third generation of EGFR-TKI used in the postoperative adjuvant treatment of the Chinese population still lacks high-level evidence-based medical evidence
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We hope that FORWARD research can fill this gap
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On September 25th, during the upcoming 24th CSCO Conference, Professor Zhou Caicun will bring Professor Cheng Ying, Dean of Jilin Cancer Hospital, Professor Shi Yuankai, Deputy Dean of Cancer Hospital of Chinese Academy of Medical Sciences, and First Affiliated Hospital of Guangzhou Medical University Professor Jianxing Chang, Professor Feng Jifeng, Secretary of the Party Committee of Jiangsu Cancer Hospital/Nanjing Medical University Affiliated Cancer Hospital, and Professor Lu You from the Department of Thoracic Oncology, West China Hospital of Sichuan University, co-chaired the Vometinib Satellite Symposium
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At that time, the FAVOUR research lead will be Professor Han Baohui, Department of Respiratory Medicine, Shanghai Chest Hospital, Jiaotong University, Professor Hu Jian, Director of the Lung Disease Diagnosis and Treatment Center of the First Affiliated Hospital of Zhejiang University School of Medicine, and Professor Dong Xiaorong, Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology The latest clinical research progress of third-generation EGFR-TKIs including vometinib for advanced and early-mid-term NSCLC will be presented
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Expert profile Professor Zhou Caicun, PhD, chief physician, and doctoral supervisor, Director of the Department of Oncology, Shanghai Pulmonary Hospital, Tongji University, Director, Institute of Oncology, Tongji University School of Medicine, enjoys special allowance from the State Council, member of the Presidium of the International Association for Lung Cancer Research (IASLC) CSCO non-small cell Chairperson of the Lung Cancer Special Committee Chairperson of the Thoracic Oncology Branch of the China Medical Promotion Association Shanghai Leading Talents, the most important subject leader, Shanghai Anti-Cancer Association Lung Cancer Molecular Targeting and Immunotherapy Committee Chairperson, Chinese Anti-Cancer Association Lung Cancer Specialty Committee Standing Committee Member of the Chinese Medical Association Oncology Branch Standing Committee Member of the Chinese Association of Elderly Oncology Executive Committee Reference: [1].
Baohui Han et al.
, Preclinical and Preliminary Clinical Investigations of Furmonertinib in NSCLC with EGFR exon 20 insertions (20ins); 2021 ESMO, Abstract 1325 [2].
Piotrowsa Z et al.
, ECOG-ACRIN EA5162: A phase II study of high-dose osimertinib in NSCLC with EGFR exon 20 insertions; 2021 ASCO [3].
Y.
Shi et al.
, CNS Efficacy of AST2818 in Patients with T790M-Positive Advanced NSCLC: Data from a Phase I-II Dose-Expansion Study, 2020 WCLC, Abstract 3286