At present, EGFR-TKI has become the standard treatment drug for EGFR mutation-positive advanced non-small cell lung cancer. However, compared with chemotherapy, EGFR-TKI has its own unique adverse reactions, and the adverse reactions of EGFR-TKI are also different. Therefore, ful

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In the era of precision treatment, the successful application of targeted drugs has brought longer survival time to tumor patients, and also posed new challenges to the safety of clinical medication. At present, EGFR-TKI has become the standard treatment drug for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). However, compared with chemotherapy, EGFR-TKI has its own unique adverse reactions, and the adverse reactions of EGFR-TKI are also different. Therefore, fully understanding the adverse reactions of EGFR-TKI will help to provide more practical intervention measures for clinical practice, improve drug efficacy, and improve patients' quality of life.

Understanding the safety profile of EGFR-TKI can effectively improve patient treatment compliance and improve prognosis

Currently, seven EGFR-TKIs (gefitinib, erlotinib, icotinib, afatinib, dacomitinib, osimertinib, and ametinib) have been approved for first-line treatment of advanced NSCLC with EGFR-sensitive mutations^[1]. Among them, the key studies of first-line treatment of third-generation EGFR-TKI - FLAURA study, AENEAS study and FURLONG study [2-4] confirmed that osimertinib, ametinib and fumetinib are more effective than first-generation EGFR-TKI and can significantly extend the median progression-free survival (PFS) of patients. Therefore, third-generation EGFR-TKI is currently the new standard for first-line treatment. In addition, for patients with secondary T790M mutation after resistance to first/second generation EGFR-TKI, my country has three third-generation EGFR-TKI (osimertinib, ametinib, fumetinib) approved for second-line treatment ^[1].

Compared with chemotherapy, EGFR-TKI has its own unique adverse reactions, such as rash, diarrhea, paronychia, oral mucositis, liver damage, interstitial lung disease (ILD), etc. The types and incidence of the above common adverse reactions are also different between different EGFR-TKIs^[5]. Therefore, only by properly managing the adverse reactions caused by EGFR-TKIs, especially the adverse reactions of third-generation EGFR-TKIs, can we effectively improve patients' treatment compliance and quality of life, and maximize patients' treatment benefits.

There are differences in the safety profile of the third generation EGFR-TKI, and clinical medication needs to be fully considered.

EGFR mutation in the first-line treatment of advanced NSCLC, FLAURA Chinese cohort study ^{[2] The safety data of} shows that the common adverse reactions of osimertinib are diarrhea (24%) and rash/acne (37%), but most of them are mild adverse reactions; the safety data of in the AENEAS study ^{[3] The safety data of} show that the common adverse reactions of ametinib are ALT elevation (29.4%), ASL elevation (29.9%), rash (23.4%), diarrhea (16.4%), etc. The incidence rates of grade ≥3 ALT elevation and AST elevation were 2.8% and 1.4% respectively; FURLONG study ^{[4] The safety data of} show that common adverse reactions of fumetinib are increased alanine aminotransferase ALT (28%), aspartate aminotransferase AST increase (25%), diarrhea (25%), etc. The incidence rates of grade ≥3 ALT increase, AST increase and diarrhea are 1%, 1% and 2%.

In the second-line treatment of advanced NSCLC with EGFR mutations, the safety data of AURA3 study ^[6] show that the common adverse reactions of osimertinib are also mainly diarrhea and rash, and treatment-related adverse reactions of grade ≥3 (TARE) incidence rate is 9%, and the incidence rate of grade ≥3 diarrhea and rash is ≤1%; the safety data of APOLLO study ^[7] show that the common adverse reactions of ametinib are increased blood creatine phosphokinase (CK) and elevated aminotransferase (ALT). and AST), ≥ grade 3 TRAE The incidence rate was 16.4%, and the incidence rates of grade ≥3 CK elevation and transaminase elevation were 7.0% and 1.6% respectively; the safety data of the phase II single-arm study ^[8] of fumetinib's second-line indication showed that the common adverse reactions of fumetinib were mainly QT interval prolongation and AST and ALT elevation. The incidence rate of grade ≥3 TRAE was 11%, and the incidence rate of grade ≥3 transaminase elevation was 2%.

According to the safety data of the above-mentioned clinical studies, it can be found that the overall safety of the third-generation EGFR-TKI osimertinib, ametinib and fumetinib is good, but there are differences in common adverse reactions. Common adverse reactions of osimertinib are mainly diarrhea and rash/acne, which require early monitoring and management through medication consultation and follow-up. However, the main adverse reactions of ametinib and fumetinib are increased AST/ALT, which may be related to drug-induced liver injury , and the patient's liver function needs to be closely monitored.

Real-world evidence that the third-generation EGFR-TKI osimertinib has good adverse reactions and safety

FLOURISH study ^[9] is a Chinese real-world study of osimertinib in the first-line treatment of advanced NSCLC with EGFR-sensitive mutations. A total of 500 untreated patients were enrolled. The 2022 ESMO Congress announced the safety data of the FLOURISH study. The results showed that 10.4% of patients developed TRAE after first-line treatment with osimertinib, of which the incidence rate of grade ≥3 was only 2.1%, confirming the good safety and tolerability of osimertinib in the real world in China. Also worthy of attention is the large-scale real-world study ASTRIS^[10] of osimertinib in the treatment of patients with advanced NSCLC with EGFR T790M mutations. A total of 3,015 patients were enrolled globally, of which 69% were Asian patients. The 2022 WCLC conference announced the safety data of the Chinese subgroup. The results showed that the incidence of adverse events leading to treatment discontinuation with osimertinib was 7.0%, the incidence of treatment-related serious AEs was 3.9%, the incidence of interstitial lung disease (ILD)/ pneumonia-like events was only 0.2%, and the incidence of QT interval prolongation events was 4.4%. The overall safety was good, and no new safety signals were observed. Data from the Chinese subgroup of the ASTRIS study suggest that in real-world situations, osimertinib still shows good safety and tolerability that are highly consistent with clinical studies and the overall ASTRIS population.

In addition, we are very much looking forward to the release of real-world research evidence of third-generation EGFR-TKIs such as ametinib and fumetinib in the future, which will bring more safety data to third-generation EGFR-TKIs for first-line treatment of EGFR-sensitive mutations and second-line treatment of advanced NSCLC with T790M mutations.

Summary and Outlook

It can be found from the published data that there are differences in the safety profiles of the currently clinically approved third-generation EGFR-TKIs, which are mainly reflected in different common adverse reactions. The common adverse reactions of osimertinib are mainly diarrhea and rash/acne, while the main adverse reactions of ametinib and fumetinib are increased AST/ALT. Therefore, when selecting treatment options, clinical workers should start from the evidence of evidence-based medicine and fully consider the patient's individual situation and drug safety profile to minimize the adverse reactions caused by EGFR-TKI, thereby improving the patient's treatment compliance and quality of life.

References:

[1]. Chinese Society of Clinical Oncology (CSCO) Diagnosis and Treatment Guidelines for Non-Small Cell Lung Cancer 2022.

[2].Cheng Y, He Y, Li W, et al. Target Oncol. 2021 Mar;16(2):165-176.

[3].Lu S, Dong X, Jian H, et al. J Clin Oncol. 2022 Sep 20;40(27):3162-3171.

[4].Shi Y, Chen G, Wang X, et al. Lancet Respir Med. 2022 Nov;10(11):1019-1028.

[5].Hu Jie, Lin Lizhu, Luo Xiaoqun, et al. Expert consensus on the management of adverse reactions of EGFR-TKI[J]. Chinese Journal of Lung Cancer, 2019(2):25.

[6].Papadimitrakopoulou V A, Mok T S, Han J Y, et al. Annals of Oncology, 2020, 31(11): 1536-1544.

[7].Lu S, Wang Q, Zhang G, et al. J Thorac Oncol. 2022 Mar;17(3):411-422.

[8].Shi Y, Hu X, Zhang S, et al. Lancet Respir Med. 2021 Aug;9(8):829-839.

[9].Jianying Zhou, Jianya Zhou, Jing Zheng, et al. NSCLC Patients in China: Interim Analysis of FLOURISH Study. 2022ESMO 1123P.

[10].Marinis F, Wu Y L, de Castro Jr G, et al. Future Oncology, 2019, 15(26): 3003-3014.

[11].Zhou Q, et al. ASTRIS China: A Real-world Study of Osimertinib in Patients with EGFR T790M Positive Non-small-cell Lung Cancer (NSCLC) [J]. 2022 WCLC. EP08.02-064.

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