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晚期肺癌患者靶向治疗中，伏美替尼 vs 奥希替尼，哪个效果更好
在晚期肺癌患者的靶向治疗中，选择伏美替尼（furmonertinib）或奥希替尼（osimertinib）之间的比较需要综合考虑各自的疗效、安全性、适应症以及患者的具体病情。根据现有证据，这里将对这两种药物进行深入分析。
1. 药物简介
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奥希替尼（osimertinib）是一种第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），用于治疗携带敏感EGFR突变的非小细胞肺癌（NSCLC）患者。它能够有效靶向EGFR T790M突变，并已被广泛接受为一线治疗药物，尤其是在既往EGFR TKI治疗后出现获得性抗药性的患者中。
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伏美替尼（furmonertinib）同样也是一种第三代EGFR TKI，最近在临床试验中表现出了良好的疗效，尤其是在对其他EGFR TKI产生抗药性的患者中。从一些研究中得知，伏美替尼在控制疾病方面表现出了一定的优势，并且在处理EGFR T790M突变的患者中也展现了可观的效果。
2. 疗效比较
2.1. 奥希替尼的疗效
根据多项研究，奥希替尼显示出较高的整体响应率（ORR）和较长的无进展生存期（PFS）。例如，在一项多中心临床试验中，奥希替尼在作为一线治疗时的PFS可达18个月或更长，且对中枢神经系统转移的控制效果显著。此外，奥希替尼因其较好的耐受性，使其成为许多患者的首选药物。
在一项研究中，携带EGFR T790M突变的患者接受奥希替尼处理后，获得了明显的临床获益，进一步证实其在后线治疗中的有效性。然而，随着时间的推移，仍可能出现对奥希替尼的抗药性。
2.2. 伏美替尼的疗效
伏美替尼在临床试验中对于获得性抗药性患者同样显示了希望。近期的实证研究表明，在先前已经对奥希替尼产生抗药性的患者中，伏美替尼的使用，单药治疗达到的中位PFS为5.5个月，且在结合其他治疗时可取得更好的疗效。这表明伏美替尼可能成为耐药EGFR突变患者的合适选择。
在比较这两者的疗效时，有研究指出，伏美替尼在对抗其他靶向药物耐药的情况下增加了治疗的成功率。但目前数据较少，需进一步的前瞻性研究来确认其效果。
3. 不良反应比较
3.1. 奥希替尼的不良反应
尽管奥希替尼一般耐受性良好，但部分患者仍报告了副作用，包括皮疹、腹泻和QT间期延长等。严重不良事件的发生率较低，例如在一项研究中，约有13%的患者经历了与治疗相关的严重不良事件。
3.2. 伏美替尼的不良反应
伏美替尼在耐受性方面表现得相对较好，且在接受治疗的患者中，只有少数发生了高于2级的副作用，显示出良好的安全性。尽管如此，具体的不良反应数据仍然待完善。
4. 综合考虑与临床决策
选择哪种治疗方案不仅要考虑药物的疗效和耐受性，还需要综合患者的具体病情，例如突变类型、既往治疗经历，以及患者的整体健康状态. 对于经治疗后出现对其他EGFR TKI的抵抗的患者，伏美替尼可能是合适的替代选择。因此，医生会根据患者的具体情况、疾病进展和副作用管理来制定个体化治疗方案。
5. 结论
总体而言，奥希替尼在一线治疗EGFR突变肺癌方面仍然是标准治疗，并展现出良好的疗效和耐受性。伏美替尼则显示出在对既往EGFR TKI耐药患者上的潜力，特别是在后线治疗中。对于具体哪种药物效果更好，这取决于各个患者的具体情况和对治疗的反应，未来的研究有助于明确这两种药物的最佳适应证和疗效比较。
因此，临床医生应根据科学的证据和患者的个体特征，选择最合适的治疗策略。
References
1Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance.PubMed
Kai Fu, Fachao Xie, Fang Wang, et al.
J Hematol Oncol. 2022 Dec 8;15(1):173. doi: 10.1186/s13045-022-01391-4.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.
2Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.PubMed
Yi-Long Wu, Valentina Guarneri, Pei Jye Voon, et al.
Lancet Oncol. 2024 Aug;25(8):989-1002. doi: 10.1016/S1470-2045(24)00270-5.
BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).
3Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers.PubMed
Noura J Choudhury, Antonio Marra, Jane S Y Sui, et al.
J Thorac Oncol. 2023 Apr;18(4):463-475. doi: 10.1016/j.jtho.2022.11.022. Epub 2022 Dec 6.
INTRODUCTION: Preferred first-line treatment for patients with metastatic EGFR-mutant lung cancer is osimertinib, yet it is not known whether patient outcomes may be improved by identifying and intervening on molecular markers associated with therapeutic resistance. METHODS: All patients with metastatic EGFR-mutant lung cancer treated with first-line osimertinib at the Memorial Sloan Kettering Cancer Center (n = 327) were identified. Available pretreatment and postprogression tumor samples underwent targeted gene panel sequencing and mutational signature analysis using SigMA algorithm. Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meier method. RESULTS: Using multivariate analysis, baseline atypical EGFR (median PFS = 5.8 mo, p < 0.001) and concurrent TP53/RB1 alterations (median PFS = 10.5 mo, p = 0.015) were associated with shorter PFS on first-line osimertinib. Of 95 patients with postprogression biopsies, acquired resistance mechanisms were identified in 52% (off-target, n = 24; histologic transformation, n = 14; on-target, n = 12), with MET amplification (n = 9), small cell lung transformation (n = 7), and acquired EGFR amplification (n = 7), the most frequently identified mechanisms. Although there was no difference in postprogression survival on the basis of identified resistance (p = 0.07), patients with subsequent second-line therapy tailored to postprogression biopsy results had improved postprogression survival (hazard ratio = 0.09, p = 0.006). The paired postprogression tumors had higher tumor mutational burden (p = 0.008) and further dominant APOBEC mutational signatures (p = 0.07) compared with the pretreatment samples. CONCLUSIONS: Patients with EGFR-mutant lung cancer treated with first-line osimertinib have improved survival with treatment adaptation on the basis of identified mechanisms of resistance at time of progression using tissue-based genomic analysis. Further survival gains may be achieved using risk-based treatment adaptation of pretreatment genomic alterations.
4Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer.PubMed
Shang-Gin Wu, Jin-Yuan Shih
Mol Cancer. 2018 Feb 19;17(1):38. doi: 10.1186/s12943-018-0777-1.
Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs. EGFR TKIs improve response rates, time to progression, and overall survival. Unfortunately, patients with EGFR mutant lung cancer develop disease progression after a median of 10 to 14 months on EGFR TKI. Different mechanisms of acquired resistance to first-generation and second-generation EGFR TKIs have been reported. Optimal treatment for the various mechanisms of acquired resistance is not yet clearly defined, except for the T790M mutation. Repeated tissue biopsy is important to explore resistance mechanisms, but it has limitations and risks. Liquid biopsy is a valid alternative to tissue re-biopsy. Osimertinib has been approved for patients with T790M-positive NSCLC with acquired resistance to EGFR TKI. For other TKI-resistant mechanisms, combination therapy may be considered. In addition, the use of immunotherapy in lung cancer treatment has evolved rapidly. Understanding and clarifying the biology of the resistance mechanisms of EGFR-mutant NSCLC could guide future drug development, leading to more precise therapy and advances in treatment.
5Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy.PubMed
Yoshihisa Kobayashi, Tetsuya Mitsudomi
Cancer Sci. 2016 Sep;107(9):1179-86. doi: 10.1111/cas.12996. Epub 2016 Aug 9.
Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung. Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR-tyrosine kinase inhibitors (TKI), gefitinib, erlotinib or afatinib showed high objective response rates (ORR) of approximately 60%. Several studies suggested that Del19 might be more sensitive to EGFR-TKI than L858R. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%-50%. However, afatinib appeared to be especially effective for these tumors. Although Ins20s (except for insFQEA) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib (EGF816) is promising for the majority of them. For the further development of targeted therapy in all EGFR mutations, it is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations.
6Efficacy and safety of re-challenging 160 mg furmonertinib for advanced NSCLC after resistance to third-generation EGFR-TKIs targeted agents: A real-world study.PubMed
Rongbin Qi, Xinyu Fu, Yingying Yu, et al.
Lung Cancer. 2023 Oct;184:107346. doi: 10.1016/j.lungcan.2023.107346. Epub 2023 Aug 17.
BACKGROUND: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) show good selectivity for classical EGFR mutated and EGFR T790M mutated non-small cell lung cancer (NSCLC). However, resistance inevitably occurs to third-generation EGFR-TKI. This study describes the real-world characteristics, efficacy, and safety of treating post-progression NSCLC with 160 mg of furmonertinib (in combination with or without anti-angiogenic agents and chemotherapy) with third-generation EGFR-TKIs. METHODS: EGFR-mutated NSCLC patients with intracranial progression pattern cohort (IP cohort) or extracranial progression pattern cohort (EP cohort) were retrospectively analyzed following progression to third-generation EGFR-TKIs receiving furmonertinib 160 mg daily as second-line or later treatment in combination with or without anti-angiogenic agents and chemotherapy. RESULTS: Thirty-nine patients were included and categorized into two groups according to the progression pattern. Then, 22 patients in the IP cohort and 17 patients in the EP cohort, most of whom were in poor physical condition, were included and 84.6% had central nervous system metastases. In the IP cohort, the median PFS was 5.5 months (95% CI 4.67-8.72), and the median OS was 9.8 months (95% CI 7.25-11.20) for single-agent furmonertinib or combination therapy. In the EP cohort, the median PFS was 3.2 months (95% CI 2.18-4.70), and the median OS was 6.7 months (95% CI 4.99-8.75). Univariate analysis showed the association between the presence of a prior T790M mutation and a history of combined radiotherapy with longer PFS with furmonertinib (p = 0.048, p = 0.004). Overall, adverse events (AEs) of any grade occurred in 84.6% of patients (33/39), with the majority having grade 2 or lower AEs. CONCLUSION: Furmonertinib 160 mg is an optional regimen for patients with advanced NSCLC who develop resistance after treatment with third-generation EGFR-TKIs, especially those developing resistance due to the progression of intracranial lesions, with good efficacy and an acceptable safety profile that warrants further exploration.
7EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: From molecular mechanisms to clinical research.PubMed
Rui-Fang Dong, Miao-Lin Zhu, Ming-Ming Liu, et al.
Pharmacol Res. 2021 May;167:105583. doi: 10.1016/j.phrs.2021.105583. Epub 2021 Mar 26.
With the development of precision medicine, molecular targeted therapy has been widely used in the field of cancer, especially in non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a well-recognized and effective target for NSCLC therapies, targeted EGFR therapy with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has achieved ideal clinical efficacy in recent years. Unfortunately, resistance to EGFR-TKIs inevitably occurs due to various mechanisms after a period of therapy. EGFR mutations, such as T790M and C797S, are the most common mechanism of EGFR-TKI resistance. Here, we discuss the mechanisms of EGFR-TKIs resistance induced by secondary EGFR mutations, highlight the development of targeted drugs to overcome EGFR mutation-mediated resistance, and predict the promising directions for development of novel candidates.
8The study of primary and acquired resistance to first-line osimertinib to improve the outcome of EGFR-mutated advanced Non-small cell lung cancer patients: the challenge is open for new therapeutic strategies.PubMed
Alessandra Ferro, Gian Marco Marinato, Cristiana Mulargiu, et al.
Crit Rev Oncol Hematol. 2024 Apr;196:104295. doi: 10.1016/j.critrevonc.2024.104295. Epub 2024 Feb 20.
The development of targeted therapy in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients has radically changed their clinical perspectives. Current first-line standard treatment for advanced disease is commonly considered third-generation tyrosine kinase inhibitors (TKI), osimertinib. The study of primary and acquired resistance to front-line osimertinib is one of the main burning issues to further improve patients' outcome. Great heterogeneity has been depicted in terms of duration of clinical benefit and pattern of progression and this might be related to molecular factors including subtypes of EGFR mutations and concomitant genetic alterations. Acquired resistance can be categorized into two main classes: EGFR-dependent and EGFR-independent mechanisms and specific pattern of progression to first-line osimertinib have been demonstrated. The purpose of the manuscript is to provide a comprehensive overview of literature about molecular resistance mechanisms to first-line osimertinib, from a clinical perspective and therefore in relationship to emerging therapeutic approaches.
9Osimertinib retreatment for patients with advanced EGFR-mutated non-small cell lung cancer.PubMed
Kevin M Levine, Natalie F Uy, Ted A Gooley, et al.
Cancer Treat Res Commun. 2025 Oct 25;45:101026. doi: 10.1016/j.ctarc.2025.101026.
Resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a key challenge in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). Although retreatment with earlier-generation EGFR tyrosine kinase inhibitors has been studied, data on osimertinib rechallenge are limited. We conducted a single institution retrospective analysis of patients with EGFR-mutated NSCLC who were rechallenged with osimertinib following progression on prior osimertinib and interim systemic therapy, including chemotherapy. Seventeen patients met inclusion criteria, all with adenocarcinoma histology and either EGFR exon 19 deletions or L858R mutations. Median interval between osimertinib treatments was 10.5 months. Osimertinib retreatment resulted in a partial response in 18 % (3/17) and stable disease in 35 % of patients (6/17), for a disease control rate of 53 % (9/17). Median retreatment duration was 4.3 months, and median overall survival following retreatment initiation was 8.9 months. Among patients with central nervous system involvement, several experienced intracranial stability without additional radiation. Duration of initial osimertinib therapy did not strongly predict retreatment benefit. These findings suggest that osimertinib rechallenge may provide clinically meaningful disease control in a subset of patients, especially given its tolerability and oral formulation. Further research is needed to identify biomarkers of sensitivity and to optimize patient selection for osimertinib retreatment following interval chemotherapy.
10A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.PubMed
Lavinia Tan, Chris Brown, Antony Mersiades, et al.
Nat Commun. 2024 Feb 28;15(1):1823. doi: 10.1038/s41467-024-46008-1.
In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.
11COMPOSIT study: evaluating osimertinib combination with targeted therapies in EGFR-mutated non-small cell lung cancer.PubMed
Camille Mehlman, Aurelie Swalduz, Isabelle Monnet, et al.
Oncologist. 2025 Aug 4;30(8). doi: 10.1093/oncolo/oyae312.
INTRODUCTION: The emergence of diverse resistance mechanisms after osimertinib therapy, including on-target epidermal growth factor receptor (EGFR) mutations and off-target alterations, warrants investigation of novel therapeutics to overcome these challenges and improve patient outcomes. METHODS: COMPOSIT was a French, retrospective, multicenter, cohort study of the effectiveness and tolerability of osimertinib in combination with other targeted therapies in patients with advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) who harbored other oncogenic drivers as primary or acquired resistance mechanisms. Real-world progression-free survival (rwPFS), overall survival (OS), and objective response rate (ORR) were the primary endpoints. RESULTS: The study included 61 patients (63.9% women; median age, 61 years). Chemotherapy was administered to 26 patients (42.6%) before the combinations. The most frequently targeted resistance mechanisms were MET amplification (n = 40) and BRAF alterations (n = 11). Sixteen combinations of osimertinib with other targeted therapies were reported. Overall (except for 10 patients in clinical trials), median rwPFS and OS were 3.9 (95% CI, 2.9-5.2) and 9.8 months (95% CI, 6.8-14.8). Best ORR (n = 54) was 50% (95% CI, 33.0-72.8). In patients with MET amplification (n = 29), median rwPFS and OS were 4.9 (95% CI, 2.9-7.2) and 8.6 months (95% CI, 5.3-21.6). Grade ≥3 adverse events occurred in 15 patients (24.6%). No deaths were related to treatment. CONCLUSIONS: Combinations of osimertinib with other targeted therapies appeared to be feasible and safe and may offer clinical benefit to overcome resistance to osimertinib in EGFRm NSCLC, especially in patients with MET amplification.
12Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations.PubMed
Jiaqi Li, Mengqing Xie, Ruiying Zhao, et al.
Front Oncol. 2024 Mar 19;14:1357231. doi: 10.3389/fonc.2024.1357231. eCollection 2024.
BACKGROUND: For patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients. METHODS: We reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS). RESULTS: Of the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016). CONCLUSION: For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.
13Targeted and cytotoxic inhibitors used in the treatment of lung cancers.PubMed
Robert Roskoski
Pharmacol Res. 2024 Nov;209:107465. doi: 10.1016/j.phrs.2024.107465. Epub 2024 Oct 18.
Lung cancer is the leading cause of cancer deaths in the United States and the world. It is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the tumor-node-metastasis (TNM) cancer-staging classification system (Stages I/II/III/IV), the severity of neoplastic growth is characterized by the size of the tumor (T1 to T4), the extent of lymph node involvement (N0 to N3), and whether (M1) or not (M0) distant metastasis has occurred. Surgery is the treatment of choice for medically fit patients with Stage I/II NSCLC. Combination chemoradiotherapy and immune checkpoint inhibitor therapy are used across all NSCLC types. Oncogene-addicted tumors with sensitizing EGFR or BRAF mutations or activating ALK, ROS1 or NTRK translocations are treated with their cognate orally active small molecule protein kinase blockers. On the order of 20 % of NSCLCs bear activating mutations in EGFR and are treated with osimertinib and other kinase antagonists. SCLC, which accounts for approximately 15 % of lung cancer cases, is a deadly high-grade neuroendocrine carcinoma with a poor prognosis. Limited-stage SCLC is confined to one hemi-thorax and one radiation port and extensive-stage disease signifies those cancers that do not meet the criteria for limited-stage disease. Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen.
14Treatment Patterns and Clinical Outcomes in Patients With EGFR-Mutated Non-Small-Cell Lung Cancer After Progression on Osimertinib.PubMed
Nathaniel D Robinson, Maureen E Canavan, Peter L Zhan, et al.
Clin Lung Cancer. 2025 Jan;26(1):9-17.e3. doi: 10.1016/j.cllc.2024.09.006. Epub 2024 Sep 23.
INTRODUCTION: For patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) who progress on first-line osimertinib, the optimal second-line treatment regimen after progression is not known. We sought to assess practice patterns and evaluate the association between different therapies and survival in patients with EGFR-mutated NSCLC following progression on first-line osimertinib. METHODS: Retrospective cohort study of patients who received first-line treatment with osimertinib using a population-based, multicenter nationwide electronic health record-derived deidentified database. RESULTS: We identified 2373 patients who received first-line osimertinib. The majority (n = 2279) received osimertinib monotherapy. A total of 538 patients received first-line osimertinib and had second-line treatment data available. Second-line treatment regimens were varied: 65% (n = 348) included chemotherapy, 37% (n = 197) included an immune checkpoint inhibitor (ICI), and 44% (n = 234) included an EGFR tyrosine kinase inhibitor (TKI). We then analyzed the 333 patients with performance status 0-2 who received chemotherapy with osimertinib (n = 107, 32%) versus chemotherapy without osimertinib (n = 226, 68%). The continuation of osimertinib with chemotherapy was associated with superior progression-free survival (PFS; median: 10.1 versus 5.9 months, Hazard Ratio [HR]: 0.48, 95% Confidence Interval [CI]: [0.34, 0.68], P < .001) and overall survival (OS; median: 17.0 versus 12.8 months, HR: 0.64, 95% CI: [0.44, 0.93], P = .018) compared to other chemotherapy approaches without osimertinib. This effect was most pronounced in patients with an EGFR exon 19 deletion. CONCLUSIONS: Following progression on osimertinib, a wide variety of treatment regimens were used. The continuation of osimertinib with chemotherapy in the second line was associated with increased PFS and OS.
15MAP2K1 K57N Conferred an Acquired Resistance to Furmonertinib, Dabrafenib and Trametinib Combined Therapy in Advanced Lung Adenocarcinoma with EGFR Mutation and BRAF V600E.PubMed
Xiang Tan, Zuotao Wu, Mingwu Chen
Onco Targets Ther. 2024 Apr 9;17:307-312. doi: 10.2147/OTT.S454902. eCollection 2024.
Previous case reports have demonstrated the effectiveness of combination therapy involving EGFR TKI, inhibitor dabrafenib, and inhibitor trametinib in metastatic non-small-cell lung cancer (NSCLC) patients with acquired V600E and mutations. However, the current literature does not provide any reports on the presence of resistant mutations in response to the administration of three-drug combination therapy. Exploring the resistance mechanism of targeted therapy is helpful to optimize the subsequent treatment strategy of patients. Herein, we report a case of a patient with advanced positive lung adenocarcinoma harboring an acquired V600E mutation who responded to the combination of furmonertinib, dabrafenib, and trametinib therapy. Unexpectedly, a K57N acquired mutation was identified by NGS (Next-generation sequencing) analysis of re-biopsy tumor tissue after the patient was resistant to three-drug therapy. As far as we know, this is the first report demonstrating that the efficacy of using combination of furmonertinib and / inhibitors and the K57N mutation serves as a resistant mechanism to the three-drug therapy. This novel finding not only revealed a new resistant mutation but also had important implications for the identification of effective patients to EGFR/BRAF/MEK combination therapy.
16Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options.PubMed
Georgia Gomatou, Nikolaos Syrigos, Elias Kotteas
Cancers (Basel). 2023 Jan 30;15(3):841. doi: 10.3390/cancers15030841.
The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.
17Real-World Prevalence, Treatment Patterns, and Economic Impact of EGFR- and ALK-Targeted Therapies in Non-Small Cell Lung Cancer: A Nationwide Analysis from Greece.PubMed
George Gourzoulidis, Catherine Kastanioti, George Mavridoglou, et al.
Curr Oncol. 2025 Sep 27;32(10):542. doi: 10.3390/curroncol32100542.
OBJECTIVES: To determine the prescribing prevalence of epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients in Greece and examine patterns of first-line tyrosine kinase inhibitor (TKI) utilization and associated treatment costs using nationwide real-world data. METHODS: A retrospective analysis of the national e-prescription database was performed, identifying patients initiating first-line treatment (FLT) for EGFR- or ALK-positive NSCLC between 1 January 2020 and 31 December 2022. Demographic characteristics, prescribing prevalence data, drug utilization patterns, total annual drug expenditures, and per patient treatment costs were assessed. All statistical analyses were performed using the statistical software SPSS-v.29. RESULTS: Overall, 1188 EGFR-positive (mean age of 70.93 ± 11.6) and 246 (mean age of 64.26 ± 12.6) ALK-positive NSCLC patients initiated FLT during the three-year study period. EGFR mutations were slightly more common in females (53%), peaking in the 70-79 age group (35%). ALK mutations were also more common among females (52%), particularly within the 60-79 age group. In EGFR-positive patients, osimertinib usage markedly increased from 41% in 2020 to 63% in 2022, primarily displacing afatinib (from 32% to 22%) and erlotinib (from 24% to 14%), with gefitinib prescriptions falling below 2%. Among ALK-positive patients, crizotinib utilization declined significantly from 60% to 16%, whereas alectinib increased to 59% by 2022. Annual EGFR-related total drug expenditures remained stable (€11.5 million in 2020 vs. €11.9 million in 2022), driven primarily by increasing osimertinib usage. Similarly, ALK-related annual drug expenditures showed stability, with costs predominantly attributed to rising alectinib utilization. CONCLUSIONS: This nationwide analysis highlights the rapid adoption of second- and third-generation TKIs for EGFR- and ALK-positive NSCLC in Greece, reflecting evolving clinical practice patterns. Although the target patient populations are relatively small, the associated economic burden is considerable. To ensure long-term sustainability of the Greek healthcare system, policymakers should critically assess the cost-effectiveness of these innovative therapies and align resource allocation with value-based care principles.
18Efficacy and safety of metronomic oral vinorelbine and its combination therapy as second- and later-line regimens for advanced non-small-cell lung cancer: a retrospective analysis.PubMed
ShiJie Chen, ZhiYong He, MeiFang Li, et al.
Clin Transl Oncol. 2024 Dec;26(12):3202-3210. doi: 10.1007/s12094-024-03543-z. Epub 2024 Jun 9.
OBJECTIVE: This retrospective analysis aimed to evaluate the efficacy and adverse reactions of metronomic oral vinorelbine and its combination therapy as second- and later-line regimens for advanced non-small-cell lung cancer (NSCLC). METHODS: NSCLC patients undergoing metronomic oral vinorelbine as second- and later-line regimens in Fujian Cancer Hospital from October 2018 to October 2022 were enrolled, and patients' demographic and clinical characteristics were collected. The efficacy and safety of metronomic oral vinorelbine monotherapy and its combination therapy regimens were compared. RESULTS: Of 57 study subjects, 63.2% received third- and later-line therapy, with median progression-free survival (mPFS) of 4 months, overall response rate (ORR) of 10.5%, and disease control rate (DCR) of 80.7%. The incidence of therapy-related adverse events was 42.1%, and there was only one case presenting grades 3 and 4 adverse events (1.8%). Among driver gene-negative participants, vinorelbine combination therapy regimens achieved longer mPFS (4.6 vs. 1.2 months, hazards ratio = 0.11, P < 0.0001) and comparable toxicity in relative to metronomic oral vinorelbine, and metronomic oral vinorelbine combined with immune checkpoint inhibitors showed the highest response, with mPFS of 5.6 months (95% CI 4.8 to 6.4 months), ORR of 25%, and DCR of 81.3%. Among participants with gradual resistance to osimertinib, continuing osimertinib in combination with metronomic oral vinorelbine achieved mPFS of 6.3 months (95% CI 0.1 to 12.5 months) and DCR of 86.7%. CONCLUSION: Metronomic oral vinorelbine and its combination therapy regimens are favorable options as second- and later-line therapy for advanced NSCLC patients, with acceptable efficacy and tolerable toxicity. Vinorelbine combination therapy regimens show higher efficacy and comparable toxicity in relative to metronomic oral vinorelbine, and metronomic oral vinorelbine may have a synergistic effect with immunotherapy and EGFR-TKI targeted therapy.
19EGFR plus MET Targeted Therapies for Overcoming Treatment Resistance in EGFR-Mutant Non-Small Cell Lung Cancer: A Case Report.PubMed
Maria F Martínez-Hernandez, Luis Lara-Mejía, Carlos Izquierdo-Tolosa, et al.
Oncol Res Treat. 2024;47(12):616-623. doi: 10.1159/000541496. Epub 2024 Sep 18.
INTRODUCTION: Oncogenic-addicted non-small cell lung cancer (NSCLC) has emerged as the most prevalent form of lung cancer, presenting a dynamic landscape in treatment modalities. Among these, epidermal growth factor receptor (EGFR)-mutant NSCLC remains the predominant oncogenic mutation, particularly prevalent in regions such as Asia and Latin America. CASE PRESENTATION: This case study highlights the experience of a woman diagnosed with EGFR-sensitive (del exon 19) mutant NSCLC who demonstrated an extended duration of response to third-generation EGFR-tyrosine kinase inhibitor (TKI) therapy. Upon disease progression, detection of MET gene amplification prompted the addition of a selective MET inhibitor to the existing EGFR-TKI regimen, resulting in a complete response for the patient. DISCUSSION: The molecular heterogeneity of this condition has significantly increased in complexity over recent years, marked by the identification of baseline co-alterations and development of a broad spectrum of resistance mechanisms post-EGFR-TKI therapy. This complexity poses a substantial challenge to clinicians. Despite the rapid advancement of targeted therapies and the implementation of treatment escalation through combination strategies, there remains an ongoing debate regarding which patients would benefit most from combination therapies, both in the initial treatment phase and in the setting of disease progression, particularly when off-target resistance mechanisms or co-alterations are identified.
20Recent advances in targeted small-molecule inhibitor therapy for non-small-cell lung cancer-An update.PubMed
Shubham Atal, Pravin Asokan, Ratinder Jhaj
J Clin Pharm Ther. 2020 Jun;45(3):580-584. doi: 10.1111/jcpt.13121. Epub 2020 Feb 18.
WHAT IS KNOWN AND OBJECTIVE: Targeted small molecule EGFR Tyrosine Kinase Inhibitors (TKI's) and the Anaplastic Lymphoma Kinase (ALK) inhibitors have been promising tools for advanced non-small-cell lung cancers (NSCLCs). However, tumours tend to develop subsequent mutations, rendering them drug-resistant. Hence, alternative pathways of therapy need to be explored. COMMENT: Gefitinib, erlotinib and afatinib, once considered as alternatives to platinum-based cytotoxic chemotherapy, have been rendered ineffective in patients with NSCLCs harbouring T790M mutation. Osimertinib is effective in T790M-mutant cancers, but not against those exhibiting the subsequent C797S mutation. ALK gene alterations have rendered tumours insensitive to crizotinib. However, lorlatinib and brigatinib are effective in tumours showing ALK+ mutations. Drugs acting through alternative pathways like the PD-1 pathway, BRAF, VEGFR, EGFR antibodies and NTRK inhibition have been showing promising results. WHAT IS NEW AND CONCLUSIONS: Osimertinib, brigatinib and allosteric C797S EGFR inhibitors like AI1045, BRAF inhibitors like LXH254 under trials and entrictinib, a recently approved NTRK inhibitor, have all shown improved progression-free survival compared with earlier generations of small molecule inhibitors for NSCLCs.