Differential Responses to Targeted Therapies in Non-Small Cell Lung Cancer: A Comparative Analysis of Outcomes in Patients with Single EGFR Mutation and Concurrent Gene Alterations.

No consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. In this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150mg/day for 3months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS). Twenty patients were enrolled in this study. The median age was 63years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8-63.2), the overall RR was 55.0%, and the median PFS was 10.7months in the intention-to-treat (ITT) population. Grade 3-4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%). The primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment. UMIN ID: 000013125.

Background:In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients.Methods:The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients (N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up.Discussion:Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice.Trial registrationJapan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

1323 - Study of the Safety and Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in 97 Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

BackgroundIn the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations.MethodsWe enrolled 1,556 patients with EGFR-mutated stage IIIc–IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups.ResultsAfter PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3–24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3–12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38–0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1–54.0) vs. 34.3 months (95% CI: 30.6–38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58–1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups.ConclusionsIn real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

This study aimed to evaluate the treatment outcomes of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy alone or in combination with locoregional brain therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with brain metastases. A retrospective study involving 72 advanced EGFR-mutant NSCLC patients with brain metastases at the Vietnam National Cancer Hospital were conducted. Patients were divided into 2 groups: EGFR-TKI (erlotinib) monotherapy and EGFR-TKI combined with locoregional therapy (γ knife surgery - GKS or whole-brain radiation therapy). Evaluation criteria included clinical and laboratory characteristics, central nervous system (CNS) progression time, progression-free survival (PFS), overall survival (OS), T790M mutation rate, and adverse events. Epidermal growth factor receptor tyrosine kinase inhibitor monotherapy patients had better performance status (PS), fewer CNS symptoms, and significantly fewer brain metastases (p < 0.05). Median PFS and OS were 11 and 25 months, respectively, in both groups. Patients with PS 0-1 had longer median PFS (15 months) than those with PS 2 (7 months) (p = 0.039). Exon 19 deletion patients in both groups had longer median OS (26 months) than those with L858R exon 21 (15 months) (p = 0.023). Patients with T790M mutation who received osimertinib after progression had longer median OS (41 months vs. 23 months, p = 0.0001). Median time to CNS progression was 13.9 months (48 patients). Longer time to CNS progression correlated with longer OS (R2 = 0.89). Epidermal growth factor receptor tyrosine kinase inhibitor therapy, with or without locoregional therapy, is effective for advanced EGFR-mutant NSCLC patients with brain metastases. Exon 19 deletion patients had better prognosis.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, routine clinical practice is different between countries/institutions.Patients and methodsThe REFLECT study (NCT04031898) is a retrospective medical chart review that explored real-life treatment and outcomes of EGFRm NSCLC patients receiving first-line (1L) first-/second-generation (1G/2G) EGFR TKIs in 8 countries. This study included adult patients with documented advanced/metastatic EGFRm NSCLC with 1L 1G/2G EGFR TKIs initiated between Jan 2015 – Jun 2018. We reviewed data on clinical characteristics, treatments, EGFR/T790M testing patterns, and survival outcomes. Here, we report data from 120 medical charts in 3 study sites from Slovenia.ResultsThe Slovenian cohort (median age 70 years, 74% females) received 37% erlotinib, 32% afatinib, 31% gefitinib. At the time of data collection, 94 (78%) discontinuations of 1L TKI, and 89 (74%) progression events on 1L treatment were reported. Among patients progressing on 1L, 73 (82%) were tested for T790M mutation yielding 50 (68%) positive results, and 62 (85%) received 2L treatment. 82% of patients received osimertinib. Attrition rate between 1L and 2L was 10%. The median (95% CI) real-world progression free survival on 1L EGFR TKIs was 15.6 (12.6, 19.2) months; median overall survival (95% CI) was 28.9 (25.0, 34.3) months.ConclusionsThis real-world study provides valuable information about 1G/2G EGFR TKIs treatment outcomes and attrition rates in Slovenian EGFRm NSCLC patients. The reduced attrition rate and improved survival outcomes emphasize the importance of 1L treatment decision.

The sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) remains a matter of controversy. This cohort study analyzed the overall survival (OS) and progression-free survival (PFS) of afatinib compared with erlotinib and gefitinib first-line. EGFRm+, advanced NSCLC patients treated with either afatinib, erlotinib or gefitinib were retrospectively analyzed. A total of 107 patients were included. There was no statistically significant difference in PFS among the 3 groups. In the ≥ 60 years age group, the afatinib group had longer survival compared to the gefitinib group (p = 0.01). Median OS were 19.1, 22.9, and 35.6 months for gefitinib, erlotinib, and afatinib groups, respectively, with statistical significance between the gefitinib and afatinib groups (p = 0.009). Patients on afatinib also had longer median OS than erlotinib and gefitinib pooled together (35.5 versus 21.4 months; hazard ratio = 0.54, p = 0.016), despite similar median PFS. In conclusion, afatinib is a better choice compared to gefitinib or erlotinib for EGFRm+ patients. The OS obtained with afatinib is just 3 months shorter than osimertinib in the FLAURA trial. Direct comparison studies with osimertinib are still needed to determine optimal sequencing.

The sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) remains a matter of controversy. This cohort study analyzed the overall survival (OS) and progression-free survival (PFS) of afatinib compared with erlotinib and gefitinib first-line. EGFRm+, advanced NSCLC patients treated with either afatinib, erlotinib or gefitinib were retrospectively analyzed. A total of 107 patients were included. There was no statistically significant difference in PFS among the 3 groups. In the ≥ 60 years age group, the afatinib group had longer survival compared to the gefitinib group (p = 0.01). Median OS were 19.1, 22.9, and 35.6 months for gefitinib, erlotinib, and afatinib groups, respectively, with statistical significance between the gefitinib and afatinib groups (p = 0.009). Patients on afatinib also had longer median OS than erlotinib and gefitinib pooled together (35.5 versus 21.4 months; hazard ratio = 0.54, p = 0.016), despite similar median PFS. In conclusion, afatinib is a better choice compared to gefitinib or erlotinib for EGFRm+ patients. The OS obtained with afatinib is just 3 months shorter than osimertinib in the FLAURA trial. Direct comparison studies with osimertinib are still needed to determine optimal sequencing.

Successful treatment with afatinib after grade 3 hepatotoxicity induced by both gefitinib and erlotinib in EGFR mutation-positive non-small cell lung cancer

ObjectiveTo review and summarize the characteristics of the tumor immune microenvironment (TIME) in EGFR-mutated non-small cell lung cancer (NSCLC) after EGFR-TKI treatment and its role in TKI resistance.BackgroundLung cancer is one of the most commonly diagnosed cancer and the leading cause of death from cancer in both men and women around the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered a first-line treatment for EGFR-mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median progression-free survival (PFS) of 9–14 months. As immunotherapy has developed, it has become apparent that interactions between the TIME and tumor cells also affect EGFR-TKI treatment. The TIME comprises a variety of components but previous studies of the TIME following EGFR-TKI therapy of NSCLC are inconsistent. Here, we reviewed the characteristics of the TIME in NSCLC after EGFR-TKI treatment and its role in TKI resistance.MethodsPubMed, Embase, and Web of Science were searched to July 1, 2021 with the following key words: “NSCLC”, “EGFR”, and “immunotherapy”.ConclusionsThe TIME of EGFR-mutated NSCLC is different from that of non-mutated NSCLC, an explanation for EGFR-mutated NSCLC displaying a poor response to ICIs. The TIME of EGFR-mutated NSCLC also changes during treatment with EGFR-TKIs. The TIME in EGFR-TKI-resistant lung cancer can be summarized as follows: (I) compared with EGFR-TKI-sensitive tumors, EGFR-TKI-resistant tumors have a greater number of immunosuppressive cells and fewer immune-activated cells, while the tumor microenvironment is in an immunosuppressive state; (II) tumor cells and immunosuppressive cells secrete multiple negative immune regulatory factors, inhibit the recognition and presentation of tumor antigens and the antitumor effect of immune cells, resulting in immune escape; 3.EGFR-TKI-resistant tumors promote EMT. These three characteristics interact, resulting in a regulatory signaling network, which together leads to EGFR-TKI resistance.

Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients?

BackgroundWhile perioperative immunotherapy and adjuvant targeted therapy have improved outcomes for advanced non-small cell lung cancer (NSCLC), evidence on preoperative targeted strategies remains limited. This study retrospectively evaluated the efficacy and safety of neoadjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy with or without chemotherapy in resectable EGFR-mutant NSCLC.MethodsConsecutive patients with EGFR-mutant NSCLC undergoing preoperative EGFR-TKI monotherapy or EGFR-TKI plus platinum-based chemotherapy followed by surgical resection were identified from three Chinese thoracic surgery prospectively maintained databases (2010–2023) from Peking University Cancer Hospital, Sun Yat-sen University Cancer Center, and The Affiliated Hospital of Putian University. Primary endpoints included major pathological response (MPR: ≤10% viable tumor) and pathological complete response (pCR). Safety, recurrence-free survival (RFS), and perioperative outcomes were secondary endpoints.ResultsA total of 50 eligible patients were identified, including 29 females (58%) and 21 males (42%). The age range was 38 to 75 years, with an average age of 60 years. Among them, 22 patients (44%) were staged as cII, and 28 patients (56%) were staged as cIII. The EGFR mutations were found in 25 patients (50%) with exon 19 deletions, 21 patients (42%) with exon 21 L858R mutations, and 4 patients (8%) with other mutation types. Sixteen patients (32%) received first-generation TKIs, and 31 patients (62%) received third- generation TKIs. Chemotherapy mainly consisted of pemetrexed combined with carboplatin in 90% of cases. During neoadjuvant therapy, 6% of patients experienced grade 3 or higher adverse events (AEs), all in the combination therapy group. The overall objective response rate (ORR) was 64% (32/50), and 30 patients (60%) experienced a downstage in disease after treatment. The R0 resection rate was 96% (48/50), and 90% underwent video-assisted thoracoscopic surgery (VATS). Seven patients (14%) achieved pCR, and 18 patients (36%) achieved MPR postoperatively. Postoperative MPR and pCR rates were 36.0% (18/50) and 14.0% (7/50), respectively, with higher pCR in the combination group (20% vs. 5%; P=0.22). R0 resection was achieved in 96% (48/50). The overall 3-year RFS rates were 51.3% (53.4% combination vs. 46.7% monotherapy; P=0.42).ConclusionsNeoadjuvant EGFR-TKI therapy combined with chemotherapy demonstrated promising pathological responses and perioperative safety, supporting its feasibility in resectable EGFR-mutant NSCLC.

ObjectiveTo evaluate the risk of cardiovascular adverse events associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer (NSCLC).DesignSystematic review and network meta-analysis.Data sourcesPubMed, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and three clinical trial registries, from inception to 20 November 2024.Study selectionRandomised controlled trials comparing EGFR tyrosine kinase inhibitor monotherapy with placebo or other treatments in patients with EGFR-mutated NSCLC.Data extraction and synthesisPairs of reviewers extracted data and assessed risk of bias. A random effects network meta-analysis using a frequentist approach compared adverse drug reactions across different treatments. Certainty of evidence was evaluated using the confidence in network meta-analysis approach. Pairwise meta-analyses were done to compare the three generations of EGFR tyrosine kinase inhibitors.ResultsThe network meta-analysis comprised 89 randomised controlled trials involving 29 813 participants, mean follow-up 2.18 years. Compared with placebo, both first generation (odds ratio 1.51, 95% confidence interval 1.01 to 2.26; high certainty; pooled incidence 3.2%) and third generation EGFR tyrosine kinase inhibitors (2.18, 1.46 to 3.27; high certainty; 9.5%) were associated with increased risks of cardiac adverse events. Among third generation inhibitors, osimertinib (2.53, 1.53 to 4.19; high certainty; 8.9%) and lazertinib (2.84, 1.17 to 6.91; moderate certainty; 2.7%) were associated with cardiac adverse events. Combined therapies, such as antiangiogenesis with erlotinib or gefitinib, were associated with vascular adverse events (high certainty), whereas antiangiogenesis with osimertinib was associated with cardiovascular adverse events (moderate to high certainty). Also, the risk of arrhythmias was significantly higher with third generation inhibitors (3.26, 1.83 to 5.81; high certainty; 7.3%), such as osimertinib alone (3.35, 1.75 to 6.40; high certainty; 6.2%) and in combination with antiangiogenesis. Almonertinib was associated with vascular toxicity. In pairwise meta-analysis, third generation inhibitors were associated with higher risks of any grade and grade ≥3 cardiovascular adverse events compared with first generation inhibitors.ConclusionsIn patients with EGFR-mutated NSCLC, first and third generation EGFR tyrosine kinase inhibitors, as well as combination therapies with antiangiogenesis, were associated with increased risks of cardiovascular adverse events. Risks were significantly higher with third generation compared with first generation inhibitors.Systematic review registrationPROSPERO CRD42023433003.