EGFR-TKI Monotherapy Research Articles

Genomic characteristics of PD-L1-Induced resistance to EGFR-TKIs in lung adenocarcinoma.

The co-occurrence of PD-L1 positivity and EGFR mutations in advanced NSCLC often limits EGFR-TKIs effectiveness, with unclear mechanisms. We analyzed 103 treatment-naive EGFR-mutant LUAD patients from three centers, assessing PD-L1 expression and performing NGS analysis. SMO mutations and MET amplification were significantly higher in the PD-L1 ≥ 1% group versus PD-L1 < 1% group (SMO: 8% vs. 0%, p = 0.048; MET: 18% vs. 7%, p = 0.023). The DNA Damage Response and Repair (DDR) pathogenic deficiency mutations, along with biological processes and signaling pathways related to DNA recombination, cell cycle transition and abnormal phosphorylation, were more prevalent in the PD-L1 ≥ 1% group. PIK3CA and RARA clonal alterations were more common in PD-L1 < 1% group, while TP53 clonal mutations predominated in PD-L1 ≥ 1% group. Retrospective analysis showed EGFR-TKIs plus chemotherapy extended median PFS by 9.8 months, potentially overcoming EGFR-TKI monotherapy resistance. This study elucidates the genomic characteristics of PD-L1-induced resistance to EGFR-TKIs. For patients with concurrent mutations in EGFR and PD-L1 expression, a first-line treatment strategy combining EGFR-TKIs with chemotherapy may offer a more effective alternative.

In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data

BackgroundThere is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate.MethodsWe initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs).Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021.ResultsThe bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69–0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61–0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188).ConclusionsResearch on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

Molecular heterogeneity and treatment outcome of EGFR exon 20 insertion mutations in Chinese patients with advanced non-small cell lung cancer: insights from a large-scale real-world study

IntroductionThis retrospective study aimed to investigate treatment patterns and outcomes in patients with NSCLC harboring EGFR20ins in China. EGFR20ins mutations are associated with poor responses to EGFR-TKIs, and limited real-world data exist regarding the efficacy of various treatment modalities.MethodsIn this retrospective, single-center study, treatment outcomes, including PFS and ORR, were evaluated for different treatment regimens based on imaging assessments. The impact of mutation heterogeneity on treatment efficacy was also explored.ResultsData from 302 patients diagnosed with NSCLC with EGFR20ins were analyzed. EGFR-TKI monotherapy demonstrated suboptimal PFS compared to platinum-based chemotherapy in the first-line setting (3.00 m vs. 6.83 m, HR = 3.674, 95%CI = 2.48–5.44, p < 0.001). Platinum plus pemetrexed plus bevacizumab combination therapy showed improved PFS and ORR compared to platinum plus pemetrexed (7.50m vs. 5.43 m, HR = 0.593, 95%CI = 0.383–0.918, p = 0.019). In later-line treatments, monotherapy with EGFR-TKIs or ICIs exhibited suboptimal efficacy. The specific EGFR20ins subtype, A763_Y764insFQEA, showed favorable responses to EGFR-TKIs in real-world settings.ConclusionsThis large-scale real-world study provides valuable insights into the treatment patterns and outcomes of NSCLC patients with EGFR20ins mutations in China. These findings contribute to the understanding of EGFR20ins treatment and provide real-world benchmark for future clinical trials and drug development.

Cutaneous adverse event profile of epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung cancer: A meta-analysis of phase 3 randomized controlled trials.

e20049 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the frontline treatment of choice for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, EGFR-TKIs are associated with unique and dramatic dermatologic side effects that negatively impact patients’ quality of life, potentially resulting in poor adherence, including dose reductions or premature treatment cessation. Thus, it is crucial for the oncologists to be familiar with the array of dermatologic manifestations caused by these drugs for effective patient management. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for phase 3 randomized controlled trials (RCTs) comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with NSCLC. We calculated the odds ratio (OR) of all- and high-grade 10 dermatologic adverse events (dAEs). We conducted a meta-analysis using a random-effects model to compare the risk of dAEs in patients receiving EGFR-TKIs versus placebo/chemotherapy. Subgroup analysis based on control arm (placebo or chemotherapy) and individual EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib of osimertinib) were conducted. Results: 35 RCTs comprising 16,151 patients were included. In addition to all- and high-grade rash (all-grade: 12.21, 95% CI: 9.00-16.56; high-grade: OR 7.83, 95% CI: 5.11-12.00), EGFR-TKIs were associated with a significantly increased risk of all-grade acne (OR 12.24, 95% CI: 3.11-48.2), dermatitis acneiform (OR 8.46, 95% CI: 4.03-17.8), dry skin (OR 6.15, 95% CI: 4.02-9.40), palmar-plantar erythrodysesthesia syndrome (OR 11.14, 95% CI:3.00-41.4), paronychia (OR 31.97, 95% CI: 17.9-57.1), pruritus (OR 2.86, 95% CI: 2.17-3.77), skin exfoliation (OR 7.62, 95% CI: 2.55-22.8), and skin fissures (OR 11.59, 95% CI:4.86-27.6). The increased risk of EGFR-TKI-related dAEs was more prominent when compared with chemotherapy than placebo. In subgroup analyses of individual EGFR-TKIs, the risk of high-grade rash was significantly increased in patients treated with erlotinib or gefitinib but not in those treated with other EGFR-TKIs. Conclusions: This is the most comprehensive meta-analysis summarizing currently available evidence on cutaneous toxicity profile of EGFR-TKIs. These findings provide physicians with a better understanding for prompt recognition and management of these dAEs, to avoid unnecessary dose modifications and/or termination, and to prevent impairments in patients' quality of life.

Adverse Event Profile of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer: An Updated Meta-analysis.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making. This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs. We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted. Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease. Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

Comparison of the efficacy of first‑/second‑generation EGFR‑tyrosine kinase inhibitors and osimertinib for EGFR‑mutant lung cancer with negative or low PD‑L1 expression.

In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with negative or low programmed death ligand-1 (PD-L1) expression, the acquisition rate of the T790M mutation is higher after treatment with first-/second-generation EGFR-tyrosine kinase inhibitors (TKIs) and the progression-free survival (PFS) is longer in patients treated with osimertinib. The present study compared the clinical course after the initiation of each EGFR-TKI monotherapy in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. Data of patients with EGFR-mutant NSCLC with negative or low PD-L1 expression who were treated with EGFR-TKI monotherapy were retrieved and retrospectively analyzed. Between June 2013 and November 2023, 26 and 29 patients were treated with first-/second-generation EGFR-TKIs and osimertinib, respectively. The PFS time was longer in patients treated with osimertinib (median, 22.5 months) than in those treated with first-/second-generation EGFR-TKIs (median, 12.9 months). However, the EGFR-TKI treatment duration, defined as the PFS for osimertinib, or the sum of the PFS for first-/second-generation EGFR-TKIs and sequential osimertinib therapy after the acquisition of the T790M mutation, was similar between patients treated with first-/second-generation EGFR-TKIs (median, 23.0 months) and osimertinib (median, 22.5 months). The Cox proportional hazard model suggested that there was no significant difference in the EGFR-TKI treatment duration between patients treated with first-/second-generation EGFR-TKIs and patients treated with osimertinib (hazard ratio, 1.31, 95% CI, 0.55-3.13). In conclusion, first-/second-generation EGFR-TKIs and osimertinib were associated with a similar EGFR-TKI treatment duration in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. The findings suggested that both treatments are promising for this population.

MET overexpression correlated with prognosis of EGFR-mutant treatment‑naïve advanced lung adenocarcinoma: a real‑world retrospective study.

About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

The efficacy and safety of adding anlotinib in gradual progression on third-generation EGFR-TKIs for EGFR-mutant advanced nonsmall cell lung cancer.

Acquired resistance is unavoidable with the approval of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for first-line therapy of advanced non small cell lung cancer (NSCLC). Some studies have found that combining antiangiogenesis medicines with EGFR-TKI may benefit clinical outcomes in EGFR-mutant NSCLC. However, it is unclear whether EGFR-TKI paired with antiangiogenesis therapy could further improve survival for patients with gradual progression. Thus, we comprised the clinical effectiveness and safety of continuous EGFR-TKI in combination with anlotinib and EGFR-TKI alone in patients who had gradual progression on third-generation EGFR-TKI treatment. The comparison of progression-free survival (PFS) and overall survival(OS) between two groups used the Kaplan-Meier method. Our study comprised 121 eligible patients in total. The objective response rates were 25.0% and 0%, and the disease response rate was 91.7% and 86.9% in the combination group and EGFR-TKIs monotherapy group. The median PFS of combined anlotinib and EGFR-TKI treatment was 6.7 months and the median PFS was 3.6 months in the EGFR-TKI monotherapy group ( P < 0.001). There were no significant differences between the two groups in OS. The common adverse reactions were diarrhea (21.7%), hypertension (21.6%) and proteinuria (20.0%) in the combination group. Seven patients experienced a grade 3 or higher adverse event, no patients discounted the treatment or died due to the toxicity. Our study indicated that, when combined with anlotinib following gradual progression on EGFR-TKIs, it was more efficacious for EGFR-mutant NSCLC patients than EGFR-TKI monotherapy. And the toxicity was clinically manageable.

Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC.

Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.

Phase 1b study of HS-10241 combined with almonertinib in pre-treated advanced non-small cell lung cancer (NSCLC) harboring EGFR mutation.

e21134 Background: MET gene amplification is one of the most frequent acquired resistance mechanisms following prior EGFR-TKI monotherapy. HS-10241, an oral and highly selective MET-TKI, may contribute to overcoming common acquired MET-based resistance mechanisms. Here, we reported the preliminary safety and efficacy data of HS-10241 with almonertinib in treatment of advanced NSCLC with EGFR mutation. Methods: This Ph1b study (NCT05430386) was composed of dose escalation part (Part 1) and dose expansion part (Part 2). In Part 1, patients (pts) with EGFR-mutated advanced NSCLC upon disease progression on EGFR-TKI received HS-10241 (BID) plus almonertinib (110 mg QD), and HS-10241 was escalated at 200 mg and 300 mg using a rolling six design. Based on the available data of Part 1, an expansion cohort was opened at HS-10241 300 mg BID with almonertinib 110mg QD to enroll pts with EGFR mutation centrally confirmed and MET-amplification detected by central FISH (MET gene copy number[GCN] ≥5 and/or MET:CEP7 signal ratio ≥2). Results: As of 16 December 2022, 10 pts in part 1, 4 pts at 200 mg and 6 pts at 300 mg HS-10241, and 35 pts in part 2 were enrolled into this study. Of these pts, 13 (28.9%) pts received previous treatment with 1st or 2nd-generation but no 3rd-generation EGFR TKI, 15 (33.3%) pts received 3rd-generation EGFR-TKI only and 15 (33.3%) pts received both 1st/2nd and 3rd-generation EGFR TKIs, whether or not they received treatment with chemotherapy. Only one dose-limiting toxicity (grade 2 Nausea with grade 2 vomiting leading to discontinuation≥14 days) was reported in the cohort with HS-10241 300 mg. The MTD was not reached. Treatment-emergent adverse events (TEAEs) occurred in 41/45 (91.1%) pts. The most common TEAEs (≥ 20%) were increased AST, increased ALT, vomiting, nausea, increased blood creatine phosphokinase, thrombocytopenia, decreased appetite, and increased GGT. Among all the pts, 22 pts with EGFR mutation regardless of the MET gene status were evaluable for efficacy, 12 of which achieved partial response (response rate 54.5%; 8 confirmed PR), and 7 had stable disease (SD). Of the 13 pts who had centrally confirmed EGFR mutation and MET-amplification (6 with GCN ≥10, and 7 with GCN ≥5 but &lt; 10), 8 had PR (response rate 61.5%; 5 confirmed PR), and 4 had SD. Among the 8 pts achieving PR, there were 4 with GCN ≥10, and 4 with GCN ≥5 but &lt; 10.Moreover, 9 of the 13 pts received both 1st/2nd and 3rd-generation EGFR-TKI and there were 6 PRs (response rate 66.7%;3 confirmed PR) and 2 SDs. Pharmacokinetics analysis showed low risk of potential drug-drug interactions on HS-10241 combined with almonertinib. Conclusions: HS-10241 in combination with almonertinib was well tolerated, and showed encouraging antitumor activity in treatment of advanced NSCLC with EGFR mutation and MET amplification following prior EGFR-TKI, whether MET GCN ≥10 or MET GCN ≥5 but &lt; 10. Clinical trial information: NCT05430386 .

The Glasgow Prognostic Score Predicts Survival in Patients with Advanced Non-Small Cell Lung Cancer Harboring Sensitive Epidermal Growth Factor Receptor Mutations Who Are Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors

Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitive EGFR mutations. The Glasgow prognostic score (GPS) is an inflammation-assessing score based on C-reactive protein and albumin concentrations. Information regarding the association between the GPS and EGFR-TKI treatment effectiveness is limited; hence, we investigated whether the GPS can predict the response of NSCLC to EGFR-TKIs. Methods: We evaluated 340 patients with NSCLC harboring sensitive EGFR mutations who received EGFR-TKI monotherapy between March 2009 and July 2021. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). Results: After a median follow-up of 26.6 months, patients with a GPS of 0, 1, and 2 had PFS of 15.7, 10.0, and 6.3 months, respectively, and OS of 40.1, 25.8, and 14.4 months, respectively; patients with a GPS of 0 had significantly better PFS and OS than those with a GPS of 1 (p = 0.03, p = 0.001, respectively) or 2 (p < 0.001, p < 0.001, respectively). Multivariate analysis identified poor performance status, stage 4 at diagnosis, type of EGFR-TKI (gefitinib/erlotinib vs. afatinib), and GPS = 2 as predictors of a short PFS. Meanwhile, poor performance status, gefitinib/erlotinib administration, and GPS = 2 were predictors of a short OS. Conclusion: The GPS predicted the survival of NSCLC patients harboring sensitive EGFR mutations who were undergoing EGFR-TKI treatment. The GPS might be ideal for routine use in clinical practice, given that it is an easily calculated parameter.

Abstract 410: Tumor heterogeneity via AXL activation on primary resistance to EGFR tyrosine kinase inhibitors in EGFR mutated lung cancer

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatments for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, some patients show primary resistance to EGFR-TKIs at the first-line treatment setting. AXL, a member of the TAM family of receptor tyrosine kinase, was reported to be involved in primary resistance to EGFR-TKIs for EGFR mutated NSCLC patients. In the present study, we investigated spatial tumor heterogeneity using autopsy specimens from EGFR mutated NSCLC patients, showing primary resistance to erlotinib plus ramucirumab. qPCR analysis showed that the AXL mRNA expression levels differed in each metastatic site. In addition, the AXL expression levels were likely to negatively correlate with the efficacy of erlotinib plus ramucirumab therapy. The analysis of patient-derived cell lines, established from left pleural effusion before initiation of the treatment, showed that the combination of EGFR-TKIs and an AXL inhibitor remarkably inhibited cell viability compared with EGFR-TKI monotherapy or combination with ramucirumab. Our observations suggested that tumor AXL expression might play a critical role in progression of spatial tumor heterogeneity and primary resistance to EGFR-TKIs for EGFR mutated NSCLC patients. Citation Format: Tadaaki Yamada, Ryota Nakamura, Hiroyuki Fujii, Takeshi Yaoi, Kyoko Itoh, Shinsaku Tokuda, Koichi Takayama. Tumor heterogeneity via AXL activation on primary resistance to EGFR tyrosine kinase inhibitors in EGFR mutated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 410.

Optimal therapy for concomitant EGFR and TP53 mutated non-small cell lung cancer: a real-world study

BackgroundNon-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting.MethodsThis retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan–Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival.ResultsThe combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1–23.9 vs. 7.0 months; 95% CI: 6.1–7.9; p < 0.001) with greater PFS benefit in TP53 exon 4 or 7 mutations subgroup. Subgroup analysis showed a similar trend. The median duration of response was significantly longer in the combination group than in the EGFR-TKI group. Patients with 19 deletions or L858R mutations both achieved a significant PFS benefit with combination therapy versus EGFR-TKI alone.ConclusionCombination therapy had a higher efficacy than EGFR-TKI alone for patients with NSCLC having concomitant EGFR and TP53 mutations. Future prospective clinical trials are needed to determine the role of combination therapy for this patient population.

Efficacy and safety analyses of epidermal growth factor receptor tyrosine kinase inhibitors combined with chemotherapy in the treatment of advanced non–small-cell lung cancer with an EGFR/TP53 co-mutation

PurposeEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with cytotoxic chemotherapy are highly effective in the treatment of advanced non–small-cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study is to evaluate the efficacy and safety of this combination in advanced NSCLC patients with an EGFR/TP53 co-mutation.MethodsNinety-five advanced NSCLC patients with an EGFR/TP53 co-mutation were enrolled in this study. Treatments with either EGFR-TKI monotherapy (T group, n = 61) or EGFR-TKI combined with chemotherapy (TC group, n = 34) were evaluated in relation to objective response rate (ORR), disease control rate (DCR), median time to progression (TTP), and median overall survival (OS).ResultsThere were no statistically significant differences in DCR between the treatment groups. The ORR was significantly improved in the TC group versus the T group (55.9% vs. 34.4%, P = 0.042). A higher median TTP was noted in TC group compared with T group (16.1 vs. 11.1 months, P = 0.002). Patients without brain metastases in TC group had a longer median OS than in T group (48.4 vs. 28.8 months, P = 0.003). However, there was a non-significant trend towards longer OS in TC group in the entire cohort (36.9 vs. 28.2 months, P = 0.078). Cox multivariate regression analysis showed that clinical stage, brain metastases, EGFR21 L858R mutation, and T790M status at first progression were independent risk factors for OS. However, the incidence of grade 3 or higher adverse events were higher in the TC group than in the T group (32.4% vs. 13.1%, P = 0.025).ConclusionOur study indicates that EGFR-TKIs combined with chemotherapy could significantly improve the ORR and TTP of advanced NSCLC patients with an EGFR/TP53 co-mutation. Combination therapy may be a promising treatment for advanced NSCLC patients with an EGFR/TP53 co-mutation without brain metastases.

When to add anti-angiogenesis drugs to EGFR-mutated metastatic non–small cell lung cancer patients: a real-world study from Taiwan

BackgroundThe addition of anti-angiogenesis drugs to epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) or chemotherapy in patients with EGFR-mutant non–small cell lung cancer (NSCLC) can improve disease control. We conducted a study to evaluate the efficacy of combination therapeutic strategies and identify patients who could benefit from combination therapy.MethodsThis study enrolled patients with stage IV EGFR-mutant NSCLC treated with first-line EGFR-TKIs between January 2014 and December 2020. We divided patients into three groups: patients who received an anti-angiogenesis drug as first-line combination therapy, those who received an anti-angiogenesis drug as further-line combination therapy, and those with no anti-angiogenesis therapy.ResultsA total of 204 patients were enrolled in the final analysis. Progression-free survival (PFS) in patients receiving first-line anti-angiogenesis plus EGFR-TKI combination therapy was longer (18.2 months) than those treated with first-line EGFR-TKI monotherapy (10.0 months for both, p < 0.001). No difference in overall survival (OS) was observed among these three groups (30.5 vs. 42.6 vs. 33.7 months, p = 0.326). Multivariate Cox regression analysis revealed L858R mutation, pleural, liver, and bone metastasis as independent prognostic factors for poor OS. However, the addition of anti-angiogenesis therapy to patients with these poor prognostic factors improved OS to levels similar to those without these poor prognostic factors.ConclusionFirst-line combination EGFR-TKI plus anti-angiogenesis therapy improves PFS in patients with stage IV EGFR-mutant NSCLC. Adding an anti-angiogenesis drug at any line to patients harboring L858R mutation with pleural, liver, or bone metastases can provide survival benefits.

Real-world global data on targeting epidermal growth factor receptor mutations in stage III non-small-cell lung cancer: the results of the KINDLE study.

Background:Tyrosine kinase inhibitors (TKIs) are the standard of care for resectable and metastatic non-small-cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations (EGFRm). We describe the real-world practice of EGFRm testing, prevalence, treatment and outcomes in EGFRm stage III NSCLC from a multi-country, observational study.Methods:The KINDLE study retrospectively captured diagnostic information, treatments and survival outcomes in patients with stage III NSCLC from January 2013 to December 2017. Baseline characteristics and treatments were described and real-world outcomes from initial therapy were analysed using Kaplan–Meier methods.Results:A total of 3151 patients were enrolled across three regions: Asia (n = 1874), Middle East and North Africa (MENA) (n = 1046) and Latin America (LA) (n = 231). Of these, 1114 patients (35%) were tested for EGFRm (46% in Asia, 17% in MENA and 32% in LA) and EGFRm was detected in 32% of tested patients (34.3% in Asia, 20.0% in MENA and 28.4% in LA). In a multi-variate analysis, overall EGFRm patients treated with EGFR-TKI monotherapy as initial treatment, without any irradiation, had twice the risk of dying (hazard ratio: 1.983, 95% confidence interval: 1.079–3.643; p = 0.027) versus any other treatment. Finally, unresectable patients with EGFRm NSCLC who received concurrent chemoradiotherapy (cCRT) as initial therapy had longer overall survival (OS) compared with their counterparts who only received TKI monotherapy without any irradiation (48 months versus 24 months; p < 0.001).Conclusion:The KINDLE study showed that a minority of stage III NSCLC patients were tested for EGFRm. Patients with EGFRm with unresectable NSCLC had similar outcomes from cCRT as initial therapy compared with EGFR wild type with a trend in OS favouring the EGFRm group. Outcomes with EGFR-TKI monotherapy as initial therapy, without any irradiation, were worse. The ongoing LAURA study (NCT03521154) will help define the role of EGFR-TKIs in EGFRm stage III NSCLC treated with cCRT.Trial Registration:NCT03725475.

Clinical and molecular feature-based nomogram model for predicting benefit from bevacizumab combined with first-generation EGFR-tyrosine kinase inhibitor (TKI) in EGFR-mutant advanced NSCLC

BackgroundThe combination of bevacizumab and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could prolong progression-free survival (PFS) in patients with EGFR-mutant advanced non-small-cell lung cancer (NSCLC). Our study investigated the clinical and molecular factors that affect the efficacy of first-generation EGFR-TKI with or without bevacizumab and identify the subset of patients who can benefit from combination therapy.MethodsOur study included 318 patients with EGFR-mutant locally advanced/advanced NSCLC treated with either first-generation EGFR-TKI combined with bevacizumab (A+T; n = 159) or EGFR-TKI monotherapy (T; n = 159). Two nomogram models to predict PFS and overall survival (OS), respectively, were constructed using two factors that impact EGFR-TKI efficacy: metastatic site and presence of concurrent mutations. The study cohort was stratified into 2 cohorts for training (n = 176) and validation (n = 142) of the nomogram model. Using the median score from the nomogram, the patients were stratified into two groups to analyze their survival outcome.ResultsThe A+T group had significantly longer PFS (14.0 vs. 10.5 months; p < 0.001) and OS (37.0 vs. 26.0 months; p = 0.042) than the T group. Among the patients with concurrent mutations in tumor suppressor genes, those in the A+T group had significantly longer PFS and OS than the T group (PFS 14.5 vs. 8.0 months, p < 0.001; OS 39.0 vs. 20.0 months, p = 0.003). The higher scores from the nomograms were associated with the presence of brain/liver/pleural metastasis or concomitant gene mutations, which indicated a higher likelihood of shorter PFS and OS. The validation of the nomogram revealed that patients with lower scores had significantly longer PFS for the T group than those with higher scores (15.0 vs. 9.0 months, p = 0.002), but not for the A+T group (15.9 vs. 13.9 months, p = 0.256).ConclusionsUsing a nomogram, our study demonstrated that the addition of bevacizumab may enhance the therapeutic effectiveness of EGFR-TKI by overcoming the negative impact of certain clinical and molecular factors on the efficacy of EGFR-TKI.

Real-world treatment patterns of metastatic non-small cell lung cancer (mNSCLC) patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

289 Background: Among mNSCLC patients positive for EGFR mutation (EGFRm), first-line (1L) treatment with an EGFR TKI is recommended for best outcomes. This study describes real-world treatment patterns of mNSCLC patients using EGFR TKIs in the 1L setting, including osimertinib, the most recently approved EGFR TKI for 1L use. Methods: Patients with ≥1 claim for an EGFR TKI (1st generation [1G]: gefitinib, erlotinib; 2nd generation [2G]: afatinib, dacomitinib; 3rd generation: osimertinib) from January 1, 2015 – April 30, 2020 were identified in IQVIA’s prescription (LRx) and medical claims (Dx) databases; first date of EGFR TKI was the index date. Patients had 12-month baseline period before index, variable follow-up after index, ≥1 lung cancer diagnosis on index or in baseline, and earliest metastatic cancer diagnosis on or 90 days before index. Kaplan-Meier analysis was used to estimate 1L treatment duration, where treatment discontinuation was defined as &gt;60-day gap in medication supply of the index EGFR TKI. Patient characteristics and treatment patterns were stratified by 1L EGFR TKI. Results: Overall, 2,505 mNSCLC patients received 1L EGFR TKI (982 osimertinib, 1,060 1G, 463 2G). Median ages were 66-69 years, 64.6-67.1% were female, and 32.4-38.9% had central nervous system metastases on or before index. Most patients were commercially insured (50.8-62.9%), 35.3-45.9% had Medicare, and 0.6-3.3% had other payer types. Nearly all patients had 1L EGFR TKI monotherapy (97.6-99.7%). 1L treatment duration was longer for osimertinib compared to 1G or 2G EGFR TKI (median months, 17.8, 8.7, 10.5 respectively). 2L treatment was observed in 32.5% of 1G and 36.3% of 2G EGFR TKI cohorts. Osimertinib monotherapy, chemotherapy, and immunotherapy (monotherapy or combined with chemotherapy) accounted for 58.3%, 7.0%, and 4.3% of 2L treatments after 1L 1G EGFR TKI, respectively, and 60.7%, 4.2%, and 4.8% of 2L treatments after 1L 2G EGFR TKI. Conclusions: In real-world practice, 1L treatment duration is longer with osimertinib compared with other EGFR TKIs. Future studies with longer follow-up are recommended to understand treatment patterns after progression on EGFR TKIs, mainly osimertinib, given its recent approval.

Efficacy of EGFR-TKI Plus Chemotherapy or Monotherapy as First-Line Treatment for Advanced EGFR-Mutant Lung Adenocarcinoma Patients With Co-Mutations.

BackgroundCo-mutations was associated with poor response to EGFR-TKIs. First-generation EGFR-TKIs combined with chemotherapy was reported to be more effective than TKIs alone in advanced lung adenocarcinoma patients.ObjectiveThis retrospective study aimed to explore whether EGFR-mutant patients with co-mutations can benefit from EGFR-TKIs plus chemotherapy.Patients and MethodsWe retrospectively collected data of 137 EGFR-mutant patients with advanced lung adenocarcinoma who underwent next-generation sequencing in our hospital in 2018. Among them, 96 were treated with EGFR–TKIs alone and 41 received EGFR–TKIs plus chemotherapy. We analyzed the progression-free survival (PFS) of patients with co-mutations using different treatments.ResultsConcurrent TP53 mutations, especially exon 4 and 6, were associated with a markedly shorter time to progression on EGFR-TKI monotherapy (11.4 months vs. 16.6 months, P=0.003), while EGFR–TKIs plus chemotherapy would benefit those patients more (with TP53: 11.4 months vs. 19.1 months, P=0.001, HR=0.407; without TP53: 16.6 months vs. 18.9 months, P=0.379, HR=0.706). The incidence of T790M after resistance was equal in patients treated with different treatments (53% vs. 53%, P=0.985).ConclusionsIn our study, concurrent TP53 mutations were found to be risk factors for EGFR-TKI monotherapy, but TKI combined with chemotherapy could eliminate this heterogeneity.

The Efficacy and Safety of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combined With Thymosin in Advanced Non-Small Cell Lung Cancer Patients Harboring Active Epidermal Growth Factor Receptor Mutations.

ObjectiveTo explore the efficacy and safety of EGFR-TKI combined with thymosin therapy in advanced non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations.MethodsPatients confirmed as advanced NSCLC with active EGFR mutations were recruited from August 2008 to July 2018 retrospectively. Patients treated with EGFR-TKI were classified as the EGFR-TKI group. And those received EGFR-TKI and thymosin therapy were designated as the EGFR-TKI plus thymosin group. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), tumor response and adverse effects.ResultsThe median PFS was significantly longer in EGFR-TKI plus thymosin group than that in EGFR-TKI group (14.4 months vs. 9.2 months; HR=0.433, 95% CI 0.322 - 0.582, P<0.0001). The median OS was also prolonged in EGFR-TKI plus thymosin group than that in EGFR-TKI group (29.5 months vs. 19.8 months; HR=0.430, 95% CI 0.319 - 0.580, P<0.0001). The objective response rate in EGFR-TKI plus thymosin group and EGFR-TKI group were 60.0% versus 60.8% (P=0.918). The disease control rate was 96.9% in EGFR-TKI plus thymosin group and 97.7% in EGFR-TKI group (P=1.000). There were no significant differences in adverse effects between the two groups. The number of CD3+T cells in peripheral blood decreased significantly after treatment including both CD3+CD4+T and CD3+CD8+T subsets in EGFR-TKI group, but not in EGFR-TKI plus thymosin group.ConclusionsCombination of EGFR-TKI and thymosin can significantly prolong the PFS and OS compared with EGFR-TKI monotherapy without more adverse events, which offers a new strategy in clinic.