EGFR-mutant Non-small Cell Lung Cancer Research Articles

The efficacy of almonertinib and anlotinib combination therapy for advanced non-small-cell lung cancer patients who continued to experience cancer progression during third-generation EGFR-TKI treatment: a retrospective study.

Epidermal growth factor receptor (EGFR) mutations are key drivers in a significant portion of non-small-cell lung cancer (NSCLC) patients. While third-generation EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib have demonstrated efficacy, the management of patients who continue to experience disease progression during treatment remains challenging. The emergence of drug resistance, including the development of secondary mutations, necessitates exploration of alternative treatment strategies. This study aims to evaluate and observe the efficacy and safety of almonertinib combined with anlotinib in patients after cancer progression during third-generation EGFR-TKI therapy. In this retrospective analysis, we included EGFR-mutated NSCLC patients who were resistant to third-generation EGFR-TKIs. All patients were treated with almonertinib combined with anlotinib. The clinical characteristics, treatment history, clinical benefits, and adverse events of these patients were retrospectively collected. A total of 16 eligible patients were included in the analysis. The results revealed that combination therapy with almonertinib and anlotinib was effective in this patient cohort. The overall response rate was 25% and the disease control rate was 93.75%. The 6 and 12 months of PFS rates were 92.9% (95% confidence interval [CI] 80.3%, 100.0%) and 84.4% (95% CI 66.6%, 100.0%), respectively. Moreover, this combination therapy was generally well-tolerated, with manageable adverse events. Our retrospective analysis suggests that almonertinib and anlotinib combination therapy may represent a viable option for EGFR-mutated NSCLC patients who have progressed on third-generation EGFR-TKIs, especially for those with posterior lines and no standard treatment options. Further investigation and larger clinical trials are warranted to validate these observations and refine treatment guidelines.

METTL14-Mediated Bim mRNA m6A Modification Augments Osimertinib Sensitivity in EGFR-Mutant NSCLC Cells.

Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR. N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assays showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and that elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors. Implications: This study offers more evidences for the involvement of METTL14-mediated N6-methyladenosine modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors.

Real-world efficacy of low dose osimertinib as second-line treatment in patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer.

Response rates of epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) to lower doses of osimertinib [20 mg once daily (OD) and 40 mg OD] are similar to those of the recommended dose of 80 mg OD, but there is a lack of real-world evidence on the effect of the lower doses of osimertinib on survival outcomes. We conducted this study to assess the efficacy and safety of lower osimertinib doses for patients with EGFR-mutated advanced NSCLC whose disease had progressed on earlier generation EGFR tyrosine kinase inhibitors (TKIs) in a real-world clinical practice. This multicenter, retrospective study included patients with EGFR-mutated advanced NSCLC treated with low doses of osimertinib after failing first- or second-generation EGFR TKIs due to acquired T790M mutation. Data on demographics, staging, treatment history, best overall response rate (ORR) based on RECIST 1.1, and adverse events (AEs) were collected from the patients' case notes. Descriptive data were described in percentages and medians. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Of the 22 patients studied [males =8 and females =14; Eastern Cooperative Oncology Group (ECOG) 1 or 2 =7 and ECOG 3 or 4 =15], 45.5% were on 40 mg OD, 31.8% were on 80 mg every other day (EOD), and 22.7% on 40 mg EOD. First-line EGFR TKIs used included afatinib, erlotinib, and gefitinib. The ORR with lower doses of second-line osimertinib was 77.3%. Overall, the median PFS was 10.0 months [95% confidence interval (CI): 8.6-11.4] and median OS was 13.0 months (95% CI: 9.4-16.6). In patients with ECOG 1 or 2, the median PFS was 18.0 months (95% CI: 5.8-30.2) and the median OS was not reached at the time of analysis. In patients with poor ECOG performance status of 3 and 4, good survival outcomes were also seen with a median PFS of 7.0 months (95% CI: 4.7-9.3) and median OS of 10.0 months (95% CI: 7.5-12.5). All AEs except one case of paronychia were Grade 1. There were no Grade 3 or 4 AEs. Treatment with low dose osimertinib demonstrated good efficacy and tolerability in EGFR-mutated advanced NSCLC patients who failed first-line treatment with first- or second-generation EGFR TKIs due to T790M mutation.

Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib–ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib–ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

Multicenter Real-World Analysis of Combined MET and EGFR Inhibition in Patients With Non-Small Cell Lung Cancer and Acquired MET Amplification or Polysomy After EGFR Inhibition

PurposeMET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. MethodsThis is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2). ResultsA total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). ConclusionIn this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.

Post-Progression Analysis of EGFR-Mutant NSCLC Following Osimertinib Therapy in Real-World Settings.

Platinum-based chemotherapy is the current standard treatment option in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who progress on osimertinib. However, outcomes with chemotherapy are dismal, and the treatment of central nervous system (CNS) disease is an unmet need in this setting. Patients with EGFR-mutant NSCLC who were candidates to receive osimertinib in the metastatic setting at our Center from 2015 to 2022 were retrospectively evaluated to identify patients who received standard platinum-based chemotherapy post-osimertinib. Data were collected on treatment outcomes, with a focus on brain metastases and progression patterns. A total of 220 patients received indication for osimertinib in the study period; n = 176 had adequate follow-up data. Overall, n = 117 patients experienced disease progression on osimertinib. The median time to osimertinib progressive disease (PD) was 15 months (95% confidence interval CI 13-18). Of them, 51 patients (45%) had no access to further treatments. Of the remaining patients, n = 8 received experimental treatments, and n = 55 received standard platinum-based chemotherapy and were considered for this study. Median duration of chemotherapy was 3 months (95% CI 2-5); the best responses among 53 evaluable patients were observed as follows: 15% partial response/complete response (PR/CR), 40% stable disease (SD), 45% PD. Median progression-free survival (PFS) and overall survival (OS) were 3 (95% CI 2-5) and 10 (95% CI 6-15) months, respectively. All patients had baseline and follow-up brain radiologic assessments, and n = 23 had brain metastases at the start of chemotherapy. With a median follow-up of 13 months, intracranial PD occurred in 47% patients, being the first site of PD in 59% of cases. The median time for intracranial (IC) PD was 2 months (95% CI 2-7). IC PD occurred as oligometastatic in 29%, whereas in 71% of cases, it was associated with systemic PD. Access to subsequent treatments and CNS progression are confirmed unmet needs in EGFR-mutant NSCLC patients. Clinical and CNS-specific outcomes in patients receiving standard chemotherapy after the failure of osimertinib are dismal. Novel upfront treatment options with demonstrated prolonged PFS and better CNS outcomes may help address this important issue.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. ClinicalTrials.gov number, NCT03849768.

Neoadjuvant targeted therapy versus targeted combined with chemotherapy for resectable EGFR-mutant non-small cell lung cancer: a retrospective controlled real-world study.

This study aimed to assess the role and effect of neoadjuvant targeted therapy (TT) versus targeted combined with chemotherapy (TC) for resectable EGFR-mutant non-small cell lung cancer (NSCLC). Between March 2021 and June 2023, 20 patients with stage IA3-IIIB NSCLC were enrolled in the study. Eleven patients received EGFR-TKIs in the TT group, while nine patients received EGFR-TKIs and two cycles of cisplatin-based doublet chemotherapy (TC group). We compare the differences between the two groups through the following variables, including age, sex, surgical approach, postoperative complications, neoadjuvant therapy adverse events, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), major pathologic response (MPR), and pathologic complete response (pCR). Patients were predominantly female (75%) and never-smokers (95%). The average age was 59.2 years (range 46-79 years). Fifty-five percent harbored an exon 19 EGFR mutation and 45% an exon 21 mutation. The average targeted drug dosing time was 2.91 ± 1.7 (range 1-6) months in the TT group and 3.56 ± 3.54 (range 1-12) months in the TC group (P=0.598). The most common side effects were rash and diarrhea. No grade 5 events with neoadjuvant therapy were observed. The rate of R0 resection was 100% in all patients. Among the 11 patients in the TT group, 6 achieved a PR and 5 had SD, resulting in an ORR of 54.5%. Among the 9 patients in the TC group, 6 had PR and the remaining 3 had SD, resulting in an ORR of 66.6%. one patient (11.1%) in the TC group achieved pCR, while no patients in the TT group achieved pCR (P = 0.142). Two patients (18.2%) in the TT group reached MPR, and 2 patients (22.2%) in the TC group reached MPR (P = 0.257). The overall clinical downstage rate is 60%. Only 9 (45%) cases of yield clinical TNM (ycTNM) were consistent with yield pathologic TNM (ypTNM). Results from this retrospective controlled research indicate that the neoadjuvant TT group is likely to be more effective outcomes and has safer profile in patients with EGFR-positive NSCLC than the neoadjuvant TC group. However, our results need to be validated in a multicenter, large sample prospective study.

EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis.

We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2-13.4 months) and PFS was 3.2 months (95% CI 2.5-3.9 months). ORR was 15% (95% CI 10-21%) and DCR was 61% (95% CI 53-67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited.

Analysis of tumor abnormal protein expression and epidermal growth factor receptor mutation status in non-small cell lung cancer

BackgroundThe level of tumor abnormal protein (TAP) level has a significant impact on tumor growth, recurrence, and metastasis. Previous studies have highlighted the influence of the mutations in exons 19 and 21 of the epidermal growth factor receptor (EGFR), particularly the sensitivity displayed by tumor cells to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Our study is centered on exploring the clinical relevance of TAP and EGFR mutations in patients with non-small cell lung cancer (NSCLC).Material and methodsIn this study, tissue samples were collected from a total of 176 patients diagnosed with non-small cell lung cancer (NSCLC). Real-time PCR technology was utilized to detect mutations within exons 19 and 21 of the epidermal growth factor receptor (EGFR) gene in these samples. This approach enables precise identification of EGFR mutations associated with NSCLC. Furthermore, the study investigated the impact of various tumor markers, including tumor abnormal protein (TAP) and carcinoembryonic antigen (CEA), on EGFR mutation status. Established assays were employed to evaluate TAP and CEA levels, aiming to ascertain their potential correlation with EGFR mutation in NSCLC patients.ResultsEGFR exhibited mutation rates of 23.86% and 12.50% in exons 19 and 21, respectively. EGFR mutations were more prevalent in younger women (< 60 years old) and in cases with pleural invasion, vessel invasion, CEA > 6.5 ng/mL, and TAP > 228 µm2 for both genders. Increased TAP levels independently predicted EGFR mutations (P = 0.001 for males; P = 0.000 for females). An area under the curve (AUC) of 0.833 indecated EGFR mutation prediction with sensitivity and specificity of 79.7% and 87.0%, respectively. For females, the sensitivity increased to 89.7% and specificity increased to 93.8%.ConclusionsTAP effectively predicts EGFR mutations in NSCLC patients with moderate accuracy, particularly benefiting diagnosis in females with high sensitivity and specificity. Integrating TAP assessment into EGFR mutation testing can significantly enhance diagnostic precision, especially in female NSCLC cases.

Real-World Treatment Patterns and Clinical Outcomes Among Patients with Metastatic or Unresectable EGFR-Mutated Non-Small Cell Lung Cancer Previously Treated with Osimertinib and Platinum-Based Chemotherapy.

For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3‑DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population. This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28days apart). In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%. The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

Protocol for a systematic review with prospective individual patient data meta-analysis in EGFR-mutant NSCLC with brain metastases to assess the effect of SRS+osimertinib compared to osimertinib alone: the STARLET Collaboration

BackgroundPatients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop brain metastases (BM). The optimal...

Unusual response with tyrosine kinase inhibitor in small-cell lung cancer

Abstract: The discovery of targetable mutations in non-small-cell lung cancer (NSCLC) has opened up a plethora of therapeutic options. Epidermal growth factor receptor (EGFR) mutations are found in 10%–20% of NSCLC; however, it is extremely rare in small-cell lung cancer (SCLC), and the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in SCLC is unclear. Here, we describe the case of a 57-year-old nonsmoker lady who was diagnosed with metastatic SCLC. She received multiple lines of palliative chemotherapy. She was deemed unfit for further chemotherapy and immunotherapy and was started on tablet erlotinib empirically. On follow-up imaging with positron emission tomography-computed tomography, she had a partial response and has currently on erlotinib for 2.5 years without disease progression. Although cases with transformation of EGFR-mutated NSCLC to SCLC have been observed, de novo EGFR mutation in SCLC is infrequent. It has been observed that de novo EGFR mutation in SCLC is associated with females, non-smokers, and patients in the eastern part of the world. The current guidelines do not recommend molecular testing for EGFR mutations in SCLC. We described a case of SCLC who had a response to TKI and such cases warrant an answer to whether EGFR mutation testing should be recommended in nonsmoker, females with SCLC, or for them who have failed the first line of chemotherapy.

Narrative review of stereotactic body radiation therapy combined with tyrosine kinase inhibitors for oligometastatic EGFR-mutated non-small cell lung cancer: present and future developments.

A significant number of individuals diagnosed with non-small cell lung cancer (NSCLC) have distant metastases, and the concept of oligometastatic NSCLC has shown promise in achieving a cure. Stereotactic body radiation therapy (SBRT) is currently considered a viable treatment option for a limited number of tumor metastases. It has also been demonstrated that third-generation tyrosine kinase inhibitors (TKIs) are effective in extending the survival of patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Hence, the combination of SBRT with third-generation TKIs holds the potential to enhance treatment efficacy in patients with oligometastatic EGFR-mutated NSCLC. This review aimed to assess the possibility of combining SBRT with TKIs as an optimum treatment option for patients with oligometastatic EGFR-mutated NSCLC. We performed a narrative review by searching the PubMed, Web of Science, Elsevier and ClinicalTrials.gov databases for articles published in the English language from January 2009 to February 2024 and by reviewing the bibliographies of key references to identify important literature related to combining SBRT with third-generation TKIs in oligometastatic EGFR-mutated NSCLC. This review aimed to assess the viability of combining SBRT and EGFR-TKIs in oligometastatic EGFR-mutated NSCLC. Current clinical trials suggest that the combined therapies have better progression free survival (PFS) when using SBRT as either concurrent with EGFR-TKIs or consolidated with EGFR-TKIs. Furthermore, research with third-generation EGFR-TKIs and SBRT combinations has demonstrated tolerable toxicity levels without significant additional adverse effects as compared to prior therapies. However, further clinical trials are required to establish its effectiveness. The combined approach of SBRT and TKIs can effectively impede the progression of oligometastatic NSCLC in patients harboring EGFR mutations and, most notably, can prolong progression-free survival rates. However, the feasibility of combining SBRT with third-generation TKIs in clinical trials remains unclear.

Systemic treatment of EGFR-mutated non-small cell lung cancer

Systemic treatment of EGFR-mutated non-small cell lung cancer

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Capmatinib plus nazartinib in patients with EGFR-mutated non–small cell lung cancer

PurposeThis phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC). MethodsIn phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200–400 mg bid plus nazartinib 50–150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1–3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0–2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M−; any MET); group 4 (with food; 0–2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1–3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. ResultsThe RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET− (n = 42), T790M+ (n = 29), and T790M− (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). ConclusionCapmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. Clinical trial registrationClinicalTrials.gov NCT02335944

Modern era systemic therapies: Expanding concepts of cure in early and locally advanced non-small cell lung cancer.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104)

The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) invitro. Infiltration and Tcell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.