Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Real-world clinical outcomes in a U.S. Asian population with stage IV NSCLC treated with osimertinib (Osi) stratified by EGFR subtype.

e21128 Background: EGFR mutations are observed in 40-50% of Asian populations with NSCLC compared to 10-15% in Caucasian populations, with EGFR exon 19 deletion (ex19del) and exon 21 L858R as the most common activating mutations. The FLAURA trial demonstrated PFS and OS benefit of osi, a 3rd generation tyrosine kinase inhibitor (TKI), compared to earlier generation TKIs with a median PFS (mPFS) of 19 months (mos) and overall survival (OS) of 38.6 mos. Subgroup analysis, however, suggested this survival benefit was not seen in Asian patients (pts) or in pts with the L858R mutation. Further analysis of the 322 Asian pts enrolled at Asian sites demonstrated a mPFS of 16.5 mos (HR 0.54, p < 0.0001) with osi compared to 11.0 mos with SOC EGFR TKI, but no difference on two-year OS (2y OS) (HR 0.65, 95% CI 0.42-1.02). We evaluated the 2y OS in Asian pts treated in the U.S. with stage IV NSCLC with first-line (1L) osi. We further explored the 2y OS of Asian pts who received an earlier generation EGFR TKI prior to osi. Methods: We conducted a single institution IRB-approved retrospective study of Asian pts treated at NYU Perlmutter Cancer Center with stage IV NSCLC with EGFR ex19del or L858R mutations treated with osi from 1/1/2010 – 2/1/2021. 2y OS was compared based on EGFR mutations and receipt of 1L osi vs an earlier generation EGFR TKI prior to osi (TKI-pretreated). Log-rank test was used to calculate the P values of Kaplan-Meier curves subgroups. Cox proportional-hazards model was used to investigate the association between the survival time of pts and multiple predictor variables including age, sex, EGFR subtypes (L858R or ex19del) and smoking status. Results: Of 117 total cases: 85 (73%) were female, 32 (36%) were male. 57 (49%) had ex19del and 60 (51%) had L858R. 94 (80%) were nonsmokers. Age range at diagnosis with stage IV disease was 31-96 years. The analysis revealed no significant difference in 2y OS observed between the 1L osi vs. TKI-pretreated groups (HR 1.90, 95%CI 0.93-3.89). However, the subgroup analysis showed that the 2y OS was inferior in the 1L osi group compared to the TKI-pretreated group in pts with ex19del (HR 2.99, 95%CI 1.12 -7.96), but not in those with L858R (HR 1.29, 95%CI 0.43-3.86). No significant effect on 2y OS was observed from age (p = 0.19), sex (p = 0.50), EGFR subtype (p = 0.19) or smoking status (p = 0.67). Conclusions: In accordance with the FLAURA data, our real-world analysis revealed that Asian pts treated with 1L osi was comparable to pts treated with 1st- or 2nd- generation TKIs. Furthermore, our data showed that the use of 1L osi had a lower 2y OS in Asian pts with ex19del compared to those pre-treated with TKIs, but this was not the case with L858R. Although small numbers, the results suggest that ex19del and L858R should be considered differently when considering 1L treatment options and further investigation into alternative options, such as combination therapies, warrants exploration.

Abstract 933: Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy

Abstract Background:Third generation EGFR TKIs have emerged as a first line treatment of choice for aNSCLC patients with qualifying EGFR mutations due to high and durable response rates; however most patients will progress on therapy and may receive further treatment. Second line (2L) options include other EGFR TKIs, chemotherapy (C) and chemoimmunotherapy (C-IO). An optimal treatment strategy and utility of biomarkers in this 2L setting remain uncharacterized. In this study, we aim to describe the real-world treatment patterns and outcomes of patients with aNSCLC after treatment with first line (1L) EGFR TKIs to elucidate the potential for biomarker-guided approaches. Methods:We selected patients with non-squamous aNSCLC treated with 1L EGFR TKIs on or after April 1, 2018 (based on 1L approval of osimertinib) within the US-based de-identified Flatiron Health-Foundation Medicine (FMI) real world clinico-genomic database. Real world overall survival (rwOS) and progression free survival (rwPFS) curves and estimates of median survival time were generated using the Kaplan-Meier method. PD-L1 and tumor mutational burden (TMB) were summarized overall and by 2L treatment regimen. Results:Among 428 patients who received 1L EGFR TKI treatment, 386 (90%) received osimertinib, 30 (7%) received afatinib and 11 (3%) received erlotinib. For patients with known 2L treatment information (n=139, 32%) most received EGFR TKI alone (n=43, 31%), followed by C-IO (n=38, 27%), and C alone (n=14, 10%). Median rwOS following 2L treatment with EGFR TKI, C-IO, and C was 21.0 (95% CI 17.4-28.7) months, 9.9 (95% CI 7.7-19.8) months, and 17.4 (95% CI 4.3-NA) months respectively. Median rwPFS for the EGFR-TKI, C-IO, and C cohorts was 5.1 (95% CI 3.4-12.5) months, 5.5 (95% CI 3.3-7.0) months, and 3.5 (95% CI 1.9-NA) months. 416 (97%) of 428 patients harbored an EGFR mutation detected by FoundationOne®CDx, including 361 (84%) patients with at least one EGFR mutation in NCCN Guidelines. Among patients with available PD-L1 status (n=254, 59%), PD-L1 positivity (≥1% tumor proportion score) was more common among patients who received 2L C-IO (88%) compared to patients overall (59%). 30 (7%) of 428 patients had high TMB (≥10 mut/Mb); prevalence of high TMB was similar regardless of 2L therapy choice. Conclusions:This real-world data analysis confirmed that among patients with aNSCLC treated with EGFR TKIs, the vast majority received 1L osimertinib. Among 2L treatment options, additional EGFR TKI use was the most common and patients in this cohort had robust outcomes, with a median rwOS of 21 mos. Further analyses will describe the clinical characteristics of patients receiving different 2L treatment strategies and evaluate the association of PD-L1 status and select EGFR mutations with outcomes across therapeutic classes. Citation Format: Ericka Ebot, Jie He, David Fabrizio, Ivy Altomare, Neha Jain, Davey Daniel, Thomas Stricker, Edward Arrowsmith. Real world treatment patterns and outcomes in patients with advanced non-small cell lung cancer (aNSCLC) post-EGFR tyrosine kinase inhibitor (TKI) therapy [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 933.

Abstract 3418: Alterations in PIK3CA/PTEN as resistance mechanisms in lung cancer patients progressing on first-line next generation EGFR/ALK tyrosine kinase inhibitors

Abstract Introduction: Advent of targeted therapies has deeply changed treatment of advanced oncogene-addicted non-small cell lung cancer (NSCLC), but development of resistance remains a main issue. Given the efficacy of next generation tyrosine kinase inhibitors (TKIs) against on-target mutations, their first-line administration could increase the relevance of off-target resistance mechanisms. Activating PIK3CA mutations and PTEN loss have been described as putative off-target resistance mechanisms across generations of EGFR TKIs. The role of these alterations in the development of resistance to ALK TKIs has been less described. MATCH-R trial (NCT02517892) is an ongoing prospective study whose objective is to understand mechanisms of acquired resistance to cancer therapies and develop strategies to overcome it. Materials and methods: We collected clinical and molecular data of patients (pts) with NSCLC enrolled in the molecular target group (MTG) of MATCH-R trial. We identified pts with EGFR mutations or ALK rearrangements who developed PIK3CA/PTEN alterations in tissue biopsy and/or circulating tumor DNA upon progression to first-line osimertinib/alectinib. We established patient-derived cell lines (PDCL) from the identified MATCH-R pts and we engineered commercial cell lines (CCL) harboring EGFR mutation (PC9) or ALK fusion (H3122) to constitutively express PIK3CA mutations and/or to have a permanent loss of PTEN. Cell viability assays and Western blot studies with different EGFR/ALK/PI3K/mTOR inhibitors were performed. Results: Of the 186 pts with advanced NSCLC included in the MTG of MATCH-R, 110 (59.1%) harbored EGFR mutations (EGFR+) and 27 (14.5%) ALK rearrangements (ALK+). Among them, 19 received first-line osimertinib and seven first-line alectinib. Five and two pts developed PIK3CA/PTEN alterations in the EGFR+ and ALK+ groups, respectively. In the EGFR+ group, PIK3CA E545K (n=2), R108H, N345K and R357Q mutations were detected. PTEN mutations (F437fs*5 and Y27C) were concomitant with E545K and R357Q mutations, respectively. In both ALK+ pts, a PIK3CA E545K mutation was identified, together with PTEN exon 5 splicing in one case. We confirmed on CCL that PIK3CA E545K mutation, alone or in combination with PTEN loss, confers resistance to second-/third-generation EGFR/ALK TKIs. PTEN loss alone had a moderate impact on TKIs sensitivity. Overcoming strategies combining EGFR/ALK TKIs with PIK3CA/mTOR inhibitors are being evaluated and will be disclosed at the meeting. Conclusions: Activating PI3KCA mutations and molecular events leading to PTEN loss are frequent events at resistance to first-line EGFR/ALK TKIs, and can be detected concomitantly. Functional assays confirmed that these alterations act as resistance mechanisms. These observations are of interest as PI3KCA/mTOR inhibitors may have a role in overcoming resistance. Citation Format: Giorgia Guaitoli, Francesco Facchinetti, Juan David Flórez-Arango, Floriane Braye, Hayato Mizuta, Santiago Ponce-Aix, Damien Vasseur, Ken André Olaussen, Stefan Michiels, Mihaela Aldea, Jordi Remon, Fabrice Barlesi, Benjamin Besse, David Planchard, Luc Friboulet. Alterations in PIK3CA/PTEN as resistance mechanisms in lung cancer patients progressing on first-line next generation EGFR/ALK tyrosine kinase inhibitors [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 3418.

Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study.

Clinical guidelines advise osimertinib as preferred first line treatment for advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with deletions in exon 19 (del19) or exon 21 L858R mutation. However, for first-line osimertinib the real world overall survival (OS) in mutation subgroups remains unknown. Therefore, the aim of this study was to evaluate the real-world OS of those patients treated with different generations of EGFR-tyrosine kinase inhibitors (TKI), and to identify predictors of survival. Using real-world data from the Netherlands Cancer Registry (NCR) we assessed patients diagnosed with stage IV NSCLC with del19 or L858R mutation between January 1, 2015, and December 31, 2020, primarily treated with then regularly available TKIs (including osimertinib). Between January 1, 2015, and December 31, 2020, 57,592 patients were included in the NCR. Within this cohort we identified 1109 patients, 654 (59%) with del19 and 455 (41%) with L858R mutations, respectively; 230 (21%) patients were diagnosed with baseline brain metastases (BM). Patients were treated with gefitinib (19%, 213/1109), erlotinib (42%, 470/1109), afatinib (15%, 161/1109) or osimertinib (24%, 265/1109). Median OS was superior for del19 versus L858R (28.4 months (95% CI 25.6-30.6) versus 17.7 months (95% CI 16.1-19.5), p<0.001. In multivariable analysis, no difference in survival was observed between various TKIs in both groups. Only in the subgroup of patients with del19 and baseline BM, a benefit was observed for treatment with osimertinib. In this nationwide real-world cohort, survival of Dutch patients with advanced NSCLC and an EGFR del19 mutation was superior versus those harboring an L858R mutation. Osimertinib performed only better as first-line treatment in patients with del19 and BM. None.

Clinical efficacy and prognosis analysis of treatment regimens for EGFR mutant non-small cell lung cancer and brain metastasis: a retrospective study

BackgroundThe aims of the study were to evaluate potential differences among first-line treatment for EGFR mutant (m+) non-small cell lung cancer (NSCLC) patients with brain metastasis in China and to identify the factors influencing survival outcomes.MethodsIn this retrospective study, 172 EGFRm + patients with advanced NSCLC who received a 1st generation EGFR tyrosine kinase inhibitor (TKI) were divided into 4 groups: A, EGFR-TKI (n = 84); B, EGFR-TKI + pemetrexed + cisplatin/carboplatin chemotherapy (CT) (n = 55); C, EGFR-TKI + bevacizumab (n = 15); and D, EGFR-TKI + pemetrexed + cisplatin/carboplatin CT + bevacizumab (n = 18). Intracranial and extracranial progression-free survival (PFS), the overall survival (OS), objective remission rates (ORRs) and adverse events were analyzed.ResultsIntracranial PFS of groups C + D was longer than for groups A + B (18.9 m vs. 11.0 m, P = 0.027). Extracranial PFS were longer in group B in comparison with group A (13.0 m vs. 11.5 m, P = 0.039) and in groups C + D compared to groups A + B (18.9 m vs. 11.9 m, P = 0.008). Median OS in groups A and B were 27.9 m and 24.4 m, respectively, while groups C and D have not yet achieved median OS. Significant difference was found in intracranial ORR between groups A + B vs. C + D (31.0% vs. 65.2%, P = 0.002). Most patients suffered grade 1–2 treatment-related adverse events, which were relieved soon after symptomatic treatment.ConclusionsFirst-generation EGFR-TKI + bevacizumab treatment outperformed other regimens in EGFRm + NSCLC patients with brain metastasis. The therapy improved the control and delayed progression of intracranial lesions and prolonged survival times.

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS<1%) accounted for 47.2%, low expression (1%≤TPS<50%) accounted for 32.1%, and high expression (TPS≥50%) accounted for 20.7%. Among them, patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1, accounting for 52.9% (P<0.0001). The median progression-free survival (mPFS) of patients with PD-L1 negative expression, low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months, 10.5 months and 3.7 months, respectively, with significant statistical difference (P<0.0001). During the EGFR-TKIs treatment, patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy (mPFS: 17.0 months vs 9.3 months, P<0.0001). The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells. The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor. PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.

The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer

The discovery of potent EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has revolutionized the treatment of EGFR-mutated lung cancer. Despite the fact that EGFR-TKIs have yielded several significant benefits for lung cancer patients, the emergence of resistance to EGFR-TKIs has been a substantial impediment to improving treatment outcomes. Understanding the molecular mechanisms underlying resistance is crucial for the development of new treatments and biomarkers for disease progression. Together with the advancement in proteome and phosphoproteome analysis, a diverse set of key signaling pathways have been successfully identified that provide insight for the discovery of possible therapeutically targeted proteins. In this review, we highlight the proteome and phosphoproteomic analyses of non-small cell lung cancer (NSCLC) as well as the proteome analysis of biofluid specimens that associate with acquired resistance in response to different generations of EGFR-TKI. Furthermore, we present an overview of the targeted proteins and potential drugs that have been tested in clinical studies and discuss the challenges of implementing this discovery in future NSCLC treatment.

Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell Lung Cancer Patients with Acquired EGFR T790M Mutation

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

PD‐L1 blockade by immune checkpoint inhibitors impairs sensitivity to osimertinib in EGFR‐mutant non‐small cell lung cancer cells

In the previous studies, it was shown that osimertinib plus durvalumab did not achieve satisfactory efficacy, even inferior to osimertinib alone. We found that PD-L1 blockade impaired the efficacy of osimertinib in EGFR-mutant NSCLC cells despite the presence of the tumor microenvironment. Therefore, durvalumab has no synergistic effect on osimertinib, and combination therapy will not enhance the efficacy of osimertinib. In recent years, the management of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has developed rapidly. Osimertinib is a third generation EGFR tyrosine kinase inhibitor (TKI), which has achieved satisfactory efficacy and tolerability as the first-line (FLARUA study [ref]) and second-line (AURA series of studies [ref]) treatment of patients with EGFR-mutant NSCLC. This suggested that EGFR signaling is involved in the upregulation of programmed cell death ligand 1 (PD-L1) expression, which induces apoptosis of T cells, thereby promoting immune escape of tumor cells [1]. Therefore, several studies were conducted to explore the efficacy and safety of osimertinib combined with PD-L1 monoclonal antibody durvalumab in patients with EGFR-mutant NSCLC. The TATTON study is a phase Ib trial of osimertinib combination therapy, including durvalumab, in treatment of advanced EGFR-mutant NSCLC. Results showed that the combination of osimertinib and durvalumab resulted in an objective response rate (ORR) of 43%, but an increased incidence of interstitial lung disease (ILD) (22%). Another phase III study of osimertinib versus osimertinib plus durvalumab, the CAURAL trial, whose recruitment was terminated early due to the high incidence of ILD in the TATTON trial, showed an ORR of 80% in the osimertinib arm compared with an ORR of 64% in the combination arm [2]. Therefore, the combination of osimertinib plus durvalumab did not appear to provide a significant improvement in efficacy compared with osimertinib alone [3]. Regardless of the impact of durvalumab on the tumor microenvironment and the high incidences of adverse events, whether PD-L1 blockade itself has a synergistic effect on osimertinib treatment is still unknown. The role of PD-L1 blockade in the treatment of EGFR-mutant NSCLC with osimertinib, regardless of the effect on the tumor immune microenvironment, has not been reported. Here, we used a human EGFR-mutant NSCLC cell line HCC4006 (ATCC® CRL-2871™) to test the IC50 of osimertinib alone or in combination with different concentrations of durvalumab to explore the effect of osimertinib in blocking PD-L1. After seeding cells in 96-well plates, the cells were treated with a concentration gradient of osimertinib (manufacturer, city and country) ranging from 1 to 40 µm, diluted in serum-free medium alone or with 0.5 mg/mL durvalumab (manufacturer, city and country), 1 mg/mL durvalumab or 2 mg/mL durvalumab, respectively. After an additional 24 h of incubation, an MTS assay was performed to examine the IC50 of osimertinib against EGFR-mutant NSCLC cells using different solvents. It was proved that the IC50 of osimertinib continued to increase with the increase of durvalumab concentration compared with osimertinib alone, which was 6.202 µm, 9.28 µm, 13.37 µm, and 15.18 µm for osimertinib plus 0.5 mg/mL durvalumab, osimertinib plus 1 mg/mL durvalumab and osimertinib plus 2 mg/mL durvalumab, respectively (Figure 1). Currently, there is still a lack of evidence for first-line osimertinib combined with durvalumab or other immune checkpoint inhibitors (ICIs) in patients with EGFR-mutant NSCLC. In the above-mentioned previous studies, it was shown that combination therapy did not achieve satisfactory efficacy, even inferior to osimertinib alone. Durvalumab blocks PD-L1 on the surface of tumor cells and relieves the suppressive effect of immune cells in the tumor stroma. However, based on in vitro experiments, we found that PD-L1 blockade impaired the efficacy of osimertinib in EGFR-mutant NSCLC cells despite the presence of the tumor microenvironment. Therefore, durvalumab has no synergistic effect on osimertinib, and combination therapy will not enhance the efficacy of osimertinib. In summary, we should be cautious when choosing first-line EGFR-TKIs combined with immunotherapy. Conception/design: Dantong Sun and Junling Li. Collection and/or assembly of data: Dantong Sun and Puyuan Xing. Manuscript writing: Dantong Sun and Junling Li. Final approval of manuscript: All authors. None. The authors declare no conflict of interest. All experiments were carried out following the National Health and Family Planning Commission of the Professional Regulation Commission (PRC) guidelines. Not applicable. Data supporting this report are available from the corresponding authors on reasonable request.

362P Intracranial activity of dacomitinib in treatment naïve advanced EGFR mutated non-small cell lung cancer (NSCLC): Prespecified subgroup analysis of the ATORG-003 trial

Dacomitinib is a second generation EGFR tyrosine kinase inhibitor approved as first-line therapy in advanced EGFR mutated NSCLC. In the phase 3 ARCHER 1050 trial, PFS and OS were improved with dacomitinib compared to gefitinib. However, patients (pts) with central nervous system (CNS) metastases (mets) were ineligible to enroll into the study. ATORG-003 is an ongoing investigator-initiated single-arm phase 2 trial evaluating a dose titration strategy to improve the safety and tolerability of dacomitinib whilst maintaining efficacy.

322MO Amivantamab in combination with lazertinib in patients with atypical epidermal growth factor receptor (EGFR) mutations excluding exon 20 insertion mutations: Initial results from CHRYSALIS-2

Atypical epidermal growth factor receptor (EGFR) mutations spanning exons 18 to 21 account for 10–15% of cases of EGFR-mutated non-small cell lung cancer (NSCLC). Afatinib is the only EGFR tyrosine kinase inhibitor (TKI) approved to treat these mutations. The combination of amivantamab, an EGFR-MET bispecific antibody, and lazertinib, a 3rd generation EGFR TKI, is being evaluated in patients with atypical EGFR mutations.

Factors Associated with Outcomes in Patients with Metastatic NSCLC Receiving Osimertinib and Consolidative Radiation Therapy

<h3>Purpose/Objective(s)</h3> Outcomes for EGFR-mutated non-small cell lung cancer (NSCLC) have improved significantly with the development of osimertinib (osi), a 3^rd generation EGFR tyrosine kinase inhibitor (TKI). Effective management of oligoprogressive and oligopersistent disease on osi has become more clinically relevant, however current data is sparse. We aim to identify factors associated with improved outcomes for consolidative RT to guide clinicians prior to the completion of ongoing randomized studies. <h3>Materials/Methods</h3> We conducted a single-institution retrospective study of patients with histologically confirmed, metastatic NSCLC treated with osi and consolidative RT from 2015-2021. Consolidative RT was defined as EGFR TKI. Oligoprogression was defined as size increase of ≤5 lesions, while oligopersistent disease was defined by stable or decreased lesion size after EGFR TKI. Univariable analysis (UVA) was performed using the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), measured from end of consolidative RT. <h3>Results</h3> Patient demographics are listed in 1. < 3 lesions at time of consolidative RT (HR 0.27; p=0.046) and EGFR T790M mutation (HR 0.27; p=0.015) was associated with improved PFS. EGFR L858R mutation was associated with shorter PFS (HR 3.06, p=0.025) and size of largest treated lesion approached significance for shorter PFS (HR 1.47; p=0.056). Tumor size by TNM staging (HR 1.5; p=0.053) and EGFR T790 mutation (HR 0.27; p=0.058) approached significance for OS. <h3>Conclusion</h3> In the setting of consolidative RT after osi, improved PFS correlated with < 3 lesions at the time of consolidative RT and EGFR T790 mutation. PFS decrease was correlated with largest treated lesion size and EGFR L858R mutation. This suggests that radiation for oligoprogressive or oligopersistent disease may offer clinical benefit to selected patients, particularly those with less than 3 sites of active disease or limited lesion size. Further investigation in a prospective setting is warranted.

64 (PB054) - BDTX-1535, a fourth generation EGFR inhibitor, targeting intrinsic and acquired resistance mutations in NSCLC

Background: The classical mutations of the epidermal growth factor receptor (EGFR) in NSCLC are the exon 19 del and exon 21 (L858R) mutations. The 3rd generation EGFR tyrosine kinase inhibitor (TKI), osimertinib, has become the first-line treatment of choice for NSCLC patients with these mutations. Resistance to 3rd generation TKIs can be driven by gain of secondary EGFR alterations, e.g., substitution at cysteine-797 to serine (C797S). Real world evidence shows that in addition to C797S, other EGFR alterations are also acquired upon osimertinib treatment, including kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. In addition to the classical mutations, NSCLC tumors express a wide spectrum of primary kinase domain mutations including G719X in exon 18, S768I in exon 20, and L861Q in exon 21, which confer intrinsic resistance to approved TKIs. NCCN guidelines recommend the use of afatinib or osimertinib, however, there remains a need for an EGFR TKI that targets these mutations with high potency, good tolerability, and CNS penetration. Our MAP platform allowed us to select MasterKey inhibitor BDTX-1535, a 4th-generation CNS penetrant EGFR TKI, that potently and selectively targets multiple intrinsic and acquired resistance EGFR alterations. Materials and Methods: BDTX-1535 preclinical exposure was evaluated across species, and PK and Kpuu values were calculated in brain and plasma. Antitumor activity was assessed across a broad range of mouse PDX and allograft models. Results: BDTX-1535 is a potent and selective, CNS penetrant, wild type sparing, irreversible EGFR TKI targeting Exon 18–21 alterations which are associated with intrinsic or acquired resistance to 3rd generation EGFR inhibitors. These include a broad range of kinase domain EGFR mutations (e.g., C797S, L718Q, G724S, S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. Mouse xenograft and allograft studies showed that BDTX-1535 consistently achieves regression of tumors carrying these mutations at well tolerated doses without significant EGFR wild type associated toxicities. BDTX-1535 is orally bioavailable with a CNS Kpuu of 0.55 and 0.48 in rat and dog, respectively, and active in an intracranial PDX model. Conclusions: BDTX-1535 is a 4th generation CNS penetrant EGFR TKI discovered using the MAP platform which allows MasterKey targeting of EGFR alterations associated with intrinsic or acquired resistance to 3rd generation EGFR TKIs, while sparing wild type EGFR. This broad spectrum coverage of resistance mutations in conjunction with CNS penetration properties allows BDTX-1535 to address a key unmet medical need in EGFR mutant lung cancer. BDTX-1535 is currently under phase I clinical investigation (NCT05256290). Conflict of interest: Ownership: Black Diamond Therapeutics

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors.

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations, in order to achieve maximal response duration or treatment remission. Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment. Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy. It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs, particularly osimertinib, to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance. Hence, restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

EGFR T790M testing through repeated liquid biopsy over time: a real-world multicentric retrospective experience.

BackgroundAbout 15% of non-small cell lung cancers (NSCLCs) harbor epidermal growth factor receptor (EGFR) mutations. Upfront treatment with first and second generation EGFR tyrosine kinase inhibitors (1-2gen TKIs) is superior to chemotherapy. The most frequent resistance mechanism to 1-2gen TKIs is EGFR T790M mutation, which is targeted by osimertinib. T790M mutation can be revealed by liquid biopsy (LB) or by tissue rebiopsy (TB). LB is easily feasible but less sensitive than TB. We focused on repeated LBs and analyzed clinical features associated with EGFR T790M detection.MethodsThis is a retrospective multicenter observational study including EGFR-mutant NSCLC consecutive patients with disease progression (PD) after 1-2gen TKIs and with a first EGFR LB negative for T790M mutation, referred between 2016 and 2019. Aims of the study were to determine the prevalence of T790M mutation using LB in a real-life setting and the prevalence of T790M mutation by repeated LBs. We explored the association of T790M with clinical-pathological features and, through a survey, we evaluated the decision-making process behind LB request. Data on TBs were also collected.ResultsOne hundred and ten patients were included in the study, for a total of 326 LBs. Median number of LB per patient was 3.0. The T790M prevalence through LB was 34.5%. Over time, significantly more LBs were requested “at clinical and radiological PD” and “at radiological PD” compared to “arbitrarily”. The probability of finding the T790M mutation for a patient across each subsequent LB did not significantly change. Liver and lymph node PD were significantly correlated to T790M positivity. Notably, “at PD” compared to “arbitrarily” LB request and liver, bone or lymph node PD were correlated to the detection of any EGFR mutation in cfDNA. TB was performed in 59.7% of patients with a T790M negative LB and 18.8% of them were T790M positive. In most cases, TB was not feasible due to anatomical reasons. In our study population, the overall T790M prevalence—detected with both LB and TB—was 42.7%.ConclusionsRepeated LB testing can be useful in a real-life scenario to detect EGFR T790M mutation.

991P EGFR exon 20 insertions in non-small cell lung cancer (NSCLC): Impact of TP53 mutation status and value of immune checkpoint blockade (ICB)

About 4% of all EGFR mutations account as exon 20 insertions, which convey resistance to the first three generations of EGFR-tyrosine kinase inhibitors (TKIs). Recent research has revealed new drugs to target these mutations specifically. However, little is known about the impact of immune-checkpoint blockade (ICB) in this subgroup, especially in patients with co-occurring TP53 mutations. We analyzed co-occurring mutations in patients with EGFR exon 20 insertions and their influence on the efficacy of systemic treatment. The main focus was impact of ICB on overall survival (OS) in these patients with or without TP53 mutations. Co-mutational status was assessed using next-generation-sequencing (NGS) panels. TP53 mutations were further divided into truncating vs. non-truncating mutations. Real-world-data (RWD) of 159 advanced NSCLC patients with EGFR exon 20 insertion in the timeframe of 2014-2020 were analyzed. TP53 mutation was the most common co-occurring mutation in 69 (43.6%) patients. OS of TP53 wildtype patients was significantly longer with 851 vs. 444 days (p=0.003, Log Rank). No difference of OS referring to the subtype of TP53 mutations was observed (p=0.703). In total, 66 pts were treated with ICB in one of the treatment lines and trended towards longer OS of 824 vs. 479 days, without reaching significance (p=0.402). In patients with co-occurring TP53, patients who received ICB (n=33) had longer OS than those without ICB exposure (507 vs. 369 days, p=0.086). Lack of significance might be explainable by a median follow-up time of 1498 days (4.1 years). Regardless of subtype, TP53 co-occurring mutation seems to be a strong negative prognostic factor in NSCLC patients with EGFR exon 20 insertions. However, these patients seem to benefit from the ICB, especially at the beginning of their treatment pathway.

EP08.02-034 OCELOT - Osimertinib then Chemotherapy in EGFR+ Lung Cancer with Osi Third-line Rechallenge and Osimertinib for Uncommon EGFRm in 1L

The FLAURA study established osimertinib as a preferred first-line standard of care for patients with the two ‘common’ types of epidermal growth factor receptor mutation-positive (EGFR+) advanced non-small-cell lung cancer (aNSCLC). Second-line (2L) treatment is typically platinum pemetrexed chemotherapy and the standard third-line (3L) treatment is docetaxel, which has a modest response rate of 7 - 15%. Previously, when first generation (1G) EGFR tyrosine kinase inhibitors (TKIs) were standard of care in the first-line setting, a number of prospective and retrospective studies examined 3L rechallenge with the same 1G EGFR TKI following 2L chemotherapy, with varying levels of success.

1055P The gene landscape of lung adenocarcinoma patients with progressive disease of the leptomeninges

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Still, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to the limited access to intracranial tumor tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear. 45 LM-LUAD from May 2019 to June 2021 in the Guangdong Sanjiu Brain Hospital enrolled in this study. 75% (34/45) of patients with LM harboring EGFR mutation, patients with progressive disease (PD) of LM have 3rd generation EGFR-TKI therapy, defined as Cohort 1; without 3rd generation, EGFR-TKI therapy, defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients have matched plasma (PLA). The common gene alterations discovered in CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), PIK3CG (4/45, 9%). Co-occurring mutations of TP53 and EGFR were found in 49% (22/45) patients and correlated with poor prognosis. CDKN2A mutation was identified in 20% (9/45) patients and presented slightly shorter OS than those without (OS, 7.1 versus 8.8 months, p=0.2). Cohort 1 has more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alternation of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as (CDK4, CDKN2A, MET, APC, KRAS, FGFR3, JAK2, BRAF, PIK3CG) more likely identified in CSF. All the mutant allele frequency (MAF) were much higher in CSF compared to matched PLA. CSF could be a potential candidate for the genetic profiling of LM-LUAD, demonstrating the genetic characteristic of LM in EGFR-mutated lung adenocarcinoma on diversity EGFR-TKI therapy.

EP08.02-038 Study of First-Line Aumolertinib Plus Bevacizumab and Pemetrexed Treated NSCLC with EGFR Mutation and Brain Metastasis

Brain metastases (BMs) are common among patients with lung cancer and have been associated with treatment failure and limited survival. Approximately 25% of NSCLC patients present with BMs at first diagnosis. Patients treated with 3rd generation EGFR-tyrosine kinase inhibitors (TKIs), including aumolertinib and osimertinib, showed a lower risk of progression and better responses with EGFRm NSCLC and BMs. Studies suggested EGFR-TKI plus bevacizumab had PFS benefits for patients with CNS metastases, and combination strategies of chemotherapeutic agents and TKI also demonstrated the potential to improve survival.

A Multicenter Two-arm, Phase II Trial Assessing the Safety and Efficacy of First-line Lazertinib and Locally Ablative Radiotherapy in Patients With Synchronous Oligo-metastatic EGFR-mutant Non-small Cell Lung Cancer (ABLATE, KCSG-LU21-11)

BackgroundThe current standard treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation is upfront EGFR targeted therapy. However, patients invariably experience disease progression at primary tumors or metastatic sites. Adding stereotactic body radiation therapy (SBRT) to systemic therapy can improve progression-free survival (PFS) and overall survival (OS). This multicenter, 2-arm, phase II study aims to evaluate the efficacy and safety of lazertinib, a third generation EGFR tyrosine kinase inhibitor, combined with upfront locally ablative radiotherapy in EGFR-mutant NSCLC patients with synchronous oligometastatic disease (ClinicalTrials.gov: NCT05167851). Patients and MethodsKey inclusion criteria are biopsy-proven EGFR-mutated adenocarcinoma with synchronous, oligometastatic (≤5 metastases) NSCLC. Patients will be randomized 1:1 to receive lazertinib or lazertinib + SBRT to the primary tumor and metastatic sites. The primary endpoint is PFS according to RECIST: Response Evaluation Criteria in Solid Tumor version 1.1, and the secondary endpoints are OS, objective response rate, and safety. ResultsPatient enrolment began in January 2021 and is ongoing at 7 sites in the Republic of Korea. ConclusionThis trial will provide valuable information on the efficacy and safety of lazertinib in combination with SBRT in patients with synchronous, oligometastatic EGFR-mutant NSCLC.