2nd Generation EGFR Research Articles

PDL1-status predicts primary resistance of metastatic, EGFR-mutated non small cell lung cancers to EGFR tyrosine-kinase inhibitors

BackgroundEGFR tyrosine-kinase inhibitors (TKIs) are the reference treatment for metastatic, EGFR-mutated, non-small-cell lung cancers (EGFRm NSCLCs). However, 16–20% of those tumors progress early (3–6 months) and factors predicting that resistance are unknown. This study was undertaken to examine PDL1 status as such a factor. MethodsThis retrospective analysis included metastatic, EGFRm-NSCLC patients who received first-line 1st-, 2nd- or 3rd-generation EGFR TKIs with PDL1 expression determined in pretreatment biopsies. Kaplan–Meier estimations of probabilities of progression-free survival (PFS) and overall survival (OS) were compared with log-rank test, and logistic-regression analyses. ResultsPDL1 status of the 145 included patients was ≥1% (47%), 1–49% (33%) or ≥50% (14%). For PDL1-positive vs PDL1-negative patients, respectively, median PFS lasted 8 (95% CI: 6–12) vs 12 (95% CI: 11–17) months (p = 0.008), with 18% vs. 8% (NS) of NSCLCs progressing at 3 months, and 47% vs. 18% (HR 0.25 [95% CI 0.10–0.566], p<0.001) at 6 months. Multivariate analysis retained 1st- or 2nd-generation EGFR TKI, brain metastases and albuminemia <35 g/L at diagnosis as significantly associated with shorter PFS, but not PDL1 status, which was independently associated with progression at 6 months (HR 3.76 [1.23–12.63], p = 0.02). PDL1-negative and PDL1-positive patients’ OS lasted 27 (95% CI 24–39) and 22 (95% CI 19–41) months, respectively (NS). Multivariate analysis retained only brain metastases or albuminemia <35 g/L at diagnosis as being independently associated with OS. ConclusionPDL1 expression ≥1% seems to be associated with early progression during the first 6 months of first-line EGFR-TKI treatment of metastatic EGFRm NSCLCs, without impacting OS.

24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy

24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy

995P Effectiveness of combination of osimertinib with another targeted therapy in advanced EGFR mutated non-small cell lung cancer harbouring other oncogenic drivers: The real-world COMPOSIT study

Identification of resistance mechanisms is crucial to guide therapeutic approaches in patients receiving osimertinib (O). The COMPOSIT study is a French national cohort reporting the effectiveness and tolerance of O in combination with another targeted therapy (TT) in patients with advanced EGFR mutated NSCLC harboring other oncogenic drivers. Patients (pts) treated with O between 01.01.2017 and 30.04.2021 who received a combination of O with another TT were included. Clinical pathological and molecular data were retrospectively collected. The primary endpoint was real-world progression free survival (rwPFS). 55 pts were included from 14 centers. Median age was 59 years (range 29-83); 56.3% were women, 60% never smokers and DelEx19 of EGFR was observed in 69% of cases. Combination therapy was administered to 23 pts who received O as 1st line (41.8%) and to 32 pts in whom O was administrated after receiving chemotherapy and/or 1st or 2nd generation EGFR TT (58.2%). MET pathway was the most targeted mechanism by combination therapies (66.1%). Real world PFS data was available for 54 combinations. Median follow-up was 16.7 months (95% CI; 13.3-19.1). The median rwPFS was 4.1 months (95% CI; 3.2-5.5). Overall response rate (ORR) was 49.0% (95% CI; 35.3-62.7%). The median overall survival (OS) was 11.9 months (95% CI; 8.6-19.6). In MET pathway alterations, rwPFS was 5.3 months (95 CI; 3.9-6.7), ORR 59.4% (95% CI; 42.4-76.4) and OS 14.8 months (95% CI; 7.4-33.2). Adverse events (AE) of grade >2 were reported in 13 patients (23.6%), mainly not related to O (93%). The frequency of drug interruption due to AE was 12.7%.Table: 995PCombination therapies with osimertinib (O) evaluated in COMPOSIT StudyPatients (n=55)Alteration targetedO + Targeted therapy36MET amplificationO + crizotinib (n=19) O + capmatinib (n=7) O + savolitinib (n=4) O + tepotinib (n=5) O + crizotinib then O + capmatinib (n=1)5BRAF fusionO + trametinib5BRAF V600EO + trametinib (n=1) O + dabrafenib (n=2) O + dabrafenib Trametinib (n=2)2EGFR C797S + T790MO + brigatinib1EGFR C797S + T790M cisO + gefitinib1EGFR L861Q + G724S + T790MO + afatinib2RET rearrangementO + praseltinib1ALK rearrangementO + crizotinib1FGFR1 amplificationO + erdafitinib1HER2 amplificationO + trastuzumab Open table in a new tab To our knowledge, this is the largest real-world study of combination therapies in patients with advanced EGFR-mutated NSCLC harboring other oncogenic drivers. Combination approaches with O are already used to overcome resistance by clinicians.

Abstract 3323: Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation

Abstract EGFR is a transmembrane protein that functions as a receptor tyrosine kinase (RTK). Upon ligand binding or by activating mutations (Exon19 deletion, L858R mutation, and others), EGFR turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations and amplifications are frequently found in various human cancers and, in non-small cell lung cancer (NSCLC), the EGFR gene is mutated with 10-15% frequency (about 50% in Asian patients). While the 1st and 2nd generation EGFR inhibitors are effective in targeting EGFR mutants with Exon19 deletion and L858R mutation, additional T790M mutation in the EGFR gene causes resistance. The 3rd generation EGFR inhibitor (Osimertinib) works against EGFR mutants with T790M mutation; however, another EGFR mutation occurs at the amino acid 797 position (C797S), which makes Osimertinib ineffective. This is one of the major resistance mechanisms in Osimertinib-treated patients, and the 4th generation EGFR inhibitor that can target the C797S mutant is needed. We developed a compound that effectively disables various EGFR mutations, including Del19/T790M/C797S, L858R/T790/C797S, Del19/C797S, and L858R/C797S. In vitro kinase assay and cellular assays showed high potency and selectivity. In vivo PK/PD and efficacy tests confirmed the great therapeutic potential of this inhibitor for patients with EGFR mutations. Citation Format: Dongsu Kim, Woo Seung Son, Anna Jang, Yeri Lee, Donggeon Kim, Changyu Choi, Kyung Hoon Min, Sung Pil Choi, Sang Kyun Lim. Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3323.

Abstract 5158: Detection of EGFR mutations in plasma cfDNA and paired CTCs of NSCLC patients before and after osimertinib therapy using crystal digital PCR

Abstract Background: Circulating tumor DNA (ctDNA) analysis has clinical utility in EGFR mutantNSCLC. Circulating tumor cells (CTCs) constitute a unique source of information at thecellular level. Digital PCR (dPCR) is a valuable tool for accurate and valid mutation analysisin liquid biopsy. The aim of the current study was to detect EGFR mutations in plasma cfDNA and paired CTC-fractions of NSCLC patients before the initiation of osimertinib therapy and at progression of disease using crystal digital PCR (cdPCR). Patients and Methods: Forty-eight patients with EGFR mutated lung adenocarcinomas resistant to 1st or 2nd generation EGFR TKIs were treated with osimertinib in the context of a multicenter Phase II clinical study (NCT02771314). 2 mL of plasma were used for cfDNA extraction using the IDXtract kit (ID-Solutions, France). Crystal dPCR (naica® system, StillaTechnologies, France) was used to quantify mutation allele frequencies (MAF) of EGFRmutations in 91 cfDNA samples before and after osimertinib. 80 identical plasma samples were also analyzed with the FDA-approved cobas® technology. In parallel, EGFR mutations were detected with cdPCR in 64 matched CTC-fractions enriched by Parsortix™ (ANGLE plc, UK).Quality control steps were followed both at the preanalytical and analytical level. Results: Direct comparison between cdPCR and cobas® revealed high concordance rates forall EGFR mutations; however, in case of T790M, cdPCR proved to be more sensitive. Patients with higher %MAFs at PD presented significantly lower PFS compared to those with lower levels or without EGFR mutations. Direct comparison of EGFR genotyping between primary tissue and baseline plasma cfDNA samples revealed high concordance rates, too. During EGFR mutation analysis in paired CTC-derived gDNA, 11 samples were found positive for EGFR mutations with %MAF ranging from 0.2 to 2.25%. Conclusions: Crystal dPCR combines the unique benefits of sensitivity and accuracy with the multiplexing capacity for the detection of multiple EGFR mutations in plasma cfDNA samples and CTCs. High concordance rates were observed between cdPCR and cobas® assay. For the first time, cdPCR was applied to detect EGFR mutations in CTC-derived gDNA of NSCLC patients under osimertinib. Discordance between plasma and CTC-fractions might be indicative of tumor heterogeneity and predictive for acquired resistance. Acknowledgements-The research presented was carried out within the framework of a Stavros NiarchosFoundation grant to the National and Kapodistrian University of Athens-The authors would like to thank Larry Ba (Stilla Technologies, France) and Daniel Henaff(ID-solutions, France) for kindly providing the naica® digital PCR system and the ID-solutionskits, respectively. Citation Format: Aliki Ntzifa, Athanasios Kotsakis, Vassilis Georgoulias, Evi Lianidou. Detection of EGFR mutations in plasma cfDNA and paired CTCs of NSCLC patients before and after osimertinib therapy using crystal digital PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5158.

P47.08 A Phase II, Single-arm, Multicenter, Efficacy of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With EGFR Mutated NSCLC

Leptomeningeal metastases (LM) are severe, an aggressive complication of cancer, characterized by tumor cell spread to the cerebrospinal fluid (CSF) and leptomeninges. The higher incidence of LM in EGFR mutated non-small cell lung cancer (NSCLC) has been observed, especially after treated with 1st or 2nd generation EGFR TKI. The Osimertinib, the third generation irreversible EGFR TKI, has been developed to target T790M mutation. Unlike other EGFR TKIs, Osimertinib showed homogenous distribution to the brain suggesting high penetration of blood-brain barrier, and clinical efficacy in intracranial lesions has been demonstrated from the retrospective analyses.

MA02.07 T-DM1 and Osimertinib (TRAEMOS) To Target HER2 Bypass Track Resistance in EGFRm+ NSCLC: Interim Analysis of a Phase II Trial

Despite high response rates to osimertinib in patients with EGFR mutation positive (EGFRm+) NSCLC, resistance inevitably develops. HER2 overexpression and amplification is detected in 13% of NSCLC-patients with acquired TKI-resistance. Previously, we showed that trastuzumab and paclitaxel in this setting is associated with a 41% ORR. Here, we evaluated the efficacy and toxicity of trastuzumab-emtansine (T-DM1) and osimertinib in patients with HER2 overexpression and/or amplification after progression on osimertinib as last line of treatment. We report a pre-planned interim analysis. In this multicenter single arm phase II study with a safety run-in (NCT03784599), eligible patients (≥18 years, WHO PS ≤2) with EGFRm+ NSCLC, progressing on EGFR TKI treatment and with HER2 overexpression (IHC ≥2+ in ≥10% of the cells) and/or HER2 amplification (ISH and/or NGS) were included. Patients were treated with T-DM1 3.6 mg/kg (IV infusion) every 3 weeks and osimertinib 80 mg QD. For patients with progression on 1st or 2nd generation EGFR TKIs, osimertinib monotherapy was initiated and T-DM1 was added at time of progression on osimertinib. Primary endpoints were to assess the ORR after 12 weeks and to evaluate safety of the combination treatment. In the safety run in, assessed in a classical 3+3 design, the first 3 patients received T-DM1 3.0 mg/kg. If none of these 3 patients developed a dose limiting toxicity (DLT), the T-DM1 dose was escalated to the standard dose of 3.6 mg/kg. Responses were assessed every 6 weeks according to RECIST 1.1. Treatment was continued until progression or unacceptable toxicity. Sample size was calculated using Simon’s two stage minimax design (H0=41%, H1>55%, 80% power, one-sided type I error rate of 10%, sample size: 58 patients, cohort A ORR 16/36 in order to proceed to cohort B). From January 15 2019 until April 6 2021, 27 patients were included and started with T-DM1. In the safety run in, none of the patients developed a DLT. Therefore, the study continued with osimertinib 80 mg QD and T-DM1 3.6 mg/kg IV infusion q 3 weeks. ORR and DCR after 6 weeks of treatment, evaluable in 24 patients, was 0% and 63% (16/24) respectively. One patient is not yet evaluable for the primary endpoint. ORR and DCR after 12 weeks of treatment were 13% (3/23) and 43% (10/23). DCR in HER2 IHC2+ and 3+ cohort was 36% (5/14) and 55% (5/9). Median PFS was 2.8 months (95% CI, 2.3-3.3 months), median duration of disease control was 20 weeks (range 4-47 weeks). Grade 2/3 adverse events occurred in 29%/21% of patients, including pneumonitis, LVEF decrease, fatigue, erythema and CK elevation. There were no grade 4 and 5 therapy-related adverse events. TRAEMOS is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC and progression on osimertinib to target HER2 bypass track resistance. Safety profile is favorable compared to cytotoxic chemotherapy, however this treatment strategy showed very limited efficacy. Further clinical evaluation of this regimen is not warranted.

1206P UNcommon EGFR mutations: International Case series on efficacy of Osimertinib in Real-life practice in first-liNe setting (UNICORN)

About 10% of EGFR mutations (EGFRmut) are ‘uncommon mutations’ (ucEGFRmut), correlating with lower response to 1st & 2nd generation EGFR inhibitors (EGFRi) compared to common mutations. Osimertinib is a 3rd generation EGFRi, active against common EGFRmut. Efficacy data of osimertinib in ucEGFRmut are scarce. We aimed to collect real-world data of the usage of osimertinib as the 1st EGFRi for ucEGFRmut. This is a multi-center, international, academic-initiated retrospective study of mNSCLC with ucEGFRmut treated with osimertinib prior to any other EGFRi. RECIST response was evaluated by investigators. PFS and OS were calculated by Kaplan-Meier method from initiation of Osimertinib, duration of response (DOR) was calculated for responders. 46 patients were identified in 18 centers from 8 countries (Austria, Belgium, France, Germany, Italy, Israel, Spain, Switzerland). Median age was 64 (range 37-91) years, 72% females, 89% Caucasian, never/former/current smokers were 50%/33%/15% respectively, ECOG PS was 0-1/2/3-4 in 78%/13%/6.5%. G719X was the most frequent mutation (16 pts, 34.8%), followed by de novo T790M (9 pts, 22%, 5 of them compound with common mutations) and L861Q (7 pts, 15.2%). Compound EGFR mutations were found in 16 pts (34.8%), TP53 mutations in 13 pts (28.3%). Most frequent metastatic sites were brain/bone/lung in 47%/47%/36% respectively. For 37 pts (80.4%), osimertinib was the 1st treatment given for advanced disease. Most frequent toxicities were gastrointestinal (24 pts, 52%) and skin (16 pts, 35%); 5 patients had grade 3-4 AEs. RECIST response (RR) was available for 44 pts, CR for 2 (4.5%), PR for 20 (45.5%), SD for 17 (38.6%), and PD for 5 (11.4%). Median DOR was 17.4 months (95% CI 9.1-NA). RR for G719X was 43.8%, 33.3% for T790M, and 71.4% for L861Q. Median PFS was 9.1 months (95% CI 8.1–19.2). Median OS was 18.4 months (95% CI 13.5-NR). Osimertinib showed activity in ucEGFRmut with 85% disease control rate and encouraging PFS and DOR. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRmut. UNICORN continues to recruit patients, to expand our knowledge on efficacy of osimertinib for these patients.

1214P High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from a phase II multicenter study, POSITION20

Clinical benefit to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI’s) is lacking for non-small cell lung cancer (NSCLC) patients with an EGFR exon 20 mutation (EGFRex20+), with known response rate (RR) from 0-28%, and median progression free survival (PFS) of ∼3 months to 1st and 2nd generation EGFR TKI’s (Remon, Cancer Treatment Reviews 2020). A high dose of the 3rd generation TKI osimertinib shows promising antitumor activity to EGFRex20+ in vitro. The safety and efficacy results from a multicenter single arm phase II study investigating osimertinib in EGFRex20+ NSCLC patients are reported here.

Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive NSCLC in Korea: KCSG LU-19-22.

9053 Background: While osimertinib showed impressive efficacy and safety profile in 1st-line setting for EGFR mutation-positive (EGFR M+) NSCLC patients, there are no standard targeted therapy following progression. Thus, interest has been growing on sequential treatment of osimertinib as 2nd-line treatment for patients acquiring T790M resistance mutation after 2nd generation EGFR TKIs. We did a retrospective study to support the hypothesis that sequential approach of afatinib followed by osimertinib represents a practical treatment option in ‘real-world’ practice. Methods: In this non-interventional, multicenter study, EGFR M+ NSCLC patients had to start 1st-line afatinib treatment ≥ 13 months prior to data entry. They were categorized into 4 cohorts according to 2nd-line treatments with retesting results: T790M+ patients sequentially treated with osimertinib in cohort A, T790M patients treated with chemotherapy or other treatments in cohort B, and patients with unknown mutation status in cohort C. Cohort D included patients who were still ongoing with afatinib. Primary outcome was the time on treatment (TOT) of patients receiving 1st-line afatinib (TOT-1) followed by 2nd-line treatments (TOT-2). Secondary endpoints were acquisition rate of T790M after progression, objective response rates of afatinib (ORR-1) and 2nd-line treatments (ORR-2), and overall survival (OS). Results: Among a total of 761 enrolled patients, 737 patients excluding 24 screening failures were allocated into cohort A (n=116), B (n=143), C (n=111), and D (n=367). Median age was 62 years (22 - 90) with 53.05% of female proportion. Brain metastasis was discovered in 38.94% at initial diagnosis. Regarding genotypes of EGFR mutations, del19 was 57.53%, 31.48% for L858R, 7.33% for uncommon mutations, and 3.66% for compound mutation. Median TOTs in cohort A, B, C, and D were 35.09 months (95% CI, 30.09 to 43.53), 18.76 months (95% CI, 16.92 to 20.20), 12.02 months (95% CI, 10.22 to 14.98), and 42.61 months (95% CI, 30.95 to 59.23), respectively. Particularly, in cohort A, median TOT-1 and TOT-2 were 17.43 months (95% CI, 15.21 to 19.32) and 11.04 months (95% CI, 7.10 to 14.13), respectively. Retesting was attempted in 262 of 370 patients (70.81%) with 44.27% of T790M detection rate. ORR-1 and -2 in cohort A, B, and C were 84.48% and 56.03%, 82.52% and 29.08%, 54.95% and 21.70%, respectively and 68.94% of ORR for cohort D. Median OS has was not reached. Conclusions: These data suggest that, in real-world practice, sequential afatinib followed by osimertinib be a feasible and effective therapeutic strategy for EGFR M+ NSCLC patients acquiring T790M during the period of afatinib treatment. Of note, median TOT in cohort D is over 3.5 years, suggesting that 1st-line afatinib potentially allow certain patients to maintain long-term, chemotherapy-free state. Further analysis is currently being undertaken and will be presented.

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non-Small Cell Lung Cancer.

PurposeEpidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.Materials and MethodsWe identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.ResultsIn cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.ConclusionOur study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

FP14.07 Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions

Selpercatinib is a highly selective and potent FDA-approved RET inhibitor that has demonstrated marked and durable efficacy in RET fusion-positive NSCLC. While RET fusions are the primary oncogenic driver in ∼2% of NSCLC, RET fusions have also been identified as acquired resistance alterations following treatment with EGFR inhibitors, including osimertinib, in EGFR-mutant NSCLC. We sought to evaluate the safety and preliminary efficacy of the combination of osimertinib and selpercatinib in patients progressing on osimertinib. Patients received selpercatinib in combination with osimertinib across three selpercatinib compassionate access programs: single patient protocols (SPP), named patient programs (NPPs), and an expanded access program (EAP). All patients had advanced EGFR-mutated NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected retrospectively. Across 12 patients identified, 11 had an EGFR exon 19 deletion (92%) and one had an EGFR L858R mutation (8%). The most common emergent RET fusion was CCDC6-RET (five patients, 42%), followed by NCOA4-RET (four patients, 33%), KIF5B-RET (two patients, 17%), and RUFY2-RET (one patient, 8%). All patients had received prior osimertinib and seven (58%) had also received a 1st or 2nd generation EGFR TKI. Most patients received selpercatinib at 80 mg BID (92%, range 100 mg QD - 120 mg BID) and osimertinib at 80 mg daily (75%, range 40 mg QD - 80 mg BID). Of twelve identified patients, 10 were evaluable for response per RECIST 1.1. Among RECIST evaluable patients five had a response (50%, four confirmed partial responses, one unconfirmed partial response). One patient, unevaluable per RECIST for non-measurable disease at baseline, demonstrated sustained clinical radiographic improvement ongoing at 8.2 months. The second unevaluable patient discontinued treatment prior to reassessment for unrelated clinical events preventing oral medication administration. The median duration of combination treatment across all 12 identified patients was 7.4 months (range 0.6 – 16.7+ months). For patients who achieved a RECIST response, the median treatment duration was 11 months (range 7.4 – 16.7+ months). Treatment was discontinued due to disease progression in seven patients, one patient discontinued for toxicity (grade 2 pneumonitis), one patient for intolerance to oral medication administration, and three patients remained on therapy at data cut-off. In one patient with a response lasting 10 months, plasma sequencing at resistance revealed persistence of EGFR 19del (22% AF) and RET fusion (0.4% AF) plus newly detected second-site resistance mutations in both EGFR (C797S, 0.1%) and RET (G810S, 0.8%), providing additional confirmation of the biologic relevance of the acquired RET fusion. For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, with evidence of radiographic responses and durable benefit. These findings support future investigation of this combination, which will be evaluated prospectively as an arm of the phase 2 ORCHARD platform study (NCT03944772). The availability of active combination targeted therapy strategies highlights the need for assessment for genomic mechanisms of resistance following initial EGFR targeted therapy in NSCLC.

1195P The value of detecting resistance through liquid biopsy

Liquid biopsy has been established as an important diagnostic step in identifying EGFR T790M resistance to 1st and 2nd generation EGFR TKIs. This has led to significant interest in exploring the value of liquid biopsy in patients with other oncogene-addicted cancers and acquired resistance to targeted therapy.

Abstract 5198: JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs

Abstract Background: 1st generation (erlotinib &amp; gefitinib), 2nd generation (afatinib), and 3rd generation (osimertinib) EGFR TKIs have marked efficacy in patient with EGFR-mutant NSCLC. Unfortunately, patients who show T790M (-) mutation after treated with 1st and 2nd generation EGFR TKI or have C797S (+) mutation or other mechanisms of acquired resistance to 3rd generation EGFR TKI have no therapeutic options for curing cancer in clinic. We introduce a potent therapeutics for overcoming acquired resistance to EGFR-TKIs in several EGFR mutant NSCLC models using JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and c-Met receptors. Methods: We classified PDC and PDX models into two groups: i) 1st and 2nd generation EGFR TKI acquired resistance models with T790M (-) mutation (YU-1093, YU-1152), ii) 3rd generation EGFR TKI acquired resistance models with C797S (+) mutation (YU-1097), and C797S (-) mutation with unknown resistance mechanisms (YU-1095, YU-1089, YU-1096, YUX-1024_YH1R, YHIM-1035, YHIM-1045, and YHIM-1053). We established 7 patient-derived cells (PDC) and 3 patient-derived xenografts (PDX) model from patients with broad-spectrum acquired resistance to EGFR-TKIs. We performed cell viability test and western blot to investigate antitumor activity of JNJ-372. We evaluated then in vivo antitumor activity of JNJ-372 in PDX and PDC-xenograft models. JNJ-372 was administrated i.p. twice a week at 30 mg/kg. Results: We assessed the ability of JNJ-372 to overcome broad-spectrum of EGFR-TKI acquired resistances. JNJ-372 significantly inhibited cancer cell growth in vitro and in vivo in PDC model harboring T790M (-) mutation. JNJ-372 significantly decreased cell proliferation rate and EGFR downstream signaling in BaF3 cell harboring Del19 (L858R)/T790M/C797S mutant and PDC model harboring Del19/T790M/C797S mutant with amplified KRAS and loss of Rb. C797S (-) cases of four PDCs and three PDX models had i) loss of T790M with c-Met amplification or other acquired resistance mutation and ii) T790M (+) with amplified c-Met. In these models we identified dramatic tumor regression and reduction of EGFR and c-Met expression in vitro and in vivo PDX and PDC-xenograft models. Interestingly, we observed combination treatment of JNJ-372 and c-Met inhibitor showed synergistic immune cell mediated cellular cytotoxicity in EGFR-TKI acquired resistance models harboring c-Met amplification. JNJ-372 exhibited potent inhibition of tumor growth in preclinical models through targeting EGFR and c-Met receptor, decreasing EGFR and c-Met receptor level, inhibiting EGFR downstream signaling cascade and activating ADCC effect in vivo. Conclusion: Our results suggest that JNJ-372 will provide potential and effective therapeutic options for patients with no therapeutic option to overcome broad-spectrum of acquired resistance to EGFR-TKIs. Citation Format: SooHwan Lee, Jiyeon Yun, Seo-Yoon Jeong, Chae Won Park, Seok-Young Kim, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho. JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5198.

Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients.

9514 Background: Treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations is an unmet medical need. Poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants. We evaluated the efficacy and safety of poziotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations in an independent cohort of a multi-cohort, multi-center Phase 2 study ( ZENITH20-1). Methods: ZENITH20-1 study enrolled pts with advanced NSCLC with an EGFR exon 20 insertion identified on local tissue testing who had received at least one prior line of therapy. Poziotinib (16 mg) was administered orally QD, allowing dose reductions for AEs, with follow up for 24 months. The primary endpoint was objective response rate (ORR), evaluated centrally by RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Efficacy was also evaluated by specific exon 20 insertions and prior lines of therapy. Results: 115 patients with a median age of 61 years (33-83) were enrolled. Patients had a median of 2 prior lines of therapy (range, 1-9.) The median relative dose intensity was 72% (7-100%) with 65% having dose reductions. The ORR in the as-treated population was 14.8% (95% CI 8.9 - 22.6%), and the DCR was 68.7% (95% CI 59.4 - 77.0%) with a median DoR of 7.4 months. 65% patients had tumor size reductions and the median PFS was 4.2 months. In the evaluable population (n = 88), the ORR was 19.3% and the unconfirmed ORR was 25%. Responses were predominantly observed in insertions between residues M766 to D770 of exon 20 (8/44; 18.2%). Responses were observed in patients with 2 lines (14%); ≥3 lines of therapy (16.2%). The most common treatment-related Grade ≥3 AEs were rash (28%), diarrhea (26%), stomatitis (9%) and paronychia (6%). The incidence of treatment-related pneumonitis was 4%, however some cases may have been confounded by prior checkpoint inhibitors as first line treatment. Conclusions: Although the ORR primary endpoint was not met, poziotinib induced tumor reduction in the majority of patients with durable responses, including the heavily pre-treated population. Responses were more common in patients with insertions between M766 to D770 of EGFR exon 20. The safety profile was overall consistent with other 2nd generation EGFR TKIs. Evaluation of these subgroups with refined dosing and improved toxicity management to maintain continuous treatment is warranted to assess the potential of poziotinib in Exon20 related tumors. Clinical trial information: NCT03318939 .

A phase III, open-label, randomized study of atezolizumab in combination with carboplatin + paclitaxel + bevacizumab compared with pemetrexed + cisplatin or carboplatin with stage IV non-squamous non-small cell lung cancer (NSCLC) with activating EGFR mutation or ALK translocation (ATLAS Trial).

TPS9636 Background: In patients with activating EGFR mutations and ALK fusion, target specific tyrosine kinase inhibitor (TKI) showed significant survival improvement compared to the cytotoxic chemotherapy. However, the questions remain which combination strategy will be the best option for the patients who have failed from TKI. Especially, the role of an immune checkpoint inhibitor (ICI) in this population is still unclear. This study is designed and conducted based on the recent subgroup analyses from the IMpower 150 study which showed the positive clinical outcomes of atezolizumab combined with VEGF inhibitor and conventional cytotoxic chemotherapy in EGFR mutation and ALK translocation. Methods: This study is the phase III, open-label, multicenter study of atezolizumab in combination with bevacizumab + carboplatin + paclitaxel (ABCP, Arm A) compared with pemetrexed + cisplatin or carboplatin (Arm B). The study population will be randomized to either Arm A (n = 152) or Arm B (n = 72) based on two stratification factors, EGFR vs. ALK and presence of brain metastases. In Arm A, patients will be treated with 4 or 6 cycles of ABCP followed by maintenance atezolizumab and bevacizumab every three weeks. In Arm B, pemetrexed maintenance therapy will be applied every three weeks after 4 or 6 cycles of pemetrexed + cisplatin or carboplatin. As key inclusion criteria, the patients must be diagnosed with stage IV non-squamous non-small cell lung cancer with either activating EGFR mutation or ALK translocation. All the patients need to be cytotoxic chemotherapy naïve and must have experienced disease progression to treatment with at least one EGFR or ALK TKI. If the patients have T790M mutation after 1st or 2nd generation EGFR TKI, second line 3rd generation EGFR TKI treatment is mandatory. The number of T790M positive patients is restricted to under 30% of the entire study population. The primary endpoint is progression-free survival and the major secondary endpoints are overall survival, objective response rate and duration of response. A total of 228 subjects will be enrolled to detect a hazard ratio of 0.67. The first subject received treatment in Aug. 2019 and 19 patients receive the treatment. This study is opened in 3 sites and expected to be opened at 18 sites in South Korea. The time point for the primary analyses is Q3. 2022. Clinical trial information: NCT03991403 .

Progression free survival (PFS) in Asian vs non-Asian patients (pts) with EGFR mutant non-small cell lung cancer (NSCLC) receiving osimertinib.

e21679 Background: Third generation EGFR tyrosine kinase inhibitor (TKI) osimertinib demonstrated superior PFS and OS compared to earlier generation TKIs in pts with EGFR+ NSCLC. These pts are disproportionately Asian, female, and never-smokers. Contradictory data has been reported regarding the PFS and OS to osimertinib in Asian pts as compared to 1st and 2nd generation EGFR TKI. These inconsistencies warrant further investigation. The purpose of this study is to evaluate the PFS in Asian vs non-Asian pts with EGFR+ NSCLC receiving osimertinib. Methods: We conducted a single institution IRB approved retrospective study of pts with EGFR+ NSCLC. PFS was evaluated in pts treated from 1/2013 – 12/2019. Disease and treatment characteristics were summarized using frequency distributions and Kaplan-Meier curves for comparison of subgroups. Results: Of 190 EGFR+ pts: 52 (27%) Asian, 108 (57%) Caucasian, 125 (66%) female, 172 (91%) advanced disease, 107 (56%) never-smokers. Baseline characteristics in Asian and non-Asian pts were similar in regards to de-novo stage IV disease (71% vs 65%, p = 0.80), brain metastases (42% vs 54%, p = 0.48), and differed with regards to ever-smoking (29% vs 56%, p = 0.04). Treatment: 126/172 (73%) pts with advanced disease received TKI across all lines of therapy; 92/126 received osimertinib (22 (24%) 1st line; 45 (49%) 2nd line; 18 (19%) 3rd line; 7 (8%) ≥4th line). There were insufficient number of pts who received osimertinib in the 1st line to comment on differences in PFS between Asian and non-Asian pts. In the 2nd line, 19 Asian pts and 26 non-Asian pts received osimertinib, with no observed difference in PFS (median 15.4 v 13.8 months, p = 0.20). Moreover, Asian pts who received osimertinib as second line therapy had superior PFS (median 15.4 vs 9.6 months, p &lt; 0.01) compared to Asian pts who received earlier generation TKIs, likely due to T790M resistance. Conclusions: Among second line advanced EGFR+ NSCLC, we did not observe a difference in PFS between Asian and non-Asian pts treated with osimertinib. Median PFS in Asian pts treated with osimertinib was longer compared to those treated with 1st or 2nd generation TKIs in the 2nd line setting. Our study highlights the the role of ethnic background in response to EGFR therapies and may warrant further study.

Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib

ObjectivesThe 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. Materials and methodsWe conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59–1021 cancer-related genes. Results and conclusionKnown EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

498P - An observational retrospective study to evaluate the incidence of acquired EGFR T790M resistance in NSCLC patients with EGFR mutation following progression after at least one prior EGFR TKI treatment in Taiwan: ARISE study

BackgroundIn Taiwan, gefitinib, erlotinib, and afatinib are all prescribed as the first-line therapy in NSCLC patients with EGFR sensitizing mutation. Although EGFR mutation-positive patients had favorable treatment response of EGFR TKIs, acquired resistance eventually developed, especially acquired EGFR T790M mutation. The 3rd-generation EGFR TKI, osimertinib, has been approved effectiveness for patients with acquired T790M formation after 1st-and 2nd-generation EGFR TKIs treatment. However, it is unclear whether the incidence of acquired T790M resistance differs as a result of the choice of the first-line EGFR TKI therapy. This study aimed to evaluate the association between the prior EGFR TKI therapy and the incidence of acquired T790M resistance in NSCLC patients who have progressed on EGFR TKI therapy. MethodsEligibility included NSCLC patients who had re-biopsy results for testing EGFR T790M mutation from 7 medical centers in Taiwan after June 1, 2013. The primary endpoint is to compare the incidence of acquired T790M mutation in patients who had been treated with different types of EGFR TKIs. Patients harboring tumor with de novo T790M mutations were excluded. ResultsThere were 410 patients who received re-biopsy for detection EGFR T790M after treating with 1st- or 2nd- generation EGFR TKIs. The overall acquired T790M mutation rate was 52.9%. Patients treated with gefitinib (59.8%) had higher acquired T790M incidence than those treated with erlotinib (45.5%; p = 0.011), but no difference with those treated with afatinib (53.3%; p = 0.236). Patients who had longer time to treatment discontinuation (TTD) of EGFR TKI for more than 18 months had higher T790M incidence than those with other predefined duration categories (p < 0.001). Multivariate logistic regression analysis revealed common EGFR mutations, gefitinib (compared to erlotinib), and longer TTD of EGFR TKI were associated with higher T790M incidence. ConclusionsPatients treated with gefitinib had higher acquired T790M incidence than those treated with erlotinib. Longer TTD of EGFR TKI was also associated with the frequency of acquired T790M mutation. Legal entity responsible for the studyThe authors. FundingAstraZeneca. DisclosureS-G. Wu: Honoraria (self): Roche; Honoraria (self): AstraZeneca. C-L. Chiang: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche. J-Y. Shih: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Novartis; Honoraria (self): Eli Lilly. G-C. Chang: Honoraria (self): F. Hoffmann-La Roche, Ltd; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly and Company Oncology; Honoraria (self): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

P2.03-42 Highly Sensitive Sel-CapTM Lung Cancer Panel NGS for Detection of Tumor-Derived EGFR Mutations in Plasma Cell-Free DNA in Lung Cancer

Next-generation sequencing is a genetic analysis platform for multiple analysis and large-scale analysis. Sensitivity is limited by methods for detecting cancer mutations that are contained at low rates in blood. With two highly sensitive detection techniques for genetic alterations, we evaluated their diagnostic value for tumor-derived EGFR mutations in plasma cell-free DNA (cfDNA) and measured concordance rate of activating EGFR mutations between cfDNA and tumor tissue. We conducted this study using FFPE tissue and plasma samples which were donated from NSCLC patients (N=316) between 2011 and 2013 and stored in the Human-derived Biomaterials Bank in Seoul St. Mary’s Hospital. Meanwhile, we prospectively collected plasma samples simultaneously when tumor tissue was taken out by surgery. We also collected peripheral blood just before administration of EGFR TKIs and each time imaging study was done during the administration of EGFR TKIs. We analyzed activating EGFR mutations in both cfDNA and tumor tissues using PNAclamping, Cancer panel and Sel-CapTM Lung Cancer Panel. The sensitivity and specificity of three detection techniques, PNAclamp, cancer panel and Sel-CapTM Lung Cancer Panel NGS for EGFR mutations in tumor tissues were more than 90% in all. In particular, EGFR T790M was found not only in the patients acquiring drug resistance approximately 10-12 months following the administration of 1st or 2nd generation EGFR TKIs, but also in the patients in whom EGFR TKI was continuously maintained over 30 months. The sensitivity of Sel-CapTM Lung Cancer Panel NGS for EGFR exon19 deletion and exon21 L858R in cfDNA was 76.2% and 61.1%, respectively. In addition, the sensitivity for double mutation of 19del and T790M was about 30% higher compared to that of cancer panel sold domestically (2/20, 10.0% vs. 9/20, 45.0%), suggesting that Sel-CapTM Lung Cancer Panel NGS enables to detect EGFR mutation up to 0.1% in plasma cfDNA. As a result of tracking of outcomes of EGFR TKIs treatment over time for patients with low frequency of EGFR mutations, we found that 1st or 2nd generation EGFR TKIs were switched into 3rd generation EGFR TKIs on the basis of disease progression on radiologic imaging, when an average of 6.8 months (0.2-25.4 months) elapsed from the first detection time of T790M in cfDNA. The presence of T790M in peripheral blood harvested periodically from patients receiving EGFR TKIs was initially identified about 3-5 months ahead of disease progress assessed by imaging study. With regard to the detection of EGFR mutations in lung cancer patients, Sel-CapTM Lung Cancer Panel NGS platform showed superior sensitivity to conventional NGS-based cancer panels as well as higher concordance rate between tumor tissues and plasma cfDNA. In longitudinal plasma cfDNA samples isolated from periodic liquid biopsies, quantitative changes of EGFR mutation were found to be significantly correlated to tumor response by EGFR TKIs. Our data suggest that Sel-CapTM Lung Cancer Panel NGS is a highly sensitive diagnostic platform for detection of EGFR T790M induced by long-term administration of EGFR TKIs and for determining when 3rd generation EGFR TKI be begun.