3rd Generation EGFR TKI Research Articles

FLAIR: A Phase II, Open Label, Randomized Study of Osimertinib Plus Bevacizumab Versus Osimertinib in Recurrent or Metastatic Treatment-Naïve NSCLC Patients Harboring EGFR 21L858R Mutation

IntroductionOsimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. Materials and MethodsFLAIR is a prospective, multicenter, randomized, open label study, which is initiated by Chinese Thoracic Oncology Group (CTONG2002). Patients age ≥18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-naïve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. ResultsFLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate). ConclusionsThis study will offer better perspectives on the efficacy and safety of osimertinib plus bevacizumab combination therapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation, providing valuable guidance for clinical practice.

Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial

BackgroundIn the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. MethodsEligible patients received oral befotertinib of 50 mg (cohort A) or 75–100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. ResultsA total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1–48.3) in cohort A and 36.7 months (35.9–37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1–27.2) in cohort A and 31.5 months (26.8–35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9–26.3) and 26.4 months (95 % CI: 23.0–29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6–29.1) and 35.5 months (95 % CI: 29.3–NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. ConclusionBefotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

NGS and FISH for MET amplification detection in EGFR TKI resistant non-small cell lung cancer (NSCLC) patients: A prospective, multicenter study in China

ObjectivesComprehensive data using Next-Generation Sequence (NGS) and fluorescence in situ hybridization (FISH) for detecting MET amplification is limited in Chinese patients, we evaluating NGS performance both in tissue and plasma samples using FISH as reference. We also sought to find optimal thresholds value for NGS in detecting MET amplification via bioinformatics methods. MethodPatients progressed after 1st-, 2nd-, or 3rd-generation (G) EGFR-TKIs were enrolled. Tissue biopsy samples were performed for MET amplification detection via both NGS and FISH. Paired plasma samples were collected for MET amplification detection by NGS. The sensitivity, specificity and agreement were analyzed between NGS and FISH. Results116 eligible patients were analyzed. 44 patients were male. 82 patients were after 3rd generation EGFR-TKI. MET amplification was detected in 43 (37.1 %) patients by FISH, including 19 (16.4 %) polysomy and 24 (20.7 %) focal amplification. The positive rate of MET amplification in post 3rd generation EGFR-TKI and post 1st/2ndgeneration EGFR-TKI resistant patients was 42.7 % (35/82), and 23.5 % (8/34).The sensitivity, specificity and agreement of detecting MET amplification by NGS in tissue were 39.5 % (17/43), 98.6 % (72/73) and 76.7 % (89/116), respectively, 66.7 % (16/24), 98.6 % (72/73) and 90.7 % (88/97) for focal MET amplification in tissue and 29.2 % (7/24), 94.5 % (69/73), 78.4 % (76/97) for focal amplification in plasma. Results were shown in the table below. ConclusionNGS is an alternative method for MET focal amplification detection in tissue. While the sensitivity of NGS testing in plasma needs further improvement to maximize identification of patients with potential benefit from dual-targeted therapy.

Subcutaneous amivantamab and lazertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Results from the phase 2 PALOMA-2 study.

LBA8612 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, is approved as an intravenous (IV) formulation. IV ami + lazertinib (laz), a 3rd-generation EGFR TKI, demonstrated superior progression-free survival (PFS) in patients (pts) with treatment-naïve, advanced EGFR-mutated NSCLC vs osimertinib (Cho Ann Oncol 2023). Subcutaneous (SC) ami substantially reduced infusion-related reactions (16% vs 67%) and administration time (≤7 mins vs 2–4 hours) vs historical IV experience (Minchom JCO 2023). PALOMA-2 (NCT05498428) evaluated the efficacy, safety, and pharmacokinetics (PK) of first-line SC ami+laz. Methods: Cohorts 1 and 6 enrolled pts with treatment-naïve, EGFR Ex19del or L858R-mutated advanced NSCLC. Prophylactic anticoagulation for the first 4 months (mo) of treatment was recommended in cohort 1 and mandatory in cohort 6. SC ami was administered by manual injection in the abdomen at 1600 mg (≥80 kg: 2240 mg) weekly for the first 4 weeks and every 2 weeks thereafter. Laz was dosed orally at 240 mg daily. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1. Results: As of 6 Jan 2024, 68 and 58 pts were enrolled in cohorts 1 and 6, respectively. Overall, median age was 59 years, 60% were female, and 68% Asian. The median follow-up was 10 mo for cohort 1 and 6 mo for cohort 6. ORR (confirmed responses) in cohort 1 was 68% (95% CI, 55–79) by investigator and 72% (95% CI, 60–82) by independent central review. ORR in cohort 6 was 64% (95% CI, 49–78) and 73% (95% CI, 58–85), respectively. At data cutoff, 40/46 responders in cohort 1 and 29/29 responders in cohort 6 were receiving ongoing treatment. Best overall response rates (includes unconfirmed responses) were 81% (95% CI, 70–89) for cohort 1 and 76% (95% CI, 61–87) for cohort 6. Median time to response was 2 mo (range, 1.4–5.3). Median duration of response, PFS, and overall survival were not estimable. Administration-related reactions (ARRs) were reported in 13 (19%) pts in cohort 1 and 6 (11%) pts in cohort 6, all grade 1–2. EGFR- and MET-related AEs were primarily grade 1–2. Total of 71% of pts in cohort 1 and 100% in cohort 6 received prophylactic anticoagulation. Venous thromboembolic events (VTE) were reported in 18% and 7% of pts in cohorts 1 and 6, respectively. There were no dose reductions or discontinuations due to VTE. Rate of bleeding was 2% among pts receiving anticoagulation. Mean ami concentrations on cycle 2 day 1 were 328 µg/mL (n=49) in cohort 1 and 371 µg/mL (n=41) in cohort 6, consistent with historic IV levels. Conclusions: SC ami+laz showed a response rate similar to historic IV ami+laz in first-line EGFR-mutated NSCLC, with an improved safety profile that included significantly lower ARR rates. Further, prophylactic anticoagulation can be safely implemented and reduced incidence of VTE. Clinical trial information: NCT05498428 .

Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study.

8504 Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. Lazertinib (laz) is a CNS-penetrant, 3rd-generation EGFR TKI. In MARIPOSA (NCT04487080), first-line ami+laz provided a statistically significant improvement in progression-free survival (PFS) vs osimertinib (osi) in patients (pts) with EGFR-mutant advanced NSCLC (HR, 0.70; P< 0.001), including in pts with a history of brain metastases (HR, 0.69; Cho Ann Oncol 2023;34:S1306, LBA14). Pts with TP53co-mutations, detectable circulating tumor DNA (ctDNA), and baseline brain or liver metastases have poor prognoses. We evaluated outcomes for pts in these high-risk subgroups from MARIPOSA. Methods: MARIPOSA enrolled pts with treatment-naïve, EGFR-mutant (Ex19del or L858R) advanced NSCLC. This analysis included pts randomized to ami+laz (n = 429) or osi (n = 429). Pathogenic alterations were analyzed by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and Cycle (C) 3 Day (D) 1 with Biodesix droplet digital PCR (ddPCR). Results: Baseline ctDNA for NGS analysis of pathogenic alterations was available for 636 pts (ami+laz, n = 320; osi, n = 316). Among pts with TP53 co-mutation, mPFS was 18.2 months (mo) for ami+laz vs 12.9 mo for osi (HR, 0.65; P= 0.003). Pts with TP53 wild-type had a trend favoring ami+laz for mPFS (HR, 0.75; P =0.11). In pts with ddPCR-detectable ctDNA at baseline, ami+laz significantly prolonged mPFS vs osi (20.3 vs 14.8 mo; HR, 0.68; P= 0.002). Further, ami+laz significantly improved mPFS vs osi in pts with ctDNA clearance at C3D1 (24.0 vs 16.5 mo; HR, 0.64; P= 0.004) and in pts who did not clear ctDNA (16.5 vs 9.1 mo; HR, 0.48; P= 0.014). For pts with liver metastases at baseline, ami+laz significantly prolonged mPFS vs osi (18.2 vs 11.0 mo; HR, 0.58; P= 0.017), which is consistent with the improved PFS for ami+laz vs osi in pts with a history of brain metastases. Conclusions: Ami+laz demonstrated significantly improved mPFS vs osi in pts with biomarkers of high-risk disease. Given these features can occur in up to 85% of pts, ami+laz represents an important new standard of care for treatment-naïve EGFR-mutant advanced NSCLC. Clinical trial information: NCT04487080 . [Table: see text]

Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC).

TPS8658 Background: Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are the recommended front-line option for EGFR-mutant advanced NSCLC patients, but patients invariably develop acquired resistance and face disease progression. JIN-A02, a 4th generation EGFR-TKI intended for oral administration, selectively and reversibly binds to EGFR mutations, including the C797S and/or T790M mutation that causes resistance to 3rd generation of EGFR-TKIs. Pre-clinical studies with EGFR C797S and/or T790M mutated cell lines showed that JIN-A02 can inhibit cell growth in a dose dependent manner and has a high degree of selectivity over wild-type EGFR. In vivo studies showed that administration of JIN-A02 dose-dependently inhibited tumor growth in the C797S+ xenograft mice model. Moreover, JIN-A02 shown to penetrate blood-brain barrier and exhibit anti-tumor activity in an intracranial tumor model. The strong potency and high selectivity of JIN-A02 for mutant EGFR may offer improved therapeutic window in the clinical setting vs available EGFR-TKIs. Methods: JIN-A02 is being evaluated in this Phase 1/2, multicenter, an open-label trial (NCT05394831) for subjects with advanced NSCLC harboring C797S and/or T790M mutation as a monotherapy. The primary object of this study is to assess safety, tolerability, pharmacokinetics, and anti-tumor effect for determining the recommended phase 2 dose (RP2D) of JIN-A02. The inclusion criteria are that the subject (≥ 18 years) must have an advanced or metastatic NSCLC showed progress disease (PD) after receiving approved standard EGFR-TKI therapies and/or platinum-based anticancer chemotherapy is allowed up to 1 time after using EGFR-TKI treatment with ECOG status 0 or 1. Before enrollment in the study, the EGFR mutation status is determined using either tumor tissue and/or plasma ctDNA. This study comprises three parts, dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). In Part A, dose escalation, comprised of 5 cohorts ranged from a starting dose of 12.5 mg P.O, QD to a top dose of 150 mg P.O, QD with every three subjects, is carried out where the maximum tolerated dose (MTD) is evaluated in subjects with 28-day cycles. Dose-limiting toxicities (DLT) are evaluated for 21 days. In Part B, dose exploration is carried out to evaluate the safety of JIN-A02 further and to determine the RP2D using 2 preliminary effective dose levels from Part A in subjects. In Part C dose-expansion study, subjects (n=36 for each cohort) are divided into 5 different cohorts based on the EGFR mutation (both or single positive of C797S and T790M), and the anti-tumor activity of JIN-A02 is evaluated according to RECIST v1.1 at RP2D. Clinical trial information: NCT05394831 .

Abstract CT154: Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC)

Abstract Background: Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are the recommended front-line option for EGFR-mutant advanced NSCLC patients, but patients invariably develop acquired resistance and face disease progression. JIN-A02, a 4th generation EGFR-TKI intended for oral administration, selectively and reversibly binds to EGFR mutations, including the C797S and/or T790M mutation that causes resistance to 3rd generation of EGFR-TKIs. Pre-clinical studies with EGFR C797S and/or T790M mutated cell lines showed that JIN-A02 can inhibit cell growth in a dose dependent manner and has a high degree of selectivity over wild-type EGFR. In vivo studies showed that administration of JIN-A02 dose-dependently inhibited tumor growth in the C797S+ xenograft mice model. Moreover, JIN-A02 shown to penetrate blood-brain barrier and exhibit anti-tumor activity in an intracranial tumor model. The strong potency and high selectivity of JIN-A02 for mutant EGFR may offer improved therapeutic window in the clinical setting vs available EGFR-TKIs. Methods: JIN-A02 is being evaluated in this Phase 1/2, multicenter, an open-label trial (NCT05394831) for subjects with advanced NSCLC harboring C797S and/or T790M mutation as a monotherapy. The primary object of this study is to assess safety, tolerability, pharmacokinetics, and anti-tumor effect for determining the recommended phase 2 dose (RP2D) of JIN-A02. The inclusion criteria are that the subject (≥ 18 years) must have an advanced or metastatic NSCLC showed progress disease (PD) after receiving approved standard EGFR-TKI therapies and/or platinum-based anticancer chemotherapy is allowed up to 1 time after using EGFR-TKI treatment with ECOG status 0 or 1. Before enrollment in the study, the EGFR mutation status is determined using either tumor tissue and/or plasma ctDNA. This study comprises three parts, dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). In Part A, dose escalation, comprised of 5 cohorts ranged from a starting dose of 12.5 mg P.O, QD to a top dose of 150 mg P.O, QD with every three subjects, is carried out where the maximum tolerated dose (MTD) is evaluated in subjects with 28-day cycles. Dose-limiting toxicities (DLT) are evaluated for 21 days. In Part B, dose exploration is carried out to evaluate the safety of JIN-A02 further and to determine the RP2D using 2 preliminary effective dose levels from Part A in subjects. In Part C dose-expansion study, subjects (n=36 for each cohort) are divided into 5 different cohorts based on the EGFR mutation (both or single positive of C797S and T790M), and the anti-tumor activity of JIN-A02 is evaluated according to RECIST v1.1 at RP2D. Citation Format: Sun Min Lim, Byoung Chul Cho, Ji Youn Han, Sang We Kim, Ki Hyeong Lee, Misako Nagasaka, Anna Jo, Ethan Seah, Choonok Kim, Thanyanan Reungwetwattana. Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT154.

Abstract 1967: IN-119873, the next-generation allosteric EGFR TKI, a potent and highly selective EGFR L858R for the treatment of osimertinib-resistant NSCLC

Abstract EGFR mutations occur in approximately 50% of Asian patients and 20% of Caucasian patients with non-small cell lung cancer (NSCLC). The EGFR L858R mutation constitutes approximately half of the EGFR-mutated patients, and despite receiving first-line or second-line treatment with the 3rd generation EGFR TKI osimertinib, they continue to exhibit a poor prognosis. According to real-world analysis, the leading resistance mechanism to osimertinib is identified as EGFR C797S mutation. Furthermore, osimertinib is still associated with gastrointestinal and skin toxicity, despite its improved selectivity for EGFR WT compared to 1st-generation EGFR TKIs. Here, we show that IN-119873 can overcome C797S-mediated acquired resistance based on the results obtained by various in vitro and in vivo NSCLC models. IN-119873 binds to an EGFR allosteric site separate from the ATP-binding site with a remarkable preference for highly mutant-selective inhibition. It effectively targets EGFR L858R activating mutations while sparing the inhibition of EGFR WT, which sets it apart from ATP competitive inhibitors. Moreover, oral administration of IN-119873 showed excellent anti-tumor efficacy in a dose-dependent manner in a diverse of osimertinib-resistant CDX and PDX models. IN-119873 also demonstrated favorable blood-brain-barrier penetration with promising intracranial efficacy in the H1975-luc brain metastasis model both mono or in combination with osimertinib. As a selective, orally available, and CNS-penetrable next-generation allosteric EGFR-TKI, IN-119873 is currently undergoing IND-enabling studies and has the potential to demonstrate activity in both first-line and resistance settings, either as a monotherapy or in combination with 3rd generation EGFR TKI. Citation Format: Jong Ryoul Choi, Daseul Yoon, Seo Hyun Kim, Do Gyeong Kim, Seock Yong Kang, Seong-Il Choi, Somyi Park, Hyun Kyung Lee, Donghyun Kim, Ju Hyun Lee, Hye-Jung Kim, Bong Tae Kim. IN-119873, the next-generation allosteric EGFR TKI, a potent and highly selective EGFR L858R for the treatment of osimertinib-resistant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1967.

Abstract 3348: Identification of circSPINT2 as a tumor suppressive circular RNA sensitizing lung cancer to 3rd generation EGFR-TKI treatment

Abstract Introduction: Lung cancer remains a high incidence and mortality globally. Adenocarcinoma is the most common type of lung cancer with around 50% of patients in Asia expressing mutated EGFR, which makes EGFR an effective therapeutic target to treat lung adenocarcinoma (LAC). Unfortunately, resistance to EGFR-TKI often occurs in patients through either dynamic EGFR mutation, driver oncogenic pathway shift, or transdifferentiating to evade EGFR-TKI treatment. circRNAs are a type of RNA molecule with a circular shape. Their importance in several biological processes and disease progression was intensively studied recently, and have emerged as promising diagnostic, prognostic, and monitoring biomarkers for diseases like cancer. CircRNAs’ unique circular structure and resistance to degradation make them robust candidates for non-invasive diagnostics of cancers. Aims: This study aimed to identify and investigate the involvement of a novel circular RNA (circSPINT2) in acquired resistance against the 3rd generation EGFR-TKI Osimertinib. Materials & Methods: Comparative circRNA sequencing (circRNA-Seq), qRT-PCR, sanger sequencing, and RNase R treatment were applied to identify and verify the identity of Osimertinib-resistance-related circRNA. Biotinylated circRNA pull-down assay, miRNA-seq, and in-silico analysis were employed to delineate the downstream miRNA-mRNA regulatory axis. Osimertinib-resistant mouse xenograft model was established to explore the molecular mechanisms associated with both circSPINT2 and Osimertinib resistance. Results: We identified circSPINT2 as particularly downregulated in Osimertinib-resistant cell lines (OR) using circRNA-Seq. Overexpression of circSPINT2 in resistant cells increased cellular sensitivity to Osimertinib, whereas knockdown of circSPINT2 conferred Osimertinib resistance in parental cells. The circSPINT2-dependent regulation of Osimertinib sensitivity is mediated through modulating apoptosis. In-vitro analysis indicated high circSPINT2 increased tumor suppressor RBP1 expression by sequestering oncogenic hsa-miR-1296 further improving Osimertinib sensitivity. Molecular and histologic analysis of subcutaneous xenograft tumors corroborated our in-vitro results. Conclusion: Our study demonstrated circSPINT2 functions as a tumor suppressor, improving Osimertinib sensitivity via the hsa-miR-1296/RBP1 axis. circSPINT2 may serve as a prognostic and cancer biomarker to monitor Osimertinib resistance in LAC patients. Citation Format: Mong-Lien (Lotus) Wang, Shih-Hwa Shiou, Yi-Chen Chen, Ming-Long Tsai, Nalini Devi Verusingam, Alan Han-Kiat Ong. Identification of circSPINT2 as a tumor suppressive circular RNA sensitizing lung cancer to 3rd generation EGFR-TKI treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3348.

YTHDF3 Modulates EGFR/ATK/ERK/p21 Signaling Axis to Promote Cancer Progression and Osimertinib Resistance of Glioblastoma Cells.

Despite recent advances in EGFR-tyrosine kinase inhibitor (TKI) drugs for glioblastoma multiforme (GBM), intrinsic EGFR alterations in GBM have resulted in drug resistance and unsatisfactory clinical development of EGFR-TKIs. Determining the unknown mechanisms underlying EGFR-TKI drug resistance is an urgent, but unmet, medical need for GBM. Although several m6A RNA methylation regulators, such as reader YTHDF1/2, were recently predicted to be related to GBM recurrence, none was associated with resistance to the 3rd generation EGFR-TKI osimertinib. Osimertinib-resistant GBM cells (U87OSR) were established to ascertain the correlation between m6A expression and osimertinib resistance, prior to systemic analyses on m6A writers, erasers, and readers. YTHDF3-silencing was employed to reveal changes in IC50, cellular migration, cancer stemness, and p21-guided senescence in U87OSR cells. Signaling pathways and an in vivo xenograft model of U87OSR cells were investigated to delineate the influence of osimertinib-resistance and elevated YTHDF3 expression. YTHDF3 played a crucial role in inducing cellular proliferation, migration, and stemness in U87OSR GBM cells. Importantly, silencing of YTHDF3 markedly reduced the activation of certain signaling pathways, including EGFR- or ITGA7- AKT, and ERK in U87OSR cells. Our study also revealed the oncogenic function of YTHDF3 in inducing senescence escape via p21 down-regulation. In contrast, silencing of YTHDF3 resulted in increased p21 expression, senescence, and suppressed tumor growth in our osimertinib-resistant preclinical model. Overall, our research underscores the novel potential of YTHDF3 as a new pharmacological target in GBM treatment, specifically for patients with osimertinib-resistant or refractory tumors.

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

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

Anti-tumor activity of sunvozertinib in NSCLC with EGFR sensitizing mutations after failure of EGFR TKI treatment.

9103 Background: Sunvozertinib is a rationally designed, irreversible EGFR inhibitor targeting various EGFR mutations with wild-type EGFR selectivity. Clinical studies have showed its superior efficacy than current available therapies and favorable safety profile for treating NSCLC patients with EGFR exon20 mutations. Here we reported its anti-tumor activity in patients with EGFR sensitizing mutations (EGFRm) who failed from standard EGFR TKI treatment. Methods: This is a pooled analysis of three clinical studies in patients with EGFRm or HER2m NSCLC: WU-KONG1 (multinational phase I/II study, NCT03974022), WU-KONG2 (phase I study in China, CTR20192097), and WU-KONG15 (phase II study in China, NCT05559645). Patients were enrolled to receive sunvozertinib once daily at defined doses until discontinuation criteria were met. Patients who had EGFRm NSCLC, at least one measurable lesion at baseline, received at least one dose of sunvozertinib, and underwent at least one post-treatment RECIST assessment were evaluable for efficacy analysis. Patients with EGFRm or HER2m NSCLC who failed from standard systemic therapies and received at least one dose of sunvoertinib were included in the safety analysis. Results: As of October 17, 2022, a total of 32 patients who met efficacy evaluable criteria were included in the analysis. The doses of sunvozertinib ranged from 50 mg - 400 mg. Baseline characteristics: median age was 64.5 years old; 68.8% (22/32) were female; 75.0% (24/32) ECOG PS was 1; 34.4% (11/32) had more than three metastatic sites; 43.8% (14/32) had baseline brain metastases. Patients were heavily pretreated, with a median of 5 lines (range 1 - 16) of prior therapies. All patients had been treated with at least one type of EGFR TKI, including 68.8% (22/32) had been treated with a 3rd generation EGFR TKI. The majority of patients (29/32, 90.6%) had also been treated with chemotherapy. Anti-tumor activity was observed starting from 50 mg. Per investigators’ assessment, the best objective response rate (BoR) was 21.9% (7/32). Anti-tumor activity was observed regardless of T790M mutation status. At the data cutoff date, the median duration of response and progression-free survival were 4.0 months and 5.9 months, respectively. Sunvozertinib was well-tolerated across all dose levels. The safety profile was similar to what has been previously reported. The longest treatment duration was more than 35 months (still ongoing). Conclusions: Sunvozertinib monotherapy demonstrated promising anti-tumor activity in heavily pretreated EGFRm NSCLC patients. Further clinical evaluation of sunvozertinib in this patient population is warranted. The updated data will be presented at the conference. Clinical trial information: NCT05559645 NCT03974022 and CTR20192097 .

Abstract 3396: Discovery of BDTX-1535, a novel 4th generation, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM

Abstract Acquired resistance to 3rd generation EGFR inhibitors used in the treatment of NSCLC is common. While the EGFR C797S substitution is a frequently reported post-osimertinib resistance mutation, real world evidence indicates the emergence of additional EGFR alterations that can drive drug resistance: kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. Moreover, while osimertinib targets the classical EGFR mutations, primary NSCLC tumors are also driven by other oncogenic kinase domain mutations including G719X, S768I, and L861Q, which confer de novo (intrinsic) resistance to 3rd generation EGFR TKIs. A family of extracellular domain alterations occurs in nearly 50% of GBM patients, and these alterations are clinically resistant to all current generation inhibitors. Real world data in GBM demonstrate these EGFR alterations often co-occur and persist throughout treatment with current standard of care therapy. Of critical importance is the observation that the oncogenic isoform of EGFR in GBM is a covalent homo-dimer which can be formed and paradoxically activated by the binding of reversible 1st generation EGFR inhibitors. There is a significant clinical need to develop a potent CNS penetrant EGFR inhibitor that would target both acquired and intrinsic resistance mutations expressed in NSCLC and co-occurring EGFR alterations in GBM. An effective inhibitor should meet four design principles; 1) potent and selective against a broad family of intracellular, extracellular EGFR oncogenic alterations and amplification, 2) wild type EGFR sparing, 3) irreversible to avoid paradoxical activation, and 4) CNS penetrant. BDTX-1535 is a 4th generation irreversible CNS penetrant EGFR MasterKey inhibitor targeting a family of oncogenic EGFR extracellular domain alterations and amplification in GBM patients and EGFR resistance mutations in NSCLC. BDTX-1535 meets all four criteria for a highly effective EGFR inhibitor and was designed using the MAP Discovery Engine to target the activated conformations used by oncogenic EGFR to drive tumorigenesis. BDTX-1535 achieves potent anti-tumor activity against EGFR alterations and amplification across models including NSCLC and GBM PDX and intracranial tumors. BDTX-1535 is currently in a phase I clinical study in patients with NSCLC and GBM harboring sensitive EGFR alterations (NCT05256290). Citation Format: Matthew O'Connor, Matthew Lucas, Sherri Smith, Anthony Trombino, Sudharshan Eathiraj, Elizabeth Buck. Discovery of BDTX-1535, a novel 4th generation, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM [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 3396.

CNSC-01. THE GENE LANDSCAPE OF LUNG ADENOCARCINOMA PATIENTS WITH PROGRESSIVE DISEASE OF LEPTOMENINGE

Abstract BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear. METHODS Forty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were 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 had matched plasma (PLA). RESULTS The common gene alterations discovered in the 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%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p=0.2). Cohort 1 had 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 alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.

360P ELIOS: A multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib

Osimertinib – a 3rd-generation EGFR-TKI – is the preferred 1L treatment for EGFRm advanced NSCLC; however, pts can eventually develop progressive disease (PD). ELIOS (NCT03239340) characterised resistance mechanisms to 1L osimertinib. To our knowledge, this is the first prospective study with a primary objective comparing paired baseline and post-PD tumour tissue biopsies.

LBA12 Tumour genomics in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib in the phase II ELIOS study

Osimertinib, a 3rd-generation EGFR-TKI, is the preferred 1L treatment for EGFRm advanced NSCLC; however, resistance eventually develops. ELIOS (NCT03239340) characterised resistance mechanisms to 1L osimertinib with a primary objective comparing paired tumour tissue biopsies from baseline (BL) and after PD. We report exploratory analyses of concordance between tissue and plasma testing from BL and post-PD samples and PFS by detected plasma EGFRm at BL and by plasma EGFRm clearance at 8 wks post-treatment.

LBA53 ELIOS: A multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib

Osimertinib – a 3rd-generation EGFR-TKI – is the preferred 1L treatment for EGFRm advanced NSCLC; however, pts can eventually develop progressive disease (PD). ELIOS (NCT03239340) characterised resistance mechanisms to 1L osimertinib. To our knowledge, this is the first prospective study with a primary objective comparing paired baseline and post-PD tumour tissue biopsies.

EP08.02-137 Prospective Study of Aumolertinib in NSCLC Patients with EGFR Sensitive Mutations Who Are Intolerant to Osimertinib Treatment

Data from phase II and phase III clinical studies of the third-generation EGFR-TKI Aumolertinib showed significant treatment efficacy and a favorable safety profile for patients with EGFR-sensitive mutations (EGFRm+) in advanced non-small cell lung cancer (NSCLC). There is a difference in the incidence of AEs caused by osimertinib with the same 3rd generation EGFR-TKI, especially the low incidence of AEs caused by Aumolertinib in interstitial lung disease, cardiotoxicity, and hematotoxicity. The aim of this study was to evaluate the safety and efficacy of Aumolertinib in EGFRm+ advanced NSCLC patients with safety intolerance after treatment with oxitinib.

P68-3 Phase 2 study comparing the efficacy between afatinib & osimertinib based on immunological biomarker in EGFR-mutant NSCLC

FLAURA study did not disclose the prolonged OS in Asian subgroup (HR 1.00). On the contrary, in Japanese subgroup, OS was lower for osimertinib arm (HR 1.39). To date, no clinical trials exist comparing the survival between 2nd and 3rd generation EGFR-TKIs. Therefore, we have planned a randomized controlled trial to explore our hypothesis that 1st line afatinib might be superior to 1st line osimertinib in regard to OS in Japanese population. Also, we have planned to examine the differential effects of afatinib and osimertinib on systemic immunity by serial PBMC collection and subsequent immune monitoring to identify subsequent effectiveness of ICI and cytotoxic chemotherapy combination.

O6-3 The significance of ultra-low EGFR T790M mutations on EGFR-TKI efficacy in patients with NSCLC -the WJOG13119L study

The significance of ultra-low pretreatment EGFR T790M mutations on EGFR-tyrosine kinase inhibitor (TKI) efficacy in patients with non-small cell lung cancer (NSCLC) remains uncertain. Therefore, we retrospectively investigated the association between ultra-low EGFR T790M mutations and time to treatment failure (TTF) in patients treated with 1st, 2nd or 3rd generation (1G, 2G, 3G) EGFR-TKI.