Advanced EGFR-mutant Non-small Cell Lung Cancer Research Articles

Research Progress of Anti-PD-1/PD-L1 Therapy for Non-small Cell Lung Cancer with EGFR Mutation

The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the first line treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC), but drug resistance will be acquired within 1-2 years, and the following treatment efficacy is poor. The invention of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors has dramatically changed the situation of tumor treatment. PD-1/PD-L1 inhibitors are less effective in patients with NSCLC harboring EGFR mutation. It is a challenge to make patients with EGFR-mutated advanced NSCLC benefit from anti-PD-1/PD-L1 therapy. In this paper, the research progress on the impact of EGFR mutation on the immune status of NSCLC and related clinical studies in recent 5 years are reviewed. .

The efficacy and tolerability of combining pemetrexed-based chemotherapy with gefitinib in the first-line treatment of non-small cell lung cancer with mutated EGFR: A pooled analysis of randomized clinical trials.

BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR.MethodsWe systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes.ResultsEight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37–0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39–0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34–0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26–0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44–2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94–2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69–11.44, p = 0.1509).ConclusionCompared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation.

Design and Rationale for a Phase II, Randomized, Open-Label, Two-Cohort Multicenter Interventional Study of Osimertinib with or Without Savolitinib in De Novo MET Aberrant, EGFR-Mutant Patients with Advanced Non-Small-Cell Lung Cancer: The FLOWERS Trial

IntroductionEpidermal growth factor receptor (EGFR) mutations are well-known genetic alterations in advanced non-small cell lung cancer (NSCLC) which are associated with remarkable survival benefits from first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, around 30% of patients exhibit primary resistance to EGFR-TKIs therapy. Co-existing MET amplification/over-expression has showed shorter time to progression on EGFR-TKI monotherapy. Osimertinib (TAGRISSO, AZD9291) has been recommended in EGFR-mutant advanced NSCLC patients as first-line treatment. Savolitinib (AZD6094, HMPL-504) is a highly selective MET-TKI which has demonstrated anti-tumor activity in various cancers with MET alterations. MethodsThis FLOWERS study, a phase II, randomized, open-label, 2-cohort multicenter trial aimed to evaluate the efficacy and safety of osimertinib with or without savolitinib as first-line therapy in patients with de novo MET amplified/over-expressed, EGFR-mutant positive, locally advanced or metastatic NSCLC. Approximately 44 patients will be randomized to receive osimertinib (80 mg once daily) monotherapy or osimertinib (80 mg once daily) and savolitinib (300 mg twice daily) combination therapy; patients in osimertinib monotherapy cohort confirmed as MET positive (MET-amplified/over-expressed) after disease progression will have the opportunity to receive the cross-over combination therapy as second-line treatment. Primary endpoint will be objective response rate. Key secondary endpoints will be progression-free survival, duration of response, disease control rate, overall survival, safety and tolerability. ConclusionThe results of the study will provide better perspectives on the efficacy and safety of EGFR-TKI plus MET-TKI combination therapy (osimertinib plus savolitinib) in patients with de novo MET-amplified/over-expressed, EGFR-mutant positive, treatment naïve, advanced NSCLC and offer a meaningful guidance in clinical practice (NCT05163249).

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected. Overall, 104 patients were included. Most patients had adenocarcinoma (n=102, 98%) with an exon 19 EGFR deletion (n=54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n=4) and EGFR C797S mutation (11%; n=3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%). We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Cost-effectiveness of osimertinib versus standard EGFR-TKI as first-line treatment for EGFR-mutated advanced non-small-cell lung cancer in China

Objective: The purpose of this study was to estimate the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods: A Markov model was developed to simulate the outcomes and direct medical costs of osimertinib or standard EGFR-TKI in the first-line treatment of patients with previously untreated EGFR-mutated advanced NSCLC. Individual patient survival data were extracted from the FLAURA randomized clinical trial. Clinical costs and utilities’ input estimates were collected from the local hospital and available literature reports. The quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit (INMB), and incremental net health benefit (INHB) were calculated for the two treatment strategies over a 10-year lifetime horizon. In addition, one-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to test the robustness of the model. Results: On baseline analysis, osimertinib achieved additional 0.39 QALYs and $15,443.78 incremental costs compared with standard EGFR-TKI (gefitinib or erlotinib), which resulted in the ICER of $39,369.53/QALY. The INMB was -$755.11, and the INHB was -0.02 QALYs at a WTP threshold of $37,663.26/QALY in China. The one-way sensitivity analysis showed that the utility of PFS had the strongest association with the ICER. Osimertinib had approximately 46.4% probability of being cost-effective at the WTP threshold of $37,663.26/QALY. Conclusion: First-line osimertinib therapy might not be cost-effective in China for patients with EGFR-mutated advanced NSCLC compared with standard EGFR-TKI based on its current marketed price. A significantly more favorable cost-effectiveness could be achieved when the price of osimertinib was reduced by 5%.

EP08.02-173 Treatment Patterns and Outcomes Among Patients With EGFR-mutant Advanced NSCLC in the Frontline and Post-Osimertinib Settings

Osimertinib is recommended frontline therapy for patients with EGFR-positive advanced non-small cell lung cancer (NSCLC). This study characterizes real-world treatment patterns and outcomes in frontline and post-osimertinib settings.

Exposure-Response Analysis of Osimertinib in Patients with Advanced Non-Small-Cell Lung Cancer.

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure–response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure–toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1–Q3 group (12.2 months [CI95% = 8.0–not reached (NR)] vs. 22.7 months [CI95% = 17.1–34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure–survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1–Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6–37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.

1190TiP Pharmacokinetics, efficacy, and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)

Patients (pts) with advanced EGFRm NSCLC have limited treatment options after progression with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC). HER3, a member of the human epidermal growth factor receptor family, is expressed across a variety of solid tumors and in most EGFRm NSCLC. HER3 overexpression has been associated with poor clinical outcomes, including metastatic progression and decreased relapse-free survival. HER3-DXd is a novel antibody-drug conjugate composed of a human anti-HER3 monoclonal antibody (patritumab) linked to a topoisomerase I inhibitor payload via a stable tetrapeptide-based, tumor-selective, cleavable linker.

EP08.02-042 EGFR-TKI +/- Antiangiogenics for EGFR-mutated Advanced NSCLC

The development of genomic-driven strategies to tackle Non-Small Cell Lung Cancer (NSCLC) such as EGFR-TKIs improved Progression-Free Survival (PFS) but has failed to improve Overall Survival (OS) until the development of third-generation EGFR-TKI. More recently, a combination of EGFR-TKI plus antiangiogenic agents has emerged as another option for EGFR-mutated advanced NSCLC, although it remains unclear if this combination improves OS. Moreover, there is a paucity of data comparing third-generation EGFR-TKI with EGFR-TKI plus antiangiogenic combination.

EP08.02-016 Frontline and Post-Osimertinib Therapy for EGFR-mutant Advanced NSCLC: Treatment Patterns, Outcomes, Healthcare Use and Costs

For patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC), osimertinib is recommended frontline therapy. However, real-world treatment patterns, clinical outcomes, healthcare-resource utilization (HRU), and costs in frontline and post-osimertinib settings are unclear.

EP08.02-134 Real-world Efficacy of Dacomitinib in Patients with Previously EGFR-TKI Treated Non-small Cell Lung Cancer

Multiple studies have reported that retreatment with erlotinib is an alternative option for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who had benefited from previous EGFR-tyrosine kinase inhibitor (TKI) therapy and progressed after chemotherapy. Dacomitinib is a second-generation EGFR-TKI for the first-line treatment of EGFR-mutant advanced NSCLC. The efficacy of dacomitinib in previously EGFR-TKI treated NSCLC remains unclear in real-world practice.

EP08.02-082 Treatment Patterns and Outcomes of First-line Osimertinib-treated Advanced EGFR Mutated NSCLC Patients: A Real-world Study

Based on the survival benefit seen in the FLAURA trial, first-line osimertinib has become the standard-of-care for patients with EGFR mutation in advanced non-small cell lung cancer (NSCLC). However, treatment options are limited after progression on osimertinib. We explored survival outcomes, subsequent treatment lines, and metastatic sites post-osimertinib in patients with EGFR-mutated NSCLC treated with first-line osimertinib in a real-world setting.

EP08.02-164 The Effect of Metformin on Survival Outcomes of Advanced EGFR-mutant NSCLC Patients Treated with EGFR TKIs in Thailand

EGFR tyrosine kinase inhibitor (TKI) is mainstay treatment of advanced mutant NSCLC. Mechanism of action of EGFR TKI is inhibitory effects on cell proliferation via through down regulation of AKT and MAPK signaling pathways. Metformin may have direct effect on cancer cells by the similar pathway. The synergistic effect of metformin and EGFR TKI on survival outcomes has been explored. This is the first study in Thailand aim to evaluate the progression free survival (PFS) and overall survival (OS) in advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with or without type 2 diabetes (T2DM) who were treated with EGFR TKI and metformin/ or other oral hypoglycemic agent, and EKFR TKI alone, respectively.

EP08.02-035 Clinical Utility of Liquid Biopsy After Progression to First and Second-Generation TKIs in Advanced EGFR Mutant NSCLC Patients

Liquid biopsy (LB) has increased its usefulness in selecting precise therapy during different treatment phases in advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). In addition, it has played a prognostic and predictive role in EGFRm patients. Detection of main oncogenic driver alteration on LB has been associated with worse oncological outcomes and increased disease burden. This study aims to assess survival and clinical characteristics associated with LB findings at first EGFR-TKI progression.

Non-small cell lung cancer harboring EGFR G724S mutation and exon 19 deletion responded to afatinib monotherapy after multiple lines of target therapies.

Epidermal growth factor receptor (EGFR) G724S mutation represents a resistance mechanism to first- and third-generation EGFR tyrosine kinase inhibitors. Limited data are available regarding the efficacy of afatinib in patients with non-small cell lung cancer (NSCLC) harboring G724S mutation, particularly after osimertinib. A patient diagnosed with advanced EGFR-mutated (exon 19 deletion) NSCLC after several lines of treatment – gefitinib, osimertinib, heat shock protein inhibitors and chemotherapy-developed EGFR G724S mutation retaining the exon 19 deletion. She was then treated successfully with afatinib leading to a progression free survival of 9 months (and counting). This is the first report of the emergence of G724S mutation, together with ex19del, after three subsequent lines of therapy following progressive disease to Osimertinib, and we report for the first time the activity of afatinib against EGFR exon 18 G724S mutation in this setting.

Abstract CT184: Emerging evidence of activity of BLU-945 in patients with advanced EGFR-mutant NSCLC utilizing circulating tumor DNA (ctDNA) in the phase 1/2 SYMPHONY study

Abstract Background: Despite recent advances in the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), most patients treated with third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, experience disease progression. The most common on-target EGFR resistance mutation is at the EGFR C797 residue (i.e., C797S), which prevents covalent binding to 3G EGFR TKIs. While 3G TKIs are effective in patients with EGFR activating and T790M mutations (commonly seen post-progression after first-/second-generation TKIs), there are no targeted therapies approved after their failure. BLU-945 is an investigational, reversible, and selective next-generation EGFR TKI intended for use as a single agent or in combination with other agents to suppress activating and on-target resistance EGFR mutants, including T790M and C797S, while sparing wildtype (wt) EGFR. BLU-945 has shown in vivo antitumor activity in 3G EGFR TKI-naïve as well as resistant NSCLC patient-derived xenograft models with EGFR T790M and C797S mutations. Based on this, we started SYMPHONY (NCT04862780), a phase 1/2 study in patients with metastatic EGFRm NSCLC, to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D); and to assess the safety, pharmacokinetics (PK), and antitumor activity of BLU-945. Methods: In the ongoing phase 1 dose-escalation part of the study, patients aged ≥18 years with metastatic EGFRm NSCLC previously treated with ≥1 EGFR TKI (Eastern Cooperative Oncology Group performance status of 0-2) received BLU-945 once daily (QD) on a 28-day cycle following a Bayesian Optimal Interval escalation design. Adverse events (AEs), dose-limiting toxicities (DLTs), PK, ctDNA (in real-time using FoundationOne Liquid panel), and radiographic antitumor activity (by RECIST 1.1 criteria) were assessed in the first 4 treatment cohorts. Results: As of the January 7, 2022, data cut, 18 patients have been treated with BLU-945 at 25-200 mg QD. Of these, 14 (77.8%) patients had received ≥2 lines of prior systemic anticancer therapy in the metastatic setting. There were no DLTs, and most AEs were low grade. Treatment-related AEs (all Grade 1) occurred in 8 (44.4%) patients with the most common being nausea (n=3). EGFR mutation allele fraction assessment by ctDNA at C1D1 and C1D15 showed that tumors were heterogeneous at baseline. At doses of 50 mg QD and higher, reductions in EGFR resistance mutation allele fraction were seen in all patients (n=3) with EGFR C797S (n=2) and/or T790M (n=3) resistance mutations, with a median 48% reduction of these mutations. 50% of patients remain on treatment and dose escalation continues to determine the RP2D. Conclusion: As of the data cut, BLU-945 was generally well tolerated in heavily pre-treated patients with EGFRm NSCLC. There was also early evidence of a reduction in EGFR mutation allele fractions by ctDNA. Citation Format: Elaine Shum, Yasir Elamin, Karen L. Reckamp, Zofia Piotrowska, Julia Rotow, Daniel S. Tan, Koichi Goto, Jagan Parepally, Faris Albayya, Melinda Louie-Gao, Renata Sawtell, Alena Zalutskaya, David Spigel. Emerging evidence of activity of BLU-945 in patients with advanced EGFR-mutant NSCLC utilizing circulating tumor DNA (ctDNA) in the phase 1/2 SYMPHONY study [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 CT184.

PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.

Effect of smoking habits on the efficacy of EGFR-TKI plus anti-angiogenic agent in advanced EGFR-mutant NSCLC

BackgroundThe types of epidermal growth factor receptor (EGFR)–mutant non–small-cell lung cancer (NSCLC) patients who could obtain significant clinical benefit from the dual inhibition of EGFR/vascular EGFR (VEGFR) pathways remain unclear. No consensus has been reached on the significance of smoking habits in clinical benefit obtained from EGFR-TKI plus anti-angiogenic agents. MethodsPubMed, EMBASE, and Cochrane databases for all phase II/III randomized clinical trials (RCTs) investigating the efficacy of EGFR-TKI combined with anti-angiogenic agents stratified by smoking habits (updated October 2021) were searched systematically. The primary outcomes were the pooled HRs for PFS/OS in smokers and non-smokers, and differences in efficacy of EGFR-TKI plus anti-angiogenic treatment between smokers and non-smokers, measured by difference in PFS and OS. ResultsSeven phase II/III RCTs involving 1452 patients were identified. The pooled analysis demonstrated that EGFR-TKI plus anti-angiogenic agent could decrease the risk of progression by 40% (HR, 0.60; 95%CI 0.48–0.75) in smokers when compared with EGFR-TKI alone, but not in non-smokers (HR, 0.92; 95%CI 0.68–1.25). The comparison analysis further demonstrated that EGFR-mutated NSCLC patients who smoked obtained greater progression-free survival (PFS) benefit from treatment with EGFR-TKI plus anti-angiogenic agents (HR, 0.68; 95%CI 0.51–0.91). Consistent with the results for PFS, smokers receiving EGFR-TKI plus anti-angiogenic agents appeared to exhibit better overall survival (OS) than non-smokers but not to a statistically significant degree (HR, 0.60; 95%CI 0.23–1.52). Meta-regression analysis revealed no significant effect of the line of treatment (P = 0.52), trial phase (P = 0.52), EGFR-TKI type (P = 0.13), or anti-angiogenic agent type (P = 0.50) on PFS effect sizes under multivariate models. ConclusionComprehensive analysis suggested that EGFR-TKI plus anti-angiogenic agents led to favorable PFS among smoking EGFR-mutant patients, comparable to nonsmokers, which might provide a useful guide for clinicians.

Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with advanced EGFR-mutated NSCLC.

TPS3161 Background: Although first-line treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib improved survival in patients (pts) with advanced/metastatic EGFR-mutated ( EGFRm) non-small cell lung cancer (NSCLC), therapy after acquired resistance to osimertinib remains an unmet need. HER3 is expressed in the majority of EGFRm NSCLCs. HER3-DXd is a novel, investigational, HER3-directed antibody-drug conjugate that demonstrated preliminary single-agent clinical activity in EGFRm NSCLC. In preclinical models of EGFRm NSCLC, osimertinib increased membrane HER3 expression, improved the internalization rate of HER3-DXd, and enhanced tumor growth inhibition by HER3-DXd. Therefore, HER3-DXd with osimertinib might improve outcomes in pts with disease that progressed with osimertinib therapy. This phase 1 study (NCT04676477; U31402-A-U103) evaluates HER3-DXd in combination with osimertinib in pts with advanced EGFRm NSCLC that has progressed with first-line osimertinib therapy. Methods: This is an open-label, 2-part study of HER3-DXd in combination with osimertinib. Pts are enrolling in North America, Europe, and Asia. Dose escalation enrolls pts with locally advanced/metastatic NSCLC with an EGFR-activating mutation (exon 19 del or L858R) and progression during or after osimertinib therapy. Pts receive HER3-DXd 1.6, 3.2, 4.8, or 5.6 mg/kg intravenously (IV) every 3 weeks (Q3W) in combination with osimertinib 40 or 80 mg orally (PO) once daily (QD). Pts are enrolled in each cohort guided by safety (dose-limiting toxicities) using a Bayesian logistic regression model. Primary objectives of dose escalation are to assess safety and tolerability of the combination and identify a recommended combination dose (RCD). In dose expansion, pts will be randomized 1:1 to receive either HER3-DXd and osimertinib at the RCD (arm 1, [≈60 pts]) or HER3-DXd 5.6 mg/kg IV Q3W (arm 2, [≈60 pts]). A third arm (arm 1b, [≈60 pts]) may be added to evaluate 2 provisional RCDs of HER3-DXd + osimertinib. The primary objective of dose expansion (arms 1, 2, and 1b) is to evaluate efficacy of the combination vs that of monotherapy. The primary endpoint is objective response rate (ORR) as assessed by blinded independent central review. Other efficacy endpoints include ORR by investigator and duration of response, disease control rate, time to response, progression-free survival, and overall survival. If the RCD includes an osimertinib dose of 80 mg PO QD, ≈30 pts with advanced EGFRm NSCLC without prior treatment will be enrolled and treated at the RCD in a separate cohort; the primary objective is to assess safety and tolerability. A tumor sample after progression with osimertinib (or prior to entry) is required for pts enrolled in dose expansion for retrospective evaluation of HER3 and biomarker analyses. Clinical trial information: NCT04676477.

Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).

TPS9151 Background: Currently, EGFR-TKIs are widely accepted as the standard treatment for EGFR-mutant advanced NSCLC; however, acquired resistance is inevitable. Preclinical and clinical evidence has demonstrated that dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutant advanced NSCLC population to overcome the resistance to EGFR-TKIs. Aumolertinib (HS-10296) is a novel, third-generation EGFR-TKI approved in China to treat EGFR mutation positive non-small cell lung cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for NSCLC. Here, we aimed to evaluate the safety and anticancer activity of aumolertinib alone/with apatinib for advanced/metastatic NSCLC patients with EGFR mutation. Methods: The phase III, multicenter, randomized, open-label, controlled study is evaluating the efficacy and safety of aumolertinib plus apatinib versus aumolertinib alone as first line therapy in adult patients with EGFR+ NSCLC. Adult patients with histologically confirmed stage IIIB/IV NSCLC harboring EGFR mutations without prior EGFR TKI treatment are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 300 patients, which will be randomized (1:1) to receive oral aumolertinib once daily 110 mg or adding apatinib 250 mg a day until assessed progressive disease(PD)，stratified by EGFR mutation (Ex19del /L858R/others) and distant metastases sites (brain/liver/others). The primary endpoint is progression free survival assessed by investigators using Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints are disease control rate, duration of response, overall survival and safety. Adverse effects were graded per CTCAE v.4.03. This trial is registered as ChiCTR2100047453. Results: Recruiting. Conclusions: Recruiting. Clinical trial information: ChiCTR2100047453.