Therapy For NSCLC Research Articles

P4.07D.02 Furmonertinib as Adjuvant Therapy in Postoperative EGFR-Mutated Stage IB-IIA NSCLC with High-Risk Pathological Factors

P4.07D.02 Furmonertinib as Adjuvant Therapy in Postoperative EGFR-Mutated Stage IB-IIA NSCLC with High-Risk Pathological Factors

MA11.07 Pembrolizumab Plus Maintenance Olaparib as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 KEYLYNK-006 Study

MA11.07 Pembrolizumab Plus Maintenance Olaparib as First-Line Therapy for Metastatic Nonsquamous NSCLC: Phase 3 KEYLYNK-006 Study

The Risk and Reversibility of Osimertinib-Related Cardiotoxicity in a Real-World Population

IntroductionAlthough osimertinib, a third-generation EGFR tyrosine kinase inhibitor, as the first-line therapy for metastatic NSCLC was found to have significant survival benefits, concerns have arisen regarding its potential cardiotoxicity, particularly in real-world clinical settings. We aimed to investigate the incidence, risk factors, and reversibility of osimertinib-related cardiotoxicity. MethodsWe analyzed 1126 patients with NSCLC treated with osimertinib from May 2016 to April 2023 in two cancer centers. Osimertinib-related cardiotoxicity was defined as a composite of osimertinib-related cardiac dysfunction (ORCD), newly developed arrhythmia, and cardiac death. Total follow-up duration was 20.6 (10.8–35.2) months. ResultsThe osimertinib was administered for a median of 12.4 months. The incidence of osimertinib-related cardiotoxicity was 4.7%. Advanced age (adjusted hazard ratio with 95% confidence interval: 1.07 [1.04–1.09], p < 0.001), a history of heart failure (3.35 [1.67–9.64], p = 0.025), atrial fibrillation (3.42 [1.27–9.22], p = 0.015), and baseline low left ventricle strain (0.87 [0.79–0.96], p = 0.005) were independently associated with development of cardiotoxicity. The recovery rate of ORCD was 82.4%, which did not differ between patients who discontinued medication and those who did not. ConclusionsIn real-world practice, the incidence of osimertinib-related cardiotoxicity was 4.7%, including 3.4% for ORCD requiring cardiologic intervention, which is higher than previously reported. Given the long-term medication of osimertinib and increased mortality associated with cardiotoxicity, vigilant monitoring is crucial, especially in patients with advanced age, history of heart failure, atrial fibrillation, or decreased baseline left ventricular strain.

P3.12D.10 Phase 1b Study of AMG 193, An MTA-Cooperative PRMT5i, Alone and in Combination with Other Therapies in MTAP-deleted NSCLC

P3.12D.10 Phase 1b Study of AMG 193, An MTA-Cooperative PRMT5i, Alone and in Combination with Other Therapies in MTAP-deleted NSCLC

P3.08F.07 Efficacy and Safety of Envafolimab Plus Platinum-based Chemotherapy as Neoadjuvant Therapy in Resectable Stage II-IIIB NSCLC

P3.08F.07 Efficacy and Safety of Envafolimab Plus Platinum-based Chemotherapy as Neoadjuvant Therapy in Resectable Stage II-IIIB NSCLC

P3.06D.03 Prognostic and Predictive ctDNA Signature for Patients on Targeted Therapy for Metastatic NSCLC: A Pathway-based Approach

P3.06D.03 Prognostic and Predictive ctDNA Signature for Patients on Targeted Therapy for Metastatic NSCLC: A Pathway-based Approach

384 (PB372): TUSC2 gene therapy in KRASG12C mutant NSCLC overcomes acquired resistance to sotorasib

384 (PB372): TUSC2 gene therapy in KRASG12C mutant NSCLC overcomes acquired resistance to sotorasib

Novel DNA Repair Inhibitors Targeting XPG to Enhance Cisplatin Therapy in Non-Small Cell Lung Cancer: Insights from In Silico and Cell-Based Studies.

NSCLC is marked by low survival and resistance to platinum-based chemotherapy. The XPG endonuclease has emerged as a promising biomarker for predicting the prognosis of cisplatin-treated patients and its downregulation having been reported to increase cisplatin efficacy. This study presents an integrated strategy for identifying small molecule inhibitors of XPG to improve cisplatin therapy in NSCLC. A structure-based virtual screening approach was adopted, including a structural and physicochemical analysis of the protein, and a library of small molecules with reported inhibitory activities was retrieved. This analysis identified Lys84 as a crucial residue for XPG activity by targeting its interaction with DNA. After molecular docking and virtual screening calculations, 61 small molecules were selected as potential XPG inhibitors, acquired from the ChemBridge database and then validated in H1299 cells, a NSCLC cell line exhibiting the highest ERCC5 expression. The MTS assay was performed as a first screening approach to determine whether these potential inhibitors could enhance cisplatin-induced cytotoxicity. Overall, among the eight compounds identified as the most promising, three of them revealed to significantly increase the impact of cisplatin. The inherent cytotoxicity of these compounds was further investigated in a non-tumoral lung cell line (BEAS-2B cells), which resulted in the identification of two non-cytotoxic candidates to be used in combination with cisplatin in order to improve its efficacy in NSCLC therapy.

1277P Optimising targeted therapy in NSCLC: A comprehensive analysis of oncogenic fusion mutations and co-mutation landscapes

1277P Optimising targeted therapy in NSCLC: A comprehensive analysis of oncogenic fusion mutations and co-mutation landscapes

1229P Precision patient selection for postoperative therapy in resectable NSCLC: A comprehensive postoperative-risk model incorporating genetic and histological features

1229P Precision patient selection for postoperative therapy in resectable NSCLC: A comprehensive postoperative-risk model incorporating genetic and histological features

Hsp70 Negatively Regulates Autophagy via Governing AMPK Activation, and Dual Hsp70-Autophagy Inhibition Induces Synergetic Cell Death in NSCLC Cells.

Proteostasis mechanisms, such as proteotoxic-stress response and autophagy, are increasingly recognized for their roles in influencing various cancer hallmarks such as tumorigenesis, drug resistance, and recurrence. However, the precise mechanisms underlying their coordination remain not fully elucidated. The aim of this study is to investigate the molecular interplay between Hsp70 and autophagy in lung adenocarcinoma cells and elucidate its impact on the outcomes of anticancer therapies in vitro. For this purpose, we utilized the human lung adenocarcinoma A549 cell line and genetically modified it by knockdown of Hsp70 or HSF1, and the H1299 cell line with knockdown or overexpression of Hsp70. In addition, several treatments were employed, including treatment with Hsp70 inhibitors (VER-155008 and JG-98), HSF1 activator ML-346, or autophagy modulators (SAR405 and Rapamycin). Using immunoblotting, we found that Hsp70 negatively regulates autophagy by directly influencing AMPK activation, uncovering a novel regulatory mechanism of autophagy by Hsp70. Genetic or chemical Hsp70 overexpression was associated with the suppression of AMPK and autophagy. Conversely, the inhibition of Hsp70, genetically or chemically, resulted in the upregulation of AMPK-mediated autophagy. We further investigated whether Hsp70 suppression-mediated autophagy exhibits pro-survival- or pro-death-inducing effects via MTT test, colony formation, CellTiter-Glo 3D-Spheroid viability assay, and Annexin/PI apoptosis assay. Our results show that combined inhibition of Hsp70 and autophagy, along with cisplatin treatment, synergistically reduces tumor cell metabolic activity, growth, and viability in 2D and 3D tumor cell models. These cytotoxic effects were exerted by substantially potentiating apoptosis, while activating autophagy via rapamycin slightly rescued tumor cells from apoptosis. Therefore, our findings demonstrate that the combined inhibition of Hsp70 and autophagy represents a novel and promising therapeutic approach that may disrupt the capacity of refractory tumor cells to withstand conventional therapies in NSCLC.

Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer

IntroductionNo definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. MethodsWe retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). ResultsSixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 – 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0–22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21–34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2–23.9; p = 0.019). ConclusionChemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over −2 and MMP-10 over −13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.

SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC.

TPS218 Background: Mutations in KRAS are among the most frequent oncogenic drivers with the G12C variant found in ~13% of NSCLC. Outcomes for KRAS G12C-mutant NSCLC may be improved by combining KRAS G12C inhibitors with current 1L standard of care (SOC). Olomorasib is a potent and highly selective second-generation inhibitor of KRAS G12C, which delivers &gt;90% sustained target occupancy in preclinical models. In the LOXO-RAS-20001 phase 1/2 study, olomorasib in combination with pembrolizumab demonstrated preliminary efficacy and a favorable safety profile.1 Methods: SUNRAY-01 (NCT06119581) is a pivotal, global, phase 3 study in 1L advanced KRAS G12C-mutated NSCLC designed to seamlessly 1) optimize the dosing of olomorasib in combination with 1L SOC, and then 2) compare efficacy and safety of olomorasib plus SOC with placebo plus SOC. In the open-label randomized dose optimization (pembrolizumab plus olomorasib 50 mg vs 100 mg BID) and single arm safety lead-in (olomorasib plus pembrolizumab, pemetrexed, platinum), the optimal dose of olomorasib for combination therapy will be determined before the phase 3 study (parts A and B) is opened for enrollment. In part A, 384 participants with PD-L1 expression ≥50% are randomized (1:1) to pembrolizumab plus olomorasib or placebo. In part B, 552 participants are randomized (1:1) to pembrolizumab, pemetrexed, platinum plus olomorasib or placebo regardless of PD-L1 expression. Allocation of participants with PD-L1 expression ≥50% to either part A or part B will be at the discretion of the investigator. The primary objective is to compare efficacy based on PFS per RECIST v1.1 by blinded independent central review. Secondary endpoints include OS, ORR, DOR, DCR, TTR, PFS2, safety and tolerability, and patient-reported outcomes. Eligible participants (≥18 years) must have a KRAS G12C mutation in tumor or blood and known PD-L1 expression (0-100%), stage IIIB, IIIC, or IV NSCLC not suitable for curative intent radical surgery or radiation therapy, measurable disease per RECIST v1.1, and an ECOG PS 0-1. Participants can be enrolled based on local KRAS and PD-L1 testing results. Participants should not have received prior systemic therapy for advanced or metastatic NSCLC, however 1 cycle of SOC treatment prior to enrollment is allowed if immediate treatment is clinically indicated. Participants with asymptomatic (lesions ≤1.5 cm) or previously treated radiographically stable brain metastases are eligible. Key exclusion criteria include history of pneumonitis/interstitial lung disease and clinically significant active cardiovascular disease or malabsorption syndrome. The study opened for enrollment in December 2023. Reference: 1. Murciano-Goroff et al. 2023 Cancer Res 83 (8 Suppl): CT028. Clinical trial information: NCT06119581 .

Outcomes Analysis of Patients Receiving Local Ablative Therapy for Oligoprogressive Metastatic NSCLC Under First-Line Immunotherapy

ContextNonsmall Cell Lung Cancer (NSCLC) treatment relies on first-line immunotherapy as single agent or combined with chemotherapy. Oligoprogression may be observed in this setting. Material and MethodWe performed a European multicentric retrospective study on patients treated with first-line immunotherapy, who presented with oligoprogressive disease, treated with a local ablative treatment. ResultsA total of 61 patients were retrospectively included between 2018 and 2022. Twenty-four patients (39%) received immunotherapy as single agent, and 37 (61%) chemo-immunotherapy. First oligoprogression occurred more frequently in pre-existing metastatic sites (47% of patients). Median PFS1 (defined as time to first oligoprogression) was 11.5 months [IC95%: 10.0-12.3]. We observed that 37 patients (61%) progressed after first oligoprogression, and 20 (54%) from them presented second oligoprogression. Median OS for the whole cohort was 72.0 months [IC95%: 19.3-124.8], with positive correlation between OS and PFS1 (R=0.65, P < .0001). After loco-ablative treatment with radiotherapy, disease control rate was 89% with ablative radiotherapy: 88% with conventional radiotherapy, and 89% with stereotactic radiotherapy. ConclusionPatients with oligoprogression under/after immunotherapy have better prognosis with a high risk of subsequent oligoprogression.

Design, synthesis and biological evaluation of a new series of imidazothiazole-hydrazone hybrids as dual EGFR and Akt inhibitors for NSCLC therapy

In search of small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC), an efficient four-step synthetic route was followed for the synthesis of new imidazothiazole-hydrazone hybrids, which were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human lung fibroblast (CCD-19Lu) cells. Among them, compounds 4, 6, 13, 16, 17 and 21 exhibited selective cytotoxic activity against A549 cell line. In vitro mechanistic studies were performed to assess their effects on apoptosis, caspase-3, cell cycle, EGFR and Akt in A549 cells. Compounds 6, 16, 17 and 21 promoted apoptotic cell death more than erlotinib. According to the in vitro data, it is quite clear that compound 6 promotes apoptosis through caspase-3 activation and arrests the cell cycle at the G0/G1 phase in A549 cells. Compounds 16 and 17 arrested the cell cycle at the S phase, whereas compounds 4, 13 and 21 caused the cell cycle arrest at the G2/M phase. The most effective EGFR inhibitor in this series was found as compound 13, followed by compounds 17 and 16. Furthermore, Akt inhibitory effects of compounds 16 and 17 in A549 cells were close to that of GSK690693. In particular, it can be concluded that the cytotoxic and apoptotic effects of compounds 16 and 17 are associated with their inhibitory effects on both EGFR and Akt. Molecular docking studies suggest that compounds 16 and 17 interact with crucial amino acid residues in the binding sites of human EGFR (PDB ID: 1M17) and Akt2 (PDB ID: 3D0E). Based on the in silico data, both compounds are predicted to possess favorable oral bioavailability and drug-likeness. Further studies are required to benefit from these compounds as anticancer agents for targeted therapy of NSCLC.

OA01.07 Real-World Patient Characteristics, Biomarker Testing, and Adjuvant Therapy for Resected NSCLC at U.S. Oncology Clinics, 2019-2023

OA01.07 Real-World Patient Characteristics, Biomarker Testing, and Adjuvant Therapy for Resected NSCLC at U.S. Oncology Clinics, 2019-2023

Comprehensive analysis: efficacy of pembrolizumab as an initial therapy for PD-L1 negative NSCLC

Comprehensive analysis: efficacy of pembrolizumab as an initial therapy for PD-L1 negative NSCLC

Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study.

LBA4 Background: EGFR mutations occur in up to one-third of pts with unresectable stg III NSCLC. Consolidation durvalumab is standard of care (SoC) for pts who do not progress after concurrent CRT (cCRT), yet the benefit of consolidation immunotherapy specifically for EGFRm NSCLC remains uncertain, with limited data available. Osi, a 3rd-generation CNS-active EGFR-TKI, is recommended for EGFRm advanced/metastatic NSCLC and as adjuvant therapy for resectable EGFRm NSCLC. We report primary results from the global, double-blind, placebo (PBO)-controlled Phase 3 LAURA study (NCT03521154), assessing efficacy/safety of osi in unresectable stg III EGFRm NSCLC without progression after definitive CRT. Methods: Eligible pts: aged ≥18 years (≥20 in Japan), WHO PS 0/1, unresectable stg III EGFRm (Ex19del/L858R) NSCLC, had received definitive platinum-based cCRT/sequential CRT (sCRT) with no progression. Pts were stratified (cCRT vs sCRT; stg IIIA vs IIIB/IIIC; Chinese vs non-Chinese) and randomized 2:1 to receive osi 80 mg or PBO QD until progression (blinded independent central review [BICR]-confirmed)/discontinuation. Imaging, including brain MRI, was mandated at baseline, every 8 wks to wk 48, then every 12 wks, until progression by BICR. Open-label osi was offered after progression by BICR. Primary endpoint: progression-free survival (PFS; RECIST v1.1) assessed by BICR. Secondary endpoints included overall survival (OS) and safety. Data cut-off: January 5, 2024. Results: Overall, 216 pts were randomly assigned: osi n=143, PBO n=73. Baseline characteristics were generally balanced across osi/PBO arms: female 63/58%, stg IIIA 36/33%, IIIB 47/52%, IIIC 17/15%, Ex19del 52/59%. Osi significantly improved PFS by BICR vs PBO: HR 0.16; 95% CI 0.10, 0.24; p&lt;0.001. Median PFS was 39.1 mo (95% CI 31.5, not calculable) for osi vs 5.6 mo (95% CI 3.7, 7.4) for PBO; 12-mo PFS rate was 74% (osi) vs 22% (PBO); 24-mo PFS rate was 65% (osi) vs 13% (PBO). Investigator-assessed PFS (HR 0.19; 95% CI 0.12, 0.29; nominal p&lt;0.001) was consistent with PFS by BICR. PFS benefit was consistent across predefined subgroups. Interim OS analysis (20% maturity) showed a trend in favor of osi: HR 0.81; 95% CI 0.42, 1.56; p=0.530; 81% of pts (PBO arm) received osi after progression. All-causality AEs were reported in 98% vs 88% pts; ≥Grade 3 AEs in 35% vs 12%; serious AEs in 38% vs 15% for osi vs PBO, respectively. Radiation pneumonitis AEs (grouped term): 48% (osi) vs 38% (PBO), majority Grade 1/2. Any AEs leading to discontinuation were reported in 13% vs 5% for osi vs PBO, respectively. Conclusions: Osi after definitive CRT demonstrated a statistically significant and clinically meaningful improvement in PFS, for unresectable stg III EGFRm NSCLC, with no unexpected safety signals. These results establish osi as the new SoC for EGFRm NSCLC in this setting. Clinical trial information: NCT03521154 .

Ginsenoside Rd reduces cell proliferation of non-small cell lung cancer cells by p53-mitochondrial apoptotic pathway

Ginsenoside Rd is a tetracyclic triterpenoid derivative, widely existing in Panax ginseng, Panax notoginseng and other traditional Chinese medicines. Many studies have proved that ginsenoside Rd have a variety of significant biological activities on certain types of cancer. However, the mechanism of ginsenoside Rd remains unclear in lung cancer. The findings of this study reveal that GS-Rd inhibits the proliferation of NSCLC cells, induces apoptosis, and suppresses migration and invasion. The results showed Ginsenoside Rd inhibited the cell proliferation (∼99.52 %) by S phase arrest in cell cycle and promoted the apoptosis (∼54.85 %) of NSCLC cells. It also inhibited the migration and invasion of cells (p < 0.001). The expression levels of related mitochondrial apoptosis proteins (Bax/Bcl-2/Cytochrome C) and matrix metalloproteinases (MMP-2/-9) were significantly changed. The results showed that ginsenoside Rd inhibited the proliferation of tumor cells by activating p53/bax-mediated mitochondrial apoptosis and the expression of key enzymes for cell apoptosis caspase-3/cleaved-caspase-3 were significantly increased. This research contributes to a better understanding of the anti-tumor effects and molecular mechanisms of GS-Rd, paving the way for its potential development and clinical application in NSCLC therapy.