Non-small Cell Lung Cancer Harboring EGFR Mutations Research Articles

Efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy as 1st line treatment for patients with non-small cell lung cancer harboring HER2 mutations: Results from LC-SCRUM-Asia

IntroductionHER2 mutations are reported to occur in 2%–5% of all cases of non-small cell lung cancer (NSCLC). The clinical outcomes in patients with HER2-mutant NSCLC treated with immune checkpoint inhibitors (ICIs) plus platinum-based chemotherapy as 1st line treatment still remain unclear. MethodsUsing the large-scale clinico-genomic database of LC-SCRUM-Asia, the clinico-genomic characteristics and therapeutic outcomes of patients with HER2-mutant NSCLC were investigated. ResultsOf the 15,251 patients with NSCLC enrolled in the LC-SCRUM-Asia database, tumor HER2 mutations were detected in 402 patients (2.6 %). The most common subtype of HER2 mutations was exon 20 in-frame insertions (79 %), followed in frequency by mutations in the tyrosine kinase domain other than Exon20ins (10 %) and mutations in extracellular domains (7 %). NSCLCs harboring HER2 mutations showed a higher tumor mutation burden (TMB) as compared with NSCLCs harboring EGFR mutations or ALK fusions (median: 4.22 vs. 2.54 and 2.52 mutation per megabase, respectively). Of the 402 patients, 268 patients had received platinum-based chemotherapy with ICIs (Chemo-ICI, n = 95) or without ICI (Chemo-alone, n = 173) as 1st line treatment. The progression-free survival (PFS) was significantly longer in the Chemo-ICI group as compared with the Chemo-alone group (median 8.5 vs. 6.3 months; HR [95 %CI]: 0.66 [0.50–0.88]; P < 0.005). Multivariate analysis identified use of ICIs in addition to platinum-based chemotherapy as an independent favorable prognostic factor for PFS. There was no significant difference in the overall survival between the patients of the Chemo-ICI and Chemo-alone groups (median 31.1 vs. 23.3 months; HR [95 %CI]: 0.80 [0.57–1.12], P = 0.20). ConclusionsAddition of ICIs to platinum-based chemotherapy in 1st line treatment may improve the PFS in patients with HER2-mutant NSCLC. The relatively high TMB might be involved in the prolongation of the PFS in patients with HER2-mutant NSCLC receiving platinum-based chemotherapy with ICIs.

Early-Stage Non-Small Cell Lung Cancer: New Challenges with Immune Checkpoint Blockers and Targeted Therapies.

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC.

Efficacy and safety of aumolertinib combined with or without chemotherapy as an adjuvant treatment for stage II-IIIA non-small cell lung cancer following complete tumour resection: The first third-generation EGFR-TKI versus chemotherapy phase III clinical study (APEX).

TPS8117 Background: Patients with stage II-III A non-small cell lung cancer (NSCLC) can benefit from adjuvant targeted therapy. ADAURA study shows a remarkable advantage of disease-free survival (DFS). However, there are still unresolved clinical issues. Firstly, the control group in the trial is received placebo, making it impossible to directly compare the efficacy of adjuvant targeted therapy with the traditionally recommended adjuvant chemotherapy in guidelines. Thus, it cannot address the direct comparison of third-generation TKIs with the current standard therapy (chemotherapy). Secondly, the necessity of combining chemotherapy with adjuvant targeted therapy need to explored. Aumolertinib is a third-generation epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR sensitizing and EGFR T790M resistance mutations. This study aims to evaluate the efficacy and safety of aumolertinib combined with or without chemotherapy as adjuvant treatment for EGFR-sensitive mutations stage II-III A non-squamous NSCLC patients. Methods: This is a multicenter, randomized, open label, phase III study. Patients with histologically confirmed stage II-III A non-squamous NSCLC harboring EGFR mutations without prior EGFR TKI treatment and R0 resection are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 606 patients, will be randomized (3:2:1) to receive either aumolertinib alone (110mg, po, once daily) or aumolertinib (110mg, po, once daily) plus pemetrexed (500mg/m2, iv) and cisplatin (500mg/m2, iv) or pemetrexed (500mg/m2, iv) plus cisplatin (500mg/m2, iv). The first patient was enrolled on August 2, 2021. The primary end point is DFS, The secondary endpoints include 2, 3, 4, 5-year DFS rates, 5-year overall survival (OS), OS, safety and quality of life. Adverse effects were graded per CTCAE v.4.0. This trial is registered as NCT04762459. Clinical trial information: NCT04762459 .

Adjuvant icotinib of 12 months or 6 months versus observation following adjuvant chemotherapy for resected EGFR-mutated stage II–IIIA non-small-cell lung cancer (ICTAN, GASTO1002): A randomized phase 3 trial.

8004 Background: The efficacy, safety and ideal treatment duration of adjuvant icotinib (first-generation EGFR tyrosine kinase inhibitor) for patients with completely resected EGFR-mutated non-small-cell lung cancer (NSCLC) after adjuvant chemotherapy were not known in 2014, when this study was initiated. This phase 3 trial investigated whether icotinib following adjuvant chemotherapy improves clinical outcomes compared with observation in stage II-IIIA NSCLC harboring EGFR mutation. Methods: This is a multicenter, randomized, open-label, phase 3 trial. From July 2014 to December 2021, patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after platinum-based adjuvant chemotherapy were enrolled. Patients were assigned in a 1:1:1 ratio to receive icotinib (125mg, three times daily) for 12 months, icotinib for 6 months or to observation. The primary endpoint was disease-free survival (DFS) in the intention-to-treat population. Results: This trial was terminated early due to slow accrual.A total of 251 patients were randomized, with 84 patients in the 12-month icotinib group, 84 patients in the 6-month icotinib group, and 83 patients in the observation group. Baseline characteristics were balanced between the groups. After a median follow-up of 61.4 months, 6 months of icotinib significantly improved DFS (HR: 0.41, 95% CI, 0.27-0.62; P = 0.000025) and overall survival (OS, HR: 0.56, 95% CI, 0.32-0.98; P = 0.041) compared with observation. Adjuvant icotinib of 12 months also significantly improved DFS (HR: 0.40, 95% CI, 0.27-0.61; P = 0.000014) and OS (HR: 0.55, 95% CI, 0.32-0.96; P = 0.035) compared with observation. Adjuvant icotinib of 12 months did not improve DFS (HR: 0.97; P = 0.89) and OS (HR: 1.00; P = 0.99) compared with 6 months of this drug. Median DFS was 61.8 months (95% CI, 43.3 to 80.3) for the 12-month icotinib group, 63.2 months (95% CI, 44.8 to 81.6) for the 6-month icotinib group compared with 23.7 months (95% CI, 16.5 to 30.9) for the observation group. The 5-year DFS and OS for the 12-month icotinib, 6-month icotinib and observation groups were 51.3%, 50.1% and 24.8%; and 74.5%, 74.0% and 65.1%; respectively. No differences in efficacy pertaining to icotinib duration were found in any of the subgroups. Rates of adverse events of grade 3 or higher were 8.3%, 5.9% and 2.4% for the 12-month icotinib, 6-month icotinib and observation groups, respectively. The safety profile remained similar to the previous reports for icotinib. Conclusions: Adjuvant icotinib for 12 months and 6 months provide a significant DFS and OS benefit compared with observation in patients with completely resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile. Nevertheless, 12 months of icotinib had no additional benefit compared with 6 months. Clinical trial information: NCT01996098 .

Abstract 946: Landscape of HRD aberration in EGFR mutated lung cancer and the role of PARP-inhibitor in EGFR mutated lung cancer with HRD aberration

Abstract Introduction: Olaparib, an oral poly polymerase (PARP) inhibitor has received approval for treating malignancies displaying homologous recombination deficiency (HRD). Current data is insufficient in establishing the role of PARP inhibitors in non-small cell lung cancer (NSCLC) in the setting of third generation EGFR tyrosine kinase inhibitor (TKI) use. Preclinical investigation suggests heightened PARP inhibitor sensitivity of TKI-resistant EGFR mutant NSCLC cells compared to TKI-sensitive cells. Methods: We utilized The Cancer Genome Atlas (TCGA) to investigate the prevalence of HRD gene mutations in patients with NSCLC harboring EGFR mutations. We also present a case demonstrating a favorable response to the dual therapy of olaparib and osimertinib in NSCLC harboring EGFR, RAD50, and ARID1A mutations that progressed on osimertinib. Results: There were 2298 patients in the NSCLC cohort (MSKCC database). Among 687 patients with EGFR mutations, 24 patients (3.5%) exhibited ARID1A mutations, 8 patients (1.2%) had BRCA1 mutations, 11 patients (1.6%) had BRCA2 mutations, and 5 (0.7%) had RAD50 mutations. A 71-year-old female presented with stage IV adenocarcinoma of the lung. She had recurrent malignant pericardial effusion requiring pericardiocentesis for previous cardiac tamponade. Computed tomography (CT) of the chest revealed a 3cm irregular left hilar mass with bilateral mediastinal and hilar lymph nodes. Tissue next generation sequencing (NGS) at baseline identified EGFR exon19 deletion along with RAD50 R726H which is a HRD pathway gene. Circulating tumor DNA (ct-DNA) NGS (Guardant360) showed EGFR E746_A750del 4.8%. The patient achieved partial response to osimertinib for 28 months. Follow-up CT showed disease progression. Olaparib 200mg twice daily was added to osimertinib based on repeat ct-DNA NGS indicating a new ARID1A alteration (splice site SNV) along with the known BRCA1 mutation. Follow up scans currently have consistently demonstrated ongoing partial response for 19 months. Combining olaparib with osimertinib can be effective in an osimertinib-resistant NSCLC patient with EGFR mutation and HRD aberration. The favorable response could be attributed not only to pre-existing RAD50 mutation but also to acquired mutations in ARID1A HRD genes. Conclusion: HRD aberrations are uncommon in EGFR mutated lung cancer patients. Further investigation on the role of PARP inhibitor in EGFR mutated lung cancer is warranted. Citation Format: Jinah Kim, Horyun Choi, Liam Il-Young Chung, Young Kwang Chae. Landscape of HRD aberration in EGFR mutated lung cancer and the role of PARP-inhibitor in EGFR mutated lung cancer with HRD aberration [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 946.

Abstract C151: BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets

Abstract Introduction: Uncommon EGFR mutations in non-small cell lung cancer (NSCLC), including exon 20 insertion and atypical mutations, are generally associated with poorer clinical outcomes than common EGFR mutations. Patients (pts) with these mutations have limited effective therapeutic options. Afatinib is the only approved agent for uncommon mutations but is associated with high rates of toxicity and limited central nervous system (CNS) penetration. Amivantamab and mobocertinib are approved for patients with relapsed EGFR exon 20 insertion NSCLC but are associated with limitations in efficacy and CNS activity. BLU-451 is an investigational, CNS-penetrant, EGFR-wild-type (WT)–sparing, selective inhibitor against exon 20 insertion and uncommon EGFR mutations that is currently being evaluated in the phase 1/2 CONCERTO study (NCT05241873). Here, we report on the prevalence of uncommon EGFR mutations from a single center, real-world data set (MD Anderson Cancer Center [MDACC]), and report preclinical activity of BLU-451 on a broad spectrum of uncommon EGFR mutations by structure classification. Methods: BLU-451 cellular activity was evaluated in engineered BaF3 cell lines expressing 62 EGFR kinase domain mutations as well as in cell lines dependent on WT EGFR, using the CellTiter-Glo® Luminescent Cell Viability Assay and a phosphorylation-specific EGFR AlphaLISA® assay. The MDACC Moon Shot™ Genomic Marker-Guided Therapy Initiative (GEMINI) database was searched for pts with NSCLC whose tumors harbored EGFR kinase domain mutations. Results: In the MDACC GEMINI database, a total of 1495 unique patients with NSCLC harboring EGFR mutations were identified, including 1025 with classical mutations (exon 19 deletion and L858R) with or without T790M, 223 with exon 20 insertion mutations, and 247 with only atypical mutations. In BaF3 cells, BLU-451 demonstrated nanomolar potency in multiple atypical and exon 20 insertion mutation cell lines with selectivity against WT EGFR. Conclusion: Atypical EGFR mutations represent a sizable NSCLC pt population, of similar magnitude to that of EGFR exon 20 insertion mutations. BLU-451 preclinical data in EGFR atypical and exon 20 insertion mutations showed broad, potent, and selective activity, supporting continued evaluation of BLU-451 in the phase 1/2 CONCERTO study in pts with advanced or metastatic NSCLC harboring uncommon EGFR mutations. Citation Format: Xiuning Le, Yves Millet, Monique Nilsson, Aditya Dhande, Jeffrey Keats, Holly Ponichtera, Joseph Kim, Junqin He, Yasir Y. Elamin, John V. Heymach, Chiara Conti, Stephanie Lee. BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C151.

Abstract C022: Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results

Abstract Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (r/rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver (L858R, Ex19del), intrinsic (atypical) driver (L718Q, L861Q, S768I), and acquired resistance mutation (C797X). BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preliminary results from the Phase 1 dose escalation study (NCT05256290) are presented. Methods: BDTX-1535-101 is a first-in-human study enrolling patients with locally advanced or metastatic NSCLC harboring EGFR mutations, with or without CNS disease, following standard of care EGFR inhibitor therapy, or patients with r/rGBM expressing EGFR alterations. The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Using an adaptive Bayesian optimal interval design, eligible patients are enrolled and dosed daily for 21-day cycles until treatment discontinuation. Results: As of 20 May 2023, 51 patients (24 NSCLC, 27 r/rGBM) were enrolled and treated across 7 dose cohorts (15mg – 400mg QD). For NSCLC, mean age was 65 years (range 47-81), patients had a median of 2 prior lines of treatment (1-9), and 79% received prior osimertinib. For r/rGBM, the mean age was 58 years (41-85) with a median of 2 prior lines of treatment (range 1-4). The most common all-grade treatment-related AEs (TRAE) were rash (76%), diarrhea (51%), stomatitis (29%), paronychia (20%) and nausea (20%), vast majority Gr 1 to Gr 2. Gr 3 TRAEs greater than or equal 10% were diarrhea (12%) and rash (10%). Plasma exposure of BDTX-1535 increased dose proportionally with a half-life of ~15h supporting once daily dosing. The maximum tolerated dose is 300mg QD. Circulating tumor DNA (ctDNA) assessment in NSCLC patients with classical and intrinsic drivers as well as acquired resistance mutations revealed significant ctDNA reductions across all EGFR mutation types. Five of 12 patients with either intrinsic driver (eg, L718Q) or acquired resistance (C797S) mutations in a subgroup of NSCLC efficacy evaluable patients at doses at or above 100mg had a confirmed partial response (PR) by RECIST1.1; 1 patient had unconfirmed PR, while the remaining 6 patients had stable disease. Additional GBM data will be shared separately.Conclusions:BDTX-1535 was well-tolerated at a daily dose up to 300mg and promising preliminary clinical activity was observed in NSCLC patients harboring either intrinsic driver or acquired resistance EGFR mutations post-progression with an EGFR inhibitor. A preliminary RP2D dose is being explored in NSCLC patients in dose expansion cohorts. : Citation Format: Helena Yu, Melissa Johnson, Jason T. Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C022.

A pilot study of anlotinib with third-generation epidermal growth factor receptor tyrosine kinase inhibitors in untreated EGFR-mutant patients with advanced non-small cell lung cancer.

In recent years, osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recommended as a first-line treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). A phase III study (AENEAS) to assess the efficacy and safety of aumolertinib, another third-generation EGFR-TKI, vs. gefitinib as a first-line treatment in patients with locally advanced or metastatic NSCLC harboring EGFR mutations has also achieved positive results. Despite the improvements in progression-free survival (PFS) and overall survival (OS) of third- vs. first-generation EGFR-TKIs, combined treatment strategies to postpone drug resistance and further prolong survival benefits remain to be explored. We conducted a nonrandomized phase II trial (ChiCTR2000035140) of an oral multitarget antiangiogenic TKI (anlotinib) with third-generation EGFR-TKIs (osimertinib or aumolertinib) in untreated patients with EGFR mutation and advanced NSCLC. Anlotinib and the third-generation EGFR-TKIs were orally administrated (anlotinib at a dose of 12 mg once every other day and osimertinib at 80 mg once daily or aumolertinib at 110 mg once daily). The primary end point of the study was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), OS, PFS, and safety of the combined treatment. Enrollment was ceased due to treatment-related adverse events (trAEs) after 11 of 35 planned patients were treated. Among these 11 patients, two were lost to follow-up, and the treatment of five of the remaining nine patients was discontinued due to trAEs, including stomachache, rash, hyponatremia, pulmonary embolism, and interstitial pneumonia. AEs of grade 3 or worse were observed in five patients, but no treatment-related death occurred in these patients. Combining anlotinib and third-generation EGFR-TKIs in untreated EGFR-mutant patients with advanced NSCLC demonstrated significantly increased toxicity, suggesting that the combined treatment strategy was an inappropriate therapeutic choice in this setting.

First-Generation Epidermal Growth Factor Receptor Inhibitors Plus Antiangiogenic Drugs Versus Third-Generation Epidermal Growth Factor Receptor Inhibitors in Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the therapeutic landscape of non-small-cell lung cancer (NSCLC). However, despite significant survival improvement, the emergence of resistance mechanisms represents a common event. In this meta-analysis, we compared the efficacy and safety of third-generation EGFR-TKIs, the current standard of care, to first-generation EGFR-TKIs with antiangiogenic drugs for the first-line treatment of NSCLC harboring EGFR mutations. Randomized controlled clinical trials (RCTs) reporting survival data published before September 1, 2022, were searched through the MEDLINE databases (PubMed), the Cochrane Database of Systematic Reviews, and Central Register of Controlled Trials (Wiley). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 or higher treatment-related adverse events (≥3 TRAEs) data were analyzed. Twelve RCTs were included in our meta-analysis, with a total of 3,565 patients. We observed that third-generation EGFR-TKIs and first-generation EGFR-TKIs combined with antiangiogenic drugs provided a similar OS benefit over first-generation EGFR-TKIs in any of the subgroups. However, we indirectly observed a greater PFS benefit of third-generation EGFR-TKIs over first-generation EGFR-TKIs in females, never-smokers, in patients harboring exon 19 deletions, and in those with brain metastasis, as compared with using first-generation EGFR-TKIs plus antiangiogenic drugs. The ORR did not differ between the combination strategy and third-generation EGFR-TKIs. Finally, the risk of developing grade ≥3 TRAEs was higher using the combination of first-generation EGFR-TKIs and antiangiogenic drugs over first-generation EGFR-TKIs than third-generation EGFR-TKIs over first-generation EGFR-TKIs. This meta-analysis suggests that the combination strategy may provide an alternative to third-generation EGFR-TKIs, but more data are needed to determine the predictive clinicopathologic characteristics that can influence the treatment choice. Until then, third-generation EGFR-TKIs still represent the first choice in advanced NSCLC harboring EGFR mutations.

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment.

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development.

Survival benefits from afatinib compared with gefitinib and erlotinib among patients with common EGFR mutation in first-line setting.

BackgroundEpidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are recommended as first‐line treatment in non‐small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR‐TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first‐line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation.MethodsA retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first‐line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression‐free survival (PFS) with first‐line EGFR‐TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first‐line EGFR‐TKIs.ResultsAmong 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first‐line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first‐line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance.ConclusionsFirst‐line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR‐TKI in the first‐line setting.

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.

Final progression-free survival analysis of phase II study with the combination therapy of DFP-14323, protease inhibitor, and low-dose afatinib as first-line therapy for common EGFR mutation–positive NSCLC.

9111 Background: DFP-14323(INN: ubenimex) was developed as a biological response modifier and has been approved for maintenance therapy of AML in Japan. Ubenimex is an inhibitor of aminopeptidase N (APN), originated from Streptomyces olivoreticuli. APN is well known as one of the prognostic factors for several cancer types, including non-small-cell lung cancer (NSCLC). Meanwhile, afatinib is one of the standard treatments in NSCLC with EGFR mutation, but the toxicities often require dose reduction. Recently, it is suggested that reducing afatinib doses can decrease treatment-related adverse events without affecting efficacy. We aimed to examine efficacy of DFP-14323 with low-dose afatinib by conducting phase II study in patients with metastatic NSCLC harboring EGFR mutation. Methods: The study was a multi-center, single-arm, open-label phase II trial. Stage III/IV and treatment-naïve patients with common EGFR mutation-positive (L858R/19del) NSCLC were treated with DFP-14323 at a fixed dose of 10mg/day and afatinib at a starting dose of 20 mg/day until disease progression or intolerable toxicity. The primary endpoint was disease control rate (DCR), defined by sum the CR, PR and SD. The secondary endpoints were progression-free survival(PFS), overall response rate(ORR), N/L ratio, and safety. A sample size of 26 patients was determined, assuming a threshold DCR 70% and an expected DCR 90% with a two sided α error of 0.05 and a β error of 0.20, based on the Simon’s two stage design. Results: From July 2018 to March 2020, 26 patients were enrolled. A median age was 72 years (range, 53-82), 21(81%) were female, and 16 (62%) were never-smokers. Half of patients had Del-19 and other half had L858R. An efficacy analysis provided a DCR of 100% (previously reported) with 18 responders (ORR : 69%). Independent imaging evaluation at 72 weeks provided a median PFS was confirmed to be 16.6mts (95% CI 10.2, 22.9, median follow-up time for censored cases: 16.3mts). According to updated exploratory follow-up by physicians, as of the data cut-off of Dec 2021, median PFS was calculated 20.6 mts (95% CI, 12.6, 28.5, median follow-up time for censored case: 20.9mts). Seven Grade 3 adverse events were observed in 6patient(23%), and paronychias in 3 patients and diarrhea, stomatitis, dermatitis, and lymphocytopenia in 1 patient each. One paronychia was considered to be related to DFP-14323 and the other events to afatinib. No grade 4 or 5 adverse events were observed. One Grade 1 ILD was observed but recovered soon without treatment. Conclusions: Combination of DFP-14323 and low-dose afatinib has shown comparable potential as a first-line treatment for EGFR mutation positive NSCLC with feasible efficacy and good safety profile. We are planning a phase III study to evaluate this combination therapy as compared with other EGFR-TKIs. Clinical trial information: UMIN000033062.

Utility of Next-Generation Sequencing in the Reconstruction of Clonal Architecture in a Patient with an EGFR Mutated Advanced Non-Small Cell Lung Cancer: A Case Report

EGFR tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, targeted therapies impose a strong selective pressure against the coexisting tumor populations that lead to the emergence of resistant clones. Molecular characterization of the disease is essential for the clinical management of the patient, both at diagnosis and after progression. Next-generation sequencing (NGS) has been established as a technique capable of providing clinically useful molecular profiling of the disease in tissue samples and in non-invasive liquid biopsy samples (LB). Here, we describe a case report of a patient with metastatic NSCLC harboring EGFR mutation who developed two independent resistance mechanisms (EGFR-T790M and TP53 + RB1 mutations) to dacomitinib. Osimertinib given as a second-line treatment eliminated the EGFR-T790M population and simultaneously consolidated the proliferation of the TP53 + RB1 clone that eventually led to the histologic transformation to small-cell lung cancer (SCLC). Comprehensive NGS profiling revealed the presence of the TP53 + RB1 clone in the pretreatment biopsy, while EGFR-T790M was only detected after progression on dacomitinib. Implementation of NGS studies in routine molecular diagnosis of tissue and LB samples provides a more comprehensive view of the clonal architecture of the disease in order to guide therapeutic decision-making.

Comparison of Different EGFR Gene Mutation Status in Patients with Metastatic Non-Small Lung Cancer After First-Line EGFR-TKIs Therapy and Analyzing Its Relationship with Efficacy and Prognosis.

PurposeThe purpose of this study is to compare the different EGFR mutation status in patients with metastatic non-small cell lung cancer (NSCLC) after first-line EGFR-TKIs therapy and analyze its relationship with efficacy and prognosis.Patients and MethodsThis study retrospectively analyzed the data of patients with metastatic NSCLC harboring EGFR mutation in the Affiliated Tumor Hospital of Guangxi Medical University from June 2016 to December 2020. Samples were collected before treatment and at the time of disease progression after first-line EGFR-TKIs therapy. Amplification refractory mutation system (ARMS) PCR and next-generation sequencing (NGS) were used to detect EGFR mutation. ORR, DCR, and PFS of different EGFR mutation groups were compared.ResultsThe EGFR mutation rate of re-biopsy was 60.23%. The inconsistency rate of EGFR mutations in the same and different simple types was 72.22% (26/36) and 92.31% (48/52), respectively. Alterations in terms of EGFR mutations were divided into four groups: Group A: EGFR-sensitive mutation negative and T790M negative (39.77%); Group B: EGFR-sensitive mutation positive and T790M negative (18.19%); Group C: EGFR-sensitive mutation negative and T790M positive (36.36%); Group D: EGFR-sensitive mutation positive and T790M positive (5.68%). The differences between the four groups in ORR and DCR were not statistically significant (P>0.05). The median PFS of all patients was 10.65 months. PFS of Group A, B, C, and D was 12.26, 7.96, 10.55, and 13.81 months, respectively, with statistical significance (Log rank P = 0.014).ConclusionEGFR mutation status in metastatic NSCLC patients receiving the first- and second-generation TKIs after disease progression show diversity. Monitoring the EGFR mutation changes is of great importance for subsequent clinical decision-making and exploring the underlying mechanisms of acquired resistance.

SHOC2 Is a Critical Modulator of Sensitivity to EGFR–TKIs in Non–Small Cell Lung Cancer Cells

EGFR mutation-positive patients with non-small cell lung cancer (NSCLC) respond well to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI); however, treatment with EGFR-TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR-TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR-TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR-TKIs and that SHOC2 affects the sensitivity to EGFR-TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR-TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR-TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR-TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations. IMPLICATIONS: This study showed that SHOC2 works as a modulator of sensitivity to EGFR-TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR-TKIs.

Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11–18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11–18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11–18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

Glasgow prognostic score predicts efficacy and prognosis in patients with advanced non-small cell lung cancer receiving EGFR-TKI treatment.

BackgroundLung cancer is the leading cause of cancer‐related deaths. Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are effective for advanced non‐small cell lung cancer (NSCLC) harboring EGFR mutations, some patients experience little or no response. The Glasgow prognostic score (GPS) is an inflammation‐related score based on C‐reactive protein (CRP) and albumin concentrations, and has prognostic value in various cancer settings. This study aimed to evaluate whether GPS could predict response of NSCLC to EGFR‐TKIs.MethodsThis retrospective multicenter study evaluated patients with NSCLC harboring EGFR mutations who received EGFR‐TKI monotherapy from October 2006 to December 2016. GPS values were determined using CRP and albumin concentrations from before initiation of EGFR‐TKIs. The Kaplan‐Meier method and Cox proportional hazard models were used to evaluate progression‐free survival (PFS) and overall survival (OS).ResultsIn 214 patients, 141, 43, and two patients had GPS values of 0, 1, and 2, respectively. The GPS independently predicted the efficacy of EGFR‐TKIs; good GPS (0–1) conferred significantly better PFS (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.38–0.96, P = 0.03) and OS (HR: 0.56, 95% CI: 0.33–0.96, P = 0.03). Multivariate analysis confirmed that a good GPS (0–1) independently predicted good PFS and OS among patients who had PS of 0–1. Good GPS (0–1) independently predicted good OS among patients receiving treatment in first‐line settings.ConclusionsThe GPS independently predicted the efficacy of EGFR‐TKIs for EGFR‐mutated NSCLC; however, further studies are needed to validate our findings.Key pointsSignificant findings of the studyGlasgow prognostic score (GPS) independently predicted the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) treatment for EGFR‐mutated NSCLC.What this study addsThe findings presented in this paper will help to identify patients who will be expected to experience limited or no response to EGFR‐TKI treatment by using GPS.

Osimertinib in previously EGFR-TKI treated non-small cell lung cancer (NSCLC) patients without T790M mutation: Real-world evidence.

e21631 Background: The efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without T790M mutation remains unclear in real-world practice. We investigated whether osimertinib can provide survival benefit in EGFR-mutant patients without T790M mutation after 1st/2nd generation TKI treatment. Methods: Between January 1, 2009, and March 31, 2019, 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as≥2nd-line EGFR-TKI treatment were identified at Mayo Clinic. The time to treatment failure of osimertinib was analyzed by the Kaplan-Meier (KM) estimates. The risk of death post diagnosis was analyzed by Cox proportional hazard models. Results: Among 417 EGFR-mutant patients, higher risk of death was found in patients with age above 65 years, non-adenocarcinoma, no surgery treatment, no radiation treatment, non-exon 19 deletion/exon 21 L858R mutation, higher ECOG PS (2-4), PD-L1 expression of 50% or more, bone metastasis, live metastasis, and adrenal metastasis (all p &lt; 0.05). Moreover, osimertinib as ≥2nd-line TKI treatment in patients with or without T790M revealed lower risk of death compared to 1st/2nd generation TKI treatment without subsequent osimertinib (HR = 0.33; 0.46, and p = 0.0002; 0.0232, respectively). However, among patients receiving osimertinib as ≥2nd-line TKI treatment, patients with T790M did not have superior survival than those without (p = 0.2803). Among 154 patients receiving osimertinib, a higher risk of treatment failure for osimertinib was found in male (HR = 1.72; p = 0.0327), patients with 1st-line TKI duration ≤12 months (HR = 2.16; p = 0.0019), BMI drop &gt; 10% (HR = 1.85; p = 0.0207), PD-L1 levels of 50% or more (HR = 4.28; p = 0.0008), and 1st-line TKI with afatinib (HR = 2.19; p = 0.0136). Nonetheless, osimertinib as ≥2nd-line TKI in patients without 790M mutation did not have higher risk of treatment failure than those with T790M (p = 0.1236). Conclusions: This is the first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression &lt; 50% and may potentially gain benefit from optimizing treatment strategies including immunotherapy.

Triptolide inhibits epithelial‑mesenchymal transition and induces apoptosis in gefitinib‑resistant lung cancer cells.

The epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib, is used widely to treat non-small cell lung cancer (NSCLC) with EGFR-activating mutations. Unfortunately, the acquired drug resistance promoted by epithelial-mesenchymal transition (EMT) markedly limits the clinical effects and remains a major barrier to a cure. Our previous isobaric tags for relative and absolute quantitation-based proteomics analysis revealed that the E-cadherin protein level was markedly upregulated by triptolide (TP). The present study aimed to determine whether TP reverses the gefitinib resistance of human lung cancer cells by regulating EMT. It was revealed that TP combined with gefitinib synergistically inhibited the migration and invasion of lung adenocarcinoma cell line A549; the combination treatment had a significantly better outcome than that of TP and gefitinib alone. Moreover, TP effectively increased the sensitivity of drug resistant A549 cells to gefitinib by upregulating E-cadherin protein expression and downregulating the MMP9, SNAIL, and vimentin expression levels. The dysregulated E-cadherin expression of gefitinib-sensitive cells induced gefitinib resistance, which could be overcome by TP. Finally, TP combined with gefitinib significantly inhibited the growth of xenograft tumors induced using gefitinib-resistant A549 cells, which was associated with EMT reversal and E-cadherin signaling activation in vivo. The present results indicated that the combination of TP and TKIs may be a promising therapeutic strategy to treat patients with NSCLCs harboring EGFR mutations.