Wild-type Epidermal Growth Factor Receptor Research Articles

Synthesis and initial in vitro evaluation of olmutinib derivatives as prospective imaging probe for non-small cell lung cancer.

Imaging a non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitors (TKIs) has attracted attention due to their unique interaction with the target epidermal growth factor receptor (EGFR). Olmutinib (OTB) is one of the third-generation EGFR TKIs, which selectively inhibit EGFR L858R/T790M mutation. In this study, we aim to estimate the interaction of the iodinated OTB (I-OTB)-receptor complex by molecular docking. Furthermore, we will synthesize the I-OTB and evaluate its activity toward EGFR L858R/T790M by in vitro cytotoxicity assay. A molecular docking simulation was carried out using an AutoDock Vina program package to estimate the interaction of the ligand-receptor complex. The I-OTB, N-{3-iodo-5-[(2-{[4-(4-methylpiperazin-1-yl)phenyl]aminothieno{3,2-d}pyrimidin-4-yl)oxy]phenyl} acrylamide, was synthesized by introducing an iodine atom in the phenyl group in the 3-aryloxyanilide structure. The half inhibitory concentration (IC50) was determined by employing a 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt (WST-8) assay to evaluate the activity of I-OTB. The docking study exhibited that I-OTB could take an interaction similar to that of the parent compound. We successfully synthesized I-OTB and confirmed its structure by instrumental analysis. The binding energy of OTB and I-OTB in complex with EGFR T790M are -8.7 and -7.9 kcal/mol, respectively. The cytotoxicity assay showed that I-OTB also has an affinity towards the EGFR L858R/T790M mutation with the IC50 10.49 ± 5.64 𝜇M compared to the EGFR wild type with the IC50 over than 10 𝜇M. The cytotoxicity effect of I-OTB was comparable to that of OTB. This result indicates that the iodine substituent in OTB did not alter the parent compound selectivity toward double mutations EGFR L858R/T790M. Therefore, I-OTB is prominent for radioiodination, and [123/124I] I-OTB may be a promising candidate for EGFR L858R/T790M mutation imaging.

Design, synthesis, anticancer activity and molecular docking of novel 1H-benzo[d]imidazole derivatives as potential EGFR inhibitors

Here, we present the design, synthesis, and evaluation of a new series of 1H-benzo[d]imidazole derivatives (10a–j) to determine their anticancer efficacy. The MCF-7 and HCT116 cancer cell lines were used to test the synthesized compounds anticancer effects. Most of the newly synthesized benzimidazole compounds had a cytotoxic impact, in some cases much more potent than the reference medication. When compared to the reference drug erlotinib, compounds 10g, 10i, and 10j in particular shown strong anticancer efficacy against the tested cancer cell lines with good safety and selectivity indices. All newly synthesized compounds relative inhibitory potency against EGFR wild type (WT) and mutant EGFR L858R/T790M was evaluated in comparison to erlotinib, a standard drug. Comparing compound 10i to other members of the series, it showed the most inhibitory effect against EGFR WT and L858R/T790M with IC50 values of 4.38 and 5.69 nM, respectively. Synthetic compounds revealed substantial EGFR WT and L858R/T790M inhibition with selectivity of over 3.09 and 13.29-folds greater activity than reference medication erlotinib. One such example is compound 10i. The mode of action mechanisms between the potent molecules and the matching EGFR kinase protein were explained by molecular docking investigations. Additionally, predicting the drug-likeness of molecules were promising, indicating the compounds’ drug-like characteristics. Compounds 10g, 10i, and 10j have been shown to be good candidates and deserving further exploration.

Identifying correlates of post treatment responses for unresectable locally advanced non-small cell lung cancer (LA NSCLC).

149 Background: Curative treatment for unresectable LA NSCLC comprises chemoradiotherapy (CRT) and immunotherapy (IO). However, this uniform approach does not take into account the intrinsic heterogeneity of NSCLC and nearly half of all pts relapse within the first year. This highlights the need to define distinct molecular and phenotypic subgroups of LA NSCLC so that we can interrogate the divergent responses to CRT-IO and identify biomarkers that can guide pt specific strategies. Methods: Consecutive pts treated with CRT +/- IO from May 2010 and recruited to an observational study were retrospectively analysed (N = 336). All pts with adenocarcinoma (ADC) were subject to reflex molecular profiling including NGS and FISH testing for ALK, ROS1, MET and RET. Of note, tracking of bespoke circulating tumour DNA (ctDNA) levels was performed for 25 pts. Plasma samples were collected at longitudinal timepoints pre, during and post CRT (N = 118; median 5 samples/ pt). WES of biopsies and matched normal DNA was used to design tumour informed ctDNA assays to track 16 single nucleotide variants in plasma samples. ctDNA levels were then quantified as mean tumour molecule per mL (MTM/mL). Primary endpoint was progression free survival (PFS). Results: Median age was 61 (IQR 48, 74). Of 336 pts, 74% were male; 32% never smokers; 54% were ADC, 33% squamous cell carcinoma (SCC); 18% had EGFR mutations (EGFRm), 37%EGFR wild type (EGFRw), 40% unknown EGFR status (EGFRu), 5% ALK rearranged, 1% ROS1 rearranged. At median follow-up of 44 months (m), median PFS for the entire cohort was 16.2m. Pts who received consolidation IO had longer PFS [IO, not reached vs no IO, 14.9m; P = 0.05]. Median PFS was shorter for pts with EGFRm [EGFRm, 13m vs EGFRw, 22.5m vs EGFRu, 15.8m]. Patterns of failure were analysed according to local in-field, regional out-field and distant. EGFRm pts were less likely to fail locally in-field [EGFRm, 12% vs EGFRw,18% vs EGFRu, 28%] and significantly more likely to develop distant metastases as first site of failure post CRT [EGFRm, 51% vs EGFRw, 28% vs EGFRu, 19%; P = 0.01]. For the 25 pts with ctDNA analysed, 24 pts had evaluable ctDNA post CRT. Significant heterogeneity was noted at baseline pre CRT [EGFRm, 6.45 vs EGFRw, 7.49 vs SCC, 37.67 MTM/mL; P = 0.05]. No difference was noted in PFS between pts with high vs low baseline ctDNA. Of note, 14 of 24 (58%) pts achieved undetectable ctDNA post CRT and had significantly longer PFS [undetectable, 24.1m vs detectable, 3.5m; P = 0.02]. Conclusions: Here, we demonstrate distinct phenotypic responses to CRT based on molecular subtypes of NSCLC. Crucially, we demonstrate clinical feasibility of deploying tumour-informed ctDNA assays in LA NSCLC with detection of ctDNA post CRT serving as a potential actionable biomarker to guide intensification strategies, providing a window into developing patient-specific combinatorial approaches.

Predicting EGFR Mutation in Lung Adenocarcinoma: Development and Validation of the EGFR Mutation Predictive Score (EMPS) in Bali, Indonesia.

The examination of epidermal growth factor receptor (EGFR) mutations may not be routinely available to all patients due to the limited availability and the expensive price of the examination, especially in area with limited resources such as in Indonesia. Therefore, we aimed to build a nomogram to predict the EGFR mutation in patients with lung adenocarcinoma by incorporating significant clinical and radiological parameters. We conducted an age-matched case-control study using 160 treatment-naïve patients [80 patients with EGFR-mutated (EGFRmut) and 80 with EGFR-wild-type (EGFRwt)] with pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis taken from 2017 through 2021 in Bali, Indonesia. Radiomics features were extracted from contrast CT images. The cut-off of the tumor diameter was defined using Receiver Operating Characteristic Curve. A conditional logistic regression model was constructed to identify significant risk factors, and a nomogram was developed for predicting the risk of EGFR mutation. A cohort was done to validate the nomogram. Being female, never-smoker, having a smaller tumor diameter (<48.5mm), located in the upper lobe, have bubble-like lucency and air-bronchogram in the chest CT scan were identified as independent risk factors of EGFR mutation at the multivariate logistic regression model. The forming normogram model produced an area under the curve of 0.993 (95 % CI = 0.98-1.00) and 0.91 (95 % CI = 0.84-0.99) in development and validation group, respectively. The calibration curve showed good agreement between predicted and actual probability. At the cut-off point of the normogram score 246 shows a sensitivity of 97.5%, a specificity of 98.8%, a positive predictive value of 99.0%, and a negative predictive value of 96.8%. Our study indicated that the EGFR Mutation Normogram could provide a non-invasive way to predict the risk of EGFR mutation in patients with lung adenocarcinoma in clinical practice. This normogram need to be validated in other area in Indonesia.

Design, Synthesis and Biological Evaluation of Novel Pyrazolotriazolopyrimidine Derivatives as Potential Anticancer Agents

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

Outcome benefits of bevacizumab biosimilar (SIBP04) combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer patients with EGFR mutation: subgroup analysis of a prospective, randomized phase III clinical trial.

SIBP04 is a bevacizumab biosimilar, and bevacizumab combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer (nsqNSCLC) has been recommended as the first-line treatment choice. However, the efforts of bevacizumab combined with carboplatin and paclitaxel for nsqNSCLC patients with EGFR mutation remained unclear. Here we report an EGFR mutation subgroup analysis of a prospective, randomized phase III clinical trial (NCT05318443). In this randomized, double-blind, multi-center, parallel controlled, phase III clinical trial, locally advanced, metastatic NSCLC patients were enrolled, and EGFR expression was examined and considered as a stratification factor. All patients received 4 to 6 cycles of paclitaxel and carboplatin plus SIBP04 or bevacizumab 15mg/kg intravenously followed by SIBP04 15mg/kg maintenance until intolerable toxicity, disease progression or death. Patients with EGFR mutation and wild-type were assessed for progression-free survival (PFS) and overall survival (OS). EGFR expression was examined in 398 NSCLC patients (142 with EGFR mutation, 256 with EGFR wild type). PFS in EGFR mutation patients was significantly longer than EGFR wild-type patients (10.91 vs. 7.82months; HR = 0.692, 95% CI 0.519-0.921, P = 0.011). The median OS in patients with EGFR mutation was not reached while that of EGFR wild-type group was 17.54months (HR = 0.398, 95% CI 0.275-0.575, P < 0.001). However, there were no significant differences in objective response rate (61.97% vs. 55.86%, P = 0.237) or disease control rate (90.14% vs. 89.84%, P = 0.925). Bevacizumab combined with chemotherapy significantly prolonged the PFS and OS of advanced nsqNSCLC patients with EGFR mutation.

Preclinical and clinical activity of DZD1516, a full blood–brain barrier-penetrant, highly selective HER2 inhibitor

BackgroundPatients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood–brain barrier (BBB) penetration is highly desirable.MethodsThe design and structure–activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody–drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.ResultsDZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25–300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.ConclusionsDZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.Clinicaltrials.gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Efficacy of lazertinib for symptomatic or asymptomatic brain metastases in treatment-naive patients with advanced EGFR mutation-positive non-small cell lung cancer: Protocol of an open-label, single-arm phase II trial.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has a higher incidence of brain metastases than wild-type EGFR mutations. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), targets both EGFR-TKI sensitizing and T790M-resistance mutations and has a higher brain penetration rate relative to first- and second-generation EGFR-TKIs. Therefore, osimertinib has become a preferred first-line therapy for advanced EGFR mutation-positive NSCLC. However, lazertinib, an emerging EGFR-TKI, has shown higher selectivity toward EGFR mutations and improved penetration of the blood-brain barrier compared to osimertinib in preclinical studies. This trial will evaluate the efficacy of lazertinib as a first-line therapy in patients with EGFR mutation-positive NSCLC who have brain metastases, with or without additional local therapy. This is a single-center, open-label, single-arm phase II trial. A total of 75 patients with advanced EGFR mutation-positive NSCLC will be recruited. Eligible patients will receive oral lazertinib 240 mg, once daily until disease progression or intolerable toxicity is detected. Patients with moderate to severe symptoms related to brain metastasis will simultaneously receive local therapy for the brain. The primary endpoints are progression-free survival and intracranial progression-free survival. Lazertinib, in combination with local therapy for the brain, if necessary, is expected to improve the clinical benefit in advanced EGFR mutation-positive NSCLC with brain metastases, as a first-line treatment.

Sustaining the Activation of EGFR Signal by Inflammatory Cytokine IL17A Prompts Cell Proliferation and EGFR-TKI Resistance in Lung Cancer

Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment.

Arsenic Inhibits Proliferation and Induces Autophagy of Tumor Cells in Pleural Effusion of Patients with Non-Small Cell Lung Cancer Expressing EGFR with or without Mutations via PI3K/AKT/mTOR Pathway.

To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal growth factor receptor (EGFR) was identified. Tumor cells were isolated and treated with arsenic trioxide (ATO) or/and gefitinib. Additionally, six patients were intrapleurally administrated with ATO. Results showed that 25 samples bore EGFR wild type (WT) and 11 harbored EGFR mutations, including 6 with L858R, 3 with ΔE746-A750, and 2 with T790M. ATO diminished the number of tumor cells from patients with WT and mutant EGFR, down-regulated the expression or phosphorylation of EGFR, pmTOR, PI3K, PTEN, and p4E-BP1, and up-regulated the expression of LC3. Immunofluorescent experiments showed that ATO enhanced LC3 and P62. By contrast, gefitinib was only effective in those harboring EGFR sensitizing mutations. Notably, in patients with intrapleural ATO injection, the pleural effusion underwent a bloody to pale yellow color change, the volume of the pleural effusion was reduced, and the number of the tumor cells was significantly reduced. In conclusion, arsenic is effective against NSCLC with various EGFR genotypes in vitro and in vivo, and potentially circumvents gefitinib resistance.

Revealing distinct immune landscape in EGFR mutant and EGFR wild type lung adenocarcinoma by using single-cell RNA sequencing.

e21008 Background: Non-small cell lung cancer (NSCLC) with EGFR mutations displays heterogeneity in the extent of intratumoral immunocytes infiltration compared to those with EGFR wild types, which may explain their variable responsiveness to PD-1 blockade. Here, we performed single-cell RNA sequencing (scRNA-seq) to unveil the immunescape and heterogeneity of lung adenocarcinoma (LUAD) between EGFR mutant (EGFR-mut) patients and wild type (EGFR-wt) patients. Methods: Eleven EGFR-mut and 7 EGFR-wt NSCLC tumor samples were analyzed. Immune cells (CD45+) were enriched through fluorescence-activated cell sorting (FACS) and subjected to single-cell RNA sequencing (scRNA-seq) using the 10X Genomics platform. Sequencing reads were normalized and analyzed using the R/Seurat package. Cellular components of each sample were determined based on known marker genes. Wilcox test was used to compare promotion by subtype composition and immune cell infiltrates. Results: Different immune cell compositions were observed between EGFR-mut and EGFR-wt LUAD tumor samples. We found EGFR-wt tumors are marked by an enrichment of CCL15+ tumor-associated macrophages(TAMs), which display pro-inflammatory properties and high expressions of TNF-a-signaling genes. In contrast, EGFR-mut tumors exhibit enrichment of SPARCL1+TAMs, which are involved in epithelial-mesenchymal transition (EMT) and angiogenesis. EGFR-wt tumors exhibited enrichment of CD8-Teff-MX1 and Gamma delta T cells, both of which displayed higher cytotoxic and naive features. Moreover, the high expression of Gamma delta T corresponds with a better clinical prognosis. In contrast, CD8-Teff-XCL1 and NKT-FGFBP2 were found enriched in EGFR-mut tumors, both of which contributed to higher exhaustion and decreased cytotoxic function. Additionally, NK-IL32 was found enriched in EGFR-mut tumors, showing a downregulated T cell receptor signaling and stronger exhausted features. The high expression of this subcluster correlated with poor outcomes in LUAD patients harboring EGFR mutation. Conclusions: Our study provided a deeper understanding of the immune landscape of EGFR-mut and EGFR-wt LUAD and gained better insights into the immunological mechanisms involved in the response to ICIs. The results of our study could be instructive for the development of future immunotherapy strategies for NSCLC patients harboring EGFR mutations.

Clinical trial versus standard of care in EGFR-wild type and ALK- negative lung adenocarcinoma: A propensity-matched analysis.

e21116 Background: Clinical trials have been a vital role for survival improvement in recurrent or metastatic lung cancer. Recent advances in targeted therapy for EGFR-mutant or ALK-positive lung adenocarcinoma dramatically increased survival. However, EGFR-wild type and ALK negative lung adenocarcinoma still had relatively poor survival outcome. Clinical trial of targeted therapy for rare driver mutation or immunotherapy was introduced in 2015. Moreover, next-generation sequencing was reimbursed in 2017 in Korea. This study evaluated the benefit of clinical trials for EGFR-wild type and ALK negative lung adenocarcinoma in recent 5 years. Methods: This study included patients with recurrent or metastatic lung adenocarcinoma who received systemic treatment between March 2017 and June 2022 at Samsung Medical Center. We compared overall survival in group with clinical trial and the standard of care (SOC) by using propensity score matching (PSM) (1:1). We used cox proportional hazard models to calculate the hazard ratio (HR) and 95% confidence interval while accounting for clustering among matched pairs. Results: Of total, 1,686 EGFR-wild type and ALK negative lung adenocarcinoma were included for final analysis. Among them, 1,380 received SOC only and 306 patients enrolled at least one clinical trial. In a group of clinical trial, 41.5%, 29.1%, and 23,2% of patients were enrolled for first-, second-, and third-line treatment, respectively. To achieve the balance between the SOC group and the clinical trial group, 8 baseline characteristics (age, sex, smoking history, ECOG performance status, brain metastasis, liver metastasis, bone metastasis, and rare driver mutation) were included. After PSM, 612 patients were matched to group of the SOC (n = 306) and the group of clinical trial (n = 306). Among the clinical trial, 27.8% was a clinical trial of targeted therapy and 72.2% was a clinical trial of immunotherapy or others. Median follow-up duration was 32.8 months (range, 5.0–64.4). Median overall survival was 17.1 months (95% CI, 13.2–21.4) for SOC and 27.3 months (95% CI, 22.1–32.4) for group of clinical trial (HR = 0.71 (95% CI, 0.58–0.88, P = 0.002). Conclusions: This study showed the performance of clinical trials for patients with EGFR-wild type and ALK-negative lung adenocarcinoma at tertiary hospital. After PSM, clinical trials showed survival benefits that reduced the risk of death by 29% in patients with EGFR-wild type and ALK-negative lung adenocarcinoma.

A phase II multi-cohort single-arm study of tiragolumab with atezolizumab plus bevacizumab in previously treated advanced non-squamous non–small-cell lung cancer.

TPS9152 Background: Checkpoint inhibitor immunotherapy (CPI) offers durable, immune-mediated, anti-tumor responses to a subset of patients (pts) with advanced non-small cell lung cancer (NSCLC), but not all derive meaningful benefit. Two clinical unmet needs where CPI has fallen short include EGFR-mutated NSCLC, where CPI is minimally effective, and NSCLC with intrinsic or acquired resistance to currently available CPI. Novel combination strategies have shown promise. Two agents that have demonstrated synergy with the anti-PD-L1 CPI atezolizumab in NSCLC are bevacizumab, a vascular endothelial growth factor (VEGF)-blocking antibody, and tiragolumab, a T-cell immunoglobulin and ITIM domain (TIGIT) immune checkpoint-blocking antibody. This multi-cohort phase II trial seeks to evaluate the efficacy of tiragolumab with atezolizumab plus bevacizumab in 2 CPI-resistant cohorts - EGFR-wild type, CPI-refractory advanced NSCLC (cohort A) and EGFR-mutated, CPI-naïve advanced NSCLC (cohort B) - incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of CPI-resistance in NSCLC. Methods: This open-label, phase II study has two cohorts. Cohort A includes pts with advanced PD-L1+ (TPS ≥ 1%), EGFR/ALK/ROS1 wild type NSCLC with progression on prior anti-PD(L)1-based CPI therapy. Cohort B includes pts with targeted therapy-refractory EGFR-mutated NSCLC who are CPI-naïve. Pts must have measurable disease and those with symptomatic and/or untreated brain metastases are excluded. Pts in both arms will receive tiragolumab 600mg IV with atezolizumab 1200mg IV and bevacizumab 15mg/kg IV every 3 weeks until progressive disease or unacceptable toxicity. The primary efficacy endpoint will be assessed separately in each cohort by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Each cohort utilizes a Simon 2-stage design in which a null ORR of 4% is tested against a one-sided alternative of 20%. A sample size of 21 pts/cohort provides 80% power with a one-sided type 1 error rate of 5% to determine a true ORR of 20%. Secondary efficacy endpoints include: duration of response, progression-free survival (PFS), 6-month PFS, overall survival. Blood and tumor specimens will be acquired pre- and on-treatment. Correlative analyses to illuminate the biology of CPI resistance will include multiplex imaging mass cytometry of tumor tissue. In addition, whole exome sequencing, T-cell receptor sequencing, and MANAFEST neoantigen prediction will be used to identify neoantigen-specific T-cells and track these temporally (during/post treatment) and spatially (across biologic compartments). The study is activated and both cohorts are accruing simultaneously with enrollment ongoing. Clinical trial information: NCT04958811 .

Prevalence of EGFR mutations in patients with resected stage I-III non-squamous NSCLC: Results from the EARLY-EGFR study.

8531 Background: The prevalence of EGFR mutations ( EGFRm) in resected stage I-III NSCLC remains controversial as prior research studies were retrospective in nature. EARLY-EGFR is the first prospective, international study to determine the prevalence of EGFRm and treatment patterns in patients (pts) with early-stage NSCLC. Methods: EARLY-EGFR (NCT04742192), a non-interventional real-world study, captured data on EGFRm status, treatment patterns, demographic, clinical and pathological characteristics in consecutively enrolled pts with surgically resected stage IA-IIIB (AJCC 8th) non-squamous NSCLC (Mar 2021 – Oct 2022). The primary endpoint was prevalence of EGFRm and secondary endpoints included prevalence of EGFRm subtypes and treatment patterns. Results: Of 601 pts (median [range] age: 62 [30-86] yrs) enrolled at 33 centers across Middle East and Africa (n=16), Latin America (n=80), and Asia (n=505), 317 (52.7%) were females, 354 (58.9%) were never smokers. The majority had stage IA-IB NSCLC (64.1%) involving right lung (62.9%), no nodal involvement (81.5%), T1a-T2b tumor (82.7%), adenocarcinoma histology (98.7%), and 105/420 (25.0%) tumors were poorly differentiated. About 23.3% (130/559) were diagnosed through a screening program; 60/539 (11.1%) reported family history of lung cancer. The overall prevalence of EGFRm was 50.7% (300/592). Exon-19 deletions accounted for 50.3%, L858R mutations for 35.7%, and compound mutations for 2.3% of mutations. EGFRm tumors were found to be PD-L1 positive in 38.5% of cases (15/39). Women had higher EGFRm rate than men (63.6% vs 36.2%). Compared with EGFR wild type (wt), pts with EGFRm were more likely to be never smokers (39.5% vs 60.5%) and have stage I/II NSCLC (46.5% vs 53.5%) (Table). Of 216 stage II/III NSCLC pts, only 51.4% received systemic adjuvant therapy. Significantly higher EGFRm rates in stages I and II than in stage III NSCLC (p&lt;0.001 and p=0.050) were found, while no significant difference was found between stages I and II NSCLC (p=0.158). Conclusions: In this first prospective, real-world study of EGFRm prevalence in resected NSCLC, stage III and smoking were independent predictors associated with decreased odds of EGFRm. The results highlight the need to adhere to ASCO adjuvant chemotherapy guidelines, as only half of stage II/III NSCLC pts received adjuvant systemic therapy. Clinical trial information: NCT04742192 . [Table: see text]

BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study.

9011 Background: Despite improved frontline OSI treatment outcomes, patients (pts) with advanced EGFRm NSCLC inevitably progress, with worse outcomes in the EGFR L858R subgroup (median PFS of 14.4 vs 21.4 mo in pts with exon 19 deletions). BLU-945 is an investigational, next-generation, oral tyrosine kinase inhibitor (TKI) that targets common EGFR-activating and T790M and C797X resistance mutations, while being selective against EGFR wild type (WT). Preclinically, BLU-945 in combination (combo) with OSI had enhanced potency on L858R and extended antitumor response durability versus OSI alone. SYMPHONY (NCT04862780) is an ongoing first-in-human phase 1/2 study of BLU-945 monotherapy (mono) or combo with OSI. Methods: In the phase 1 dose escalation, pts (aged ≥18 y; metastatic EGFRm NSCLC; ECOG PS 0–1; treated with ≥1 EGFR TKI) received BLU-945 mono starting at 25 mg QD. Pts progressing on OSI could receive BLU-945 with 80 mg OSI starting at 50% of the highest safe BLU-945 mono dose. Each dose escalation followed a Bayesian Optimal Interval design. Safety, including dose-limiting toxicities (DLT), PK, and circulating tumor DNA (ctDNA) mutational status were assessed. Results: As of Jan 6, 2023, 108 pts received BLU-945 mono (25–600 mg QD; 100–300 mg BID). Pts had a median of 3 lines of prior therapy and were genomically complex with ctDNA detectable EGFR on-target and/or off-target resistance alterations (46%) at baseline. DLTs included alanine transaminase (ALT) and aspartate transaminase (AST) elevation, hepatic cytolysis, fatigue, nausea, vomiting, and hyponatremia, occurring at doses of ≥400 mg/d. The maximum tolerated dose was 500 mg/d. The most common AEs were nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%). Robust on-target EGFR activity was observed with ctDNA reduction on day 15 in 90%, 85% and 70% of EGFR T790M, C797S, and L858R alleles at ≥400 mg/d doses, respectively. At ≥400 mg/d, 48% had tumor shrinkage, including partial responses (PRs). Twenty-five pts received BLU-945 (200–400 mg QD; 100–200 mg BID) combo with OSI. Pts had a median of 2 lines of prior therapy. The most common combo AEs were fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%). Other EGFR WT AEs were dry skin (20%) and rash (8%). One DLT (Grade 4 pneumonitis) was reported in the BLU-945 300 mg QD with OSI group. Tumor reductions, including PRs in 2 pts progressing on OSI, were observed at ≥300 mg/d. Dose escalation is ongoing. Conclusions: BLU-945 mono and combo with OSI were generally well tolerated and showed robust on-target EGFR ctDNA reduction, with tumor shrinkage in genomically heterogeneous, heavily pretreated pts. Combo showed responses at BLU-945 doses lower than in mono, consistent with additive benefit. The combo safety profile and on-target activity provide rationale for further development in front line. Clinical trial information: NCT04862780 .

Dose escalation results from a first-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors.

3015 Background: c-Met overexpression is common in non-small cell lung cancer (NSCLC), gastroesophageal adenocarcinoma (GEA), and colorectal cancer (CRC). There is a need for effective therapies that target c-Met–overexpressing tumors, as there are currently no approved options available. The antibody-drug conjugate (ADC) ABBV-400 consists of the c-Met–targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload. ABBV-400 exhibited sustained antitumor activity in patient-derived xenograft models of c-Met–expressing NSCLC, GEA, and CRC. Herein, we present data from the dose escalation of the first-in-human study of ABBV-400 monotherapy. Methods: A phase 1 dose escalation/expansion study of ABBV-400 has been initiated in patients with advanced solid tumors (NCT05029882). Primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of ABBV-400, to determine the recommended phase 2 dose, and to assess preliminary efficacy. PK will be characterized for the conjugate, total antibody, and free payload. Adults (≥18 years) with an advanced solid tumor that progressed on standard therapies were enrolled during dose escalation, without restrictions on the basis of c-Met overexpression status. Results: As of January 2023, 47 patients had enrolled in dose escalation with a median follow-up of 6.5 months. Median age was 58 years (range, 34–79), 25 (53%) patients were male, and the most common cancer types were CRC (n=21), NSCLC (n=5), and GEA (n=5). The median number of prior treatment lines was 4 (1–13). Most common hematologic adverse events (AEs) were anemia (66%; grade [G]≥3: 38%), neutropenia (62%; G≥3: 43%), thrombocytopenia (43%; G≥3: 26%), and leukopenia (32%; G≥3: 19%). Nausea (60%, all grade 1–2), fatigue (49%; G≥3: 4%), and vomiting (38%, all grade 1–2) were the most frequent non-hematologic AEs. One patient experienced grade 1 interstitial lung disease. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were dose and exposure dependent. Clinical activity was observed with ABBV-400, with an objective response rate of 24.4% (11/45; 95% CI: 12.9, 39.5). All responses were confirmed partial responses (PR). In addition, 23 patients (50.0%) had stable disease (SD) and 7 (15.2%) had progressive disease. Among patients with CRC, 4/21 (19.0%) had a PR and 13/21 (61.9%) had durable SD, with a disease control rate of 81.0% (95% CI: 58.1, 94.6). Outside of CRC, PRs were observed in patients with NSCLC ( EGFR wildtype and mutant), uterine cancer, and acral melanoma. Conclusions: On the basis of DLTs, a maximum tolerated dose of ABBV-400 was identified. At this dose, safety results appear comparable with other Top1i ADCs. Promising antitumor activity was seen with ABBV-400 across tumor types, justifying further evaluation in the ongoing dose expansion in NSCLC, GEA, and CRC. Clinical trial information: NCT05029882 .

PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1

BackgroundChemoimmunotherapy represents the standard of care for patients with advanced non-small cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) <50%. Although single-agent pembrolizumab has also demonstrated some activity in...

Emerging phase 1 data of BLU-451 in advanced NSCLC with EGFR exon 20 insertions.

9064 Background: In patients (pts) with NSCLC harboring EGFR exon 20 insertions (ex20ins), treatment options are limited, with platinum-based chemotherapy with/without programmed death-ligand 1 inhibitors being the standard of care in first line, and recent accelerated approvals of mobocertinib and amivantamab in the USA for second-line treatment. These second-line therapies have overall response rates of 28% and 40%, respectively, limited CNS activity, and are associated with AEs such as severe gastrointestinal AEs and edema. BLU-451 is an investigational, CNS-penetrant, potent, selective, and wild-type sparing EGFR tyrosine kinase inhibitor that is under investigation in the ongoing phase 1/2 CONCERTO trial (NCT05241873), including in pts with ex20ins. Methods: In phase 1 dose escalation using a 3+3 design, BLU-451 monotherapy was administered orally QD or BID and given in continuous 21-day cycles. The primary objectives include maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) determinations and safety. Key secondary objectives include antitumor activity, PK, and pharmacodynamics. Pts with EGFR ex20ins–positive NSCLC after prior platinum-based chemotherapy were enrolled. Prior ex20ins–targeted therapy and asymptomatic CNS disease were permitted. Tumor response was assessed per RECIST v1.1. Serial blood samples for analysis of BLU-451 PK and circulating tumor DNA (ctDNA) were collected. Results: As of Jan 20, 2023, 28 pts have been enrolled and dosed in 5 cohorts (100 mg–400 mg QD and 200 mg BID), including 19 (68%) pts with exon 20 insertions. The median number of prior systemic lines of therapy was 2.5 (range, 1–10), and 19/28 (68%) pts had prior ex20ins-targeted agents. The most common AEs were diarrhea (21%), cough (18%), fatigue (14%), pruritis (14%) and rash (14%); all were Grade 1 or 2. There were no dose-limiting toxicities. Partial responses, including a disappearance of a CNS target lesion, were seen, and early evidence of on-target activity with ctDNA reductions was observed. Conclusions: As of the data cutoff, BLU-451 monotherapy was generally well tolerated, with early evidence of clinical activity in heavily pretreated pts with EGFR ex20ins–positive NSCLC. Early data at initial dose levels consisted of tumor reduction including responses, CNS activity, and ctDNA responses. The dose escalation is ongoing to determine the MTD and/or RP2D. Clinical trial information: NCT05241873 .

Investigating the novel CD16A and epidermal growth factor receptor (EGFR) bispecific innate cell engager, AFM24, to leverage the innate immune system: Interim results from the colorectal cancer (CRC) cohort.

e14508 Background: AFM24 is a tetravalent, bispecific innate cell engager that binds EGFR on solid tumors and CD16A on natural killer (NK) cells. AFM24 redirects NK cells to EGFR-expressing (EGFR+) solid tumors, enhancing antibody-dependent cellular cytotoxicity. AFM24 induced lysis of EGFR+ tumor cell lines in vitro independent of EGFR expression level and mutation status. The dose escalation phase (Phase 1) of the presented study (NCT04259450) previously established the recommended Phase 2 dose at 480 mg based on tolerability, receptor occupancy, and pharmacokinetics. Correlative science data revealed an activation and enrichment of immune cells in the tumor microenvironment. Here we present preliminary data from the Phase 2a CRC expansion cohort. Methods: The Phase 2a expansion phase is evaluating 480 mg AFM24 in patients with histologically or cytologically confirmed microsatellite stable, RAS wild type EGFR+ CRC. Patients have relapsed or refractory disease to ≥2 prior lines of therapy including an EGFR targeted therapy. EGFR+ is defined as positive staining for EGFR in ≥1% of tumor cells per local immunohistochemistry assay. The study follows Simon’s two-stage design. The primary endpoint is the overall response rate per RECIST v1.1 by investigator assessment; secondary endpoints include safety and tolerability; efficacy per iRECIST is exploratory. AFM24 is administered intravenously once weekly in a 28-day cycle. Tumor assessments are performed at screening, cycles 2, 4, 6, 8, and every 3 cycles thereafter. Results: As of December 2022, 16 patients with Stage 4 CRC were enrolled and treated with 480 mg AFM24 in the study. The median (range) age was 66 years (51–77); 11 males and 5 females; 9 Asian, 7 White). The median number of prior therapies was 4 (2–7) and the median treatment duration was 5.1 weeks (1.0–22.0). Treatment-related adverse events (TRAEs) were reported in 14/16 patients; infusion-related reactions (IRRs, 12), pruritus (3), lymphopenia (3), and anemia (2) were the most common. AFM24 TRAEs of Grade ≥3 occurred in 6 patients and included lymphopenia (3), decreased neutrophil count (1), increased blood bilirubin (1) and IRRs (1). To date, no objective responses were observed. Seven patients remain on treatment including 1 patient with confirmed stable disease ongoing for 5 months exhibiting a tumor reduction of –17%. Final interim results will be presented. Conclusions: The novel mechanism of action of AFM24 may provide an alternative treatment approach for patients with EGFR+ solid tumors. In this study, AFM24 monotherapy was adequately tolerated in a heavily pretreated population of patients with EGFR+ CRC. AFM24 is also being investigated in combination with atezolizumab and autologous NK cells in various EGFR+ solid tumors. Clinical trial information: NCT04259450 .