Advanced Epidermal Growth Factor Receptor Research Articles

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer.

Osimertinib is the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The present study aimed to determine the previously unclarified association of osimertinib plasma trough concentrations with efficacy, adverse events, and genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations. In this prospective study, blood samples of 25 patients who received osimertinib were collected to measure plasma osimertinib concentrations and to genotypically characterize ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2 polymorphisms. Plasma osimertinib concentrations were analyzed using validated multiple reaction monitoring mode-based liquid chromatography-tandem mass spectrometry. Osimertinib concentration necessary to achieve optimal median progression-free survival (PFS) was determined using receiver operating characteristic curve analysis. PFS and overall survival were analyzed using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Plasma osimertinib concentrations between different patient groups were compared using the Mann-Whitney U-test. Patients were divided into high and low concentration groups based on a plasma osimertinib cut-off concentration of 211 ng/ml. Median PFS was longer in the high trough concentration group than that in the low trough concentration group (46.3 vs. 16.8 months, p=0.029). Plasma osimertinib concentrations adjusted for dose and body weight did not differ between the patients with and without variant polymorphisms. Monitoring plasma trough concentrations during maintenance might improve osimertinib treatment efficacy in patients with NSCLC harboring EGFR mutations.

An Adjusted Treatment Comparison Comparing Amivantamab Versus Real-World Clinical Practice in Europe and the United States for Patients with Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Exon 20 Insertion Mutations.

Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776; Cohort D+). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence. RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D+eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW; average treatment effect among the treated [ATT]). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR; investigator- [INV] and independent review committee-assessed [IRC]), overall survival (OS), progression-free survival (PFS; INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively. Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU+US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52months (hazard ratio [HR]: 0.47; p<0.0001), 6.93 versus 4.17months (HR: 0.55; p<0.0001) and 12.42 versus 5.36months (HR: 0.44; p<0.0001) for amivantamab versus the adjusted EU+US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment. Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy. CHRYSALIS: NCT02609776.

Rationale and protocol design of a phase II study of first-line osimertinib treatment for patients with poor performance status and EGFR mutation-positive non-small cell lung cancer (OPEN/TORG2040)

BackgroundCancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status; however, no evidence exists of the drug’s effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status.MethodsThe OPEN/TORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed.DiscussionOur study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated.Trial registrationJapan Registry of Clinical Trials: jRCTs041200100 (registration date: February 12, 2021).

The effect of EGFR-TKIs on survival in advanced non-small-cell lung cancer with EGFR mutations: A real-world study.

Few large-scale studies have been published using real-world data related to overall survival (OS) improvements in advanced epidermal growth factor receptor (EGFR)-mutant lung cancer patients; therefore, little is known regarding the characteristics of patients who could benefit most from EGFR-tyrosine kinase inhibitors (TKIs). Our study aimed to assess whether EGFR-TKI treatment confers survival benefits among advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations in the Chinese population. A total of 6451 advanced NSCLC patients were diagnosed between January 1, 2013 and June 30, 2019 in Zhejiang Cancer Hospital. Ultimately, 2864 patients with a confirmed EGFR mutation genotype were enrolled in our study. OS was measured from the time of diagnosis of advanced NSCLC until death or last follow-up. Median follow-up for OS of advanced EGFR-mutant NSCLC patients was 28.33 months in our study. Patients who received EGFR-TKIs demonstrated better survival compared to those without EGFR-TKI treatment (mOS: 29.77 vs. 22.97 months, p < 0.0001). A total of 451 patients switched to third-generation EGFR-TKI treatment and obtained a significantly better survival than those who adopted first-line third-generation EGFR-TKIs or those who did not receive third-generation EGFR-TKIs after disease progression with first- or second-generation EGFR-TKI treatment (mOS: 38.0 vs. 32.5 vs. 28.3 months, p < 0.0001). As for EGFR genotypes, patients with exon 19 deletion showed better OS, followed by those with L858R mutation (32.4 vs. 24.83 months, p=0.0013). NGS versus PCR testing showed no statistical differences with respect to survival outcomes (mOS: 27.5 vs. 27.47 months, p=0.6745). Advanced EGFR-mutant patients treated with EGFR-TKIs obtained absolute superior survival in the Chinese population.

363P A multicentre, real-world observational study of efficacy and safety of first-line osimertinib treatment in patients with epidermal growth factor receptor (EGFR) activating mutation-positive advanced non-small cell lung cancer (Reiwa study)

Osimertinib is a third-generation, irreversible EGFR-tyrosine kinase inhibitor (TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR-T790M-resistant mutations. In a phase III trial (FLAURA), osimertinib showed efficacy superior to that of first-generation gefitinib and erlotinib, with a similar safety profile and lower rates of serious adverse events. Osimertinib is currently being used as the first-line treatment for patients with advanced EGFR mutation-positive NSCLC. However, the efficacy and safety of osimertinib treatment in clinical practice have not been fully verified.

Analyse de la prise en charge des cancers bronchiques avec mutation du gène de l’EGFR

Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC. Data on patients with EGFR-mutated NSCLC, eligible for TKIs, and treated between 2010 to 2019 were collected. The main therapeutic strategies adopted following progression under TKIs and the prognostic factors for survival were analyzed. The median age of the 177 patients was included in the cohort was 70years. The majority of patients (77.4%) received TKIs as first-line treatment, while 16.4% received chemotherapy. Osimertinib initiation as second-line treatment was a factor for better prognosis (OR=0.5). Finally, change of chemotherapy line was the main therapeutic strategy adopted for 41.3% of the patients having relapsed under TKIs. Therapeutic management of EGFR-mutated NSCLC patients was in accordance with regional, national and international recommendations. The characterization of progression under TKI therapy has become systematic, allowing better adaption of therapeutic strategies.

Spotlight on Furmonertinib (Alflutinib, AST2818). The Swiss Army Knife (del19, L858R, T790M, Exon 20 Insertions, "uncommon-G719X, S768I, L861Q") Among the Third-Generation EGFR TKIs?

Osimertinib, a third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is now considered the standard of care for the first-line (1L) treatment of advanced EGFR+ NSCLC due to statistically significant improved progression-free survival (PFS) and overall survival (OS) compared with first-generation (1G) treatment from the FLAURA trial. Recently two other 3G EGFR TKIs (aumolertinib and furmonertinib) have been approved in China for treatment of EGFR T790M+ NSCLC. Randomized Phase 3 trials of these two 3G EGFR TKIs have also demonstrated PFS over gefitinib respectively. Among these two Chinese home-grown, 3G EGFR TKIs, furmonertinib seems to most closely resemble osimertinib in terms of dosing regimen, efficacy and adverse events profile. In this article, we reviewed the clinical activity and adverse events of furmonertinib at 80 mg daily (approved dose), potential usage of 160 mg daily for CNS metastasis in EGFR+ NSCLC, and usage of 160 mg or 240 mg daily in EGFR exon20 insertion positive (EGFRex20ins+) NSCLC patients.

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

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

Gastrointestinal microbiota profile and clinical correlations in advanced EGFR-WT and EGFR-mutant non-small cell lung cancer

IntroductionDifference in clinical responses to cancer therapy in each patient is from several factors. Gastrointestinal microbiota is one of the reasons. However, this correlation remains unknown. This study aims to explore correlation between gastrointestinal microbiota profile and clinical outcomes in Thai advanced non-small cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) status.MethodsWe enrolled 13 patients with advanced EGFR–wild-type (WT) NSCLC who received chemotherapy and 15 patients with EGFR-mutant NSCLC who received EGFR tyrosine kinase inhibitors. We collected fecal samples at baseline and first disease evaluation and performed 16S rRNA gene sequencing by NGS to assess microbiota profile. The correlations between gastrointestinal microbiota and clinical variables were studied.ResultsThe clinical characteristics were balanced between the cohorts, excluding significantly higher albumin levels in the EGFR-mutant group. Albumin was the only significant clinical factor affecting the treatment response in multivariate analysis (ORR 15.6%, P = 0.03). Proteobacteria counts were higher in the EGFR-WT group, whereas Bacteroidetes and Firmicutes counts were higher in the EGFR-mutant group. The alpha diversity of the gastrointestinal microbiome was significantly higher in the EGFR-mutant group (Shannon index: 3.82 vs. 3.25, P = 0.022). Following treatment, Proteobacteria counts were lower and Bacteroidetes and Firmicutes counts were higher in both cohorts; the changes were more prominent in the EGFR-WT cohort. No significant correlation between microbiota profile and treatment response were demonstrated in our study. However, beta diversity was significantly different according to severity of adverse events. Enrichment of Clostridia and Bacteroidia was associated with higher adverse event risk in the EGFR-WT cohort.ConclusionsProteobacteria was dominant in Thai lung cancer patients both EGFR-WT and EGFR-mutant, and this phylum maybe associate with lung cancer carcinogenesis. Chemotherapy altered the gastrointestinal microbiota, whereas EGFR-TKIs had less effects. Our findings highlight the potential predictive utility of the gastrointestinal microbiota for lung cancer carcinogenesis. Studies with larger cohorts and comparison with the healthy Thai population are ongoing to validate this pilot study.

Pre-radiotherapy systemic immune inflammation index associated with overall survival in patients with advanced EGFR mutant non-small cell lung cancer receiving thoracic radiotherapy

PurposeThis study aimed to investigate the prognostic potential of the pre-radiotherapy systemic immune-inflammation index (SII) for the survival of advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations, which might provide a basis for optimizing the comprehensive treatment scheme.MethodsA total of 111 lung adenocarcinoma patients with EGFR mutations, who received thoracic radiotherapy, were included in this retrospective study. The primary endpoint of the study was based on the overall survival (OS) of patients. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off value of each immune inflammation index. Kaplan–Meier analysis was performed for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate regression analyses to determine the correlations of prognostic factors with the disease.ResultsSII was divided into the high SII group (≥ 620.2; 45.95%) and the low SII group (SII < 620.2; 54.05%) based on the optimal cutoff values. The median OS rates were 53.3 and 33.3 months in the low and high SII groups, respectively, showing statistically significant differences ( hazard ratio (HR) = 0.459; 95% CI 0.286–0.736; P < 0.001). The multivariate analysis showed that, after adjusting for the significant covariates, the SII values were independently associated with the improved OS of the patients (adjusted HR = 0.444; 95% CI 0.279–0.709; P = 0.001). The low NLR values were associated with the better OS of patients (HR = 0.509; 95% CI 0.326–0.792; P = 0.005) and vice versa (HR = 0.422; 95% CI 0.213–0.836; P < 0.001). The patients in the low LMR group before radiotherapy exhibited longer OS as compared to those in the high LMR group (HR = 0.497; 95% CI 0.308–0.802; P = 0.001).ConclusionsThis study showed that these inflammatory indices might have an important prognostic potential for advanced lung adenocarcinoma patients with EGFR mutations, receiving thoracic radiotherapy and might provide a basis for the individualized treatment of these patients.

EP08.02-075 Maintained Complete Response for 8+ Years with Erlotinib Alone in Advanced Lung Adenocarcinoma Harboring EGFR Exon 19 Deletion

The prognosis for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) has significantly improved with the use of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as the widely used first-generation EGFR-TKI, Erlotinib. The association between EGFR exon 19 deletions (ex19del) and prolonged survival in EGFR-TKI-treated patients has previously been widely reported, with median overall survival (OS) of approximately 31 months. Molecular factors indicating prolonged survival are not defined.

1103P Drug-related pneumonitis induced by osimertinib as first-line treatment for EGFR-positive non-small cell lung cancer: A real-world setting

Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data are currently lacking. We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest computed tomography (CT) scans and clinical information during osimertinib exposure were collected until June 2020. The primary endpoint was DRP incidence identified through central review. A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) were diagnosed with DRP (all grades), and 21 patients (4.6%) had ≥grade 3 DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and non-specific interstitial pneumonia were found in 30, 21, 18, 9, and 2 patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio: 1.72, 95% confidence interval: 1.01–2.89, P=0.046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not negatively affect treatment efficacy. For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.

EP08.02-153 The Efficacy and Safety of EGFR-TKIs plus Anlotinib in Maintenance Therapy for Oligoprogressive Advanced or Metastatic EGFR Mutant NSCLC

In recent years, Tyrosine kinase inhibitors (TKIs) targeting Epidermal growth factor receptor (EGFR) have been successfully developed and marketed globally. EGFR-TKIs is recommended for first-line treatment of EGFR-mutant NSCLC because of its advantages of convenience, better efficacy and higher quality of life compared with traditional inpatient chemotherapy. Unfortunately, resistance to EGFR-TKIs will inevitably occur eventually. Currently, there are few options for further targeted therapy after drug resistance.

EP08.02-141 ‘Our’ EGFR population - experience in a secondary center

Epidermal growth factor receptor (EGFR) mutations are the most common among non-small cell lung cancer (NSCLC), with available target treatment with tyrosine-kinase inhibitor (TKI) as first-line on advanced disease. The aim of this study was to evaluate the demographic characteristics of patients with advanced NSCLC EGFR mutated, treatments performed and outcomes.

Effects of Acid-Reducing Agents on the Pharmacokinetics of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer.

IntroductionLazertinib is an irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Co-administration of TKIs with acid-reducing agents (ARAs) can lead to potential drug–drug interactions, which decreases solubility and absorption of TKIs and is ultimately associated with reduced efficacy of TKIs. This retrospective analysis evaluated the effect of ARAs on the pharmacokinetics of lazertinib using data obtained from patients with advanced EGFR mutation-positive non-small-cell lung cancer.MethodsIn a total of 234 patients with lazertinib pharmacokinetics observed at steady state, dose-normalized (DN) area under the concentration–time curve (AUCss), maximum concentration (Cmax,ss), and/or trough concentration on day 15 (CD15) were compared between a group receiving ARA concomitantly for at least 4 days (ARA group) and another group not receiving ARA (non-ARA group) in a dose-proportional range. Additionally, a comparison of pharmacokinetic parameters at a therapeutic dose of 240 mg once daily was evaluated.ResultsGeometric mean ratios (GMRs) with 90% confidence intervals (CIs) of ARA group to non-ARA group for DNAUCss, DNCmax,ss, and DNCD15 at 40 mg to 320 mg once daily showing the dose proportionality were 0.8743 (0.7285–1.0493), 0.9035 (0.7482–1.0910), and 0.9126 (0.7364–1.1311), respectively. GMRs with 90% CIs for AUCss, Cmax,ss, and CD15 at 240 mg were 0.9136 (0.6637–1.2576), 0.9012 (0.6703–1.2116), and 0.8850 (0.6463–1.2118), respectively.ConclusionAll pharmacokinetic parameters were not significantly different between the two groups (p values > 0.05), indicating that co-administered ARAs did not significantly affect the steady state pharmacokinetics of lazertinib. Therefore, no dose adjustment of lazertinib is required in patients receiving concomitant ARAs.ClinicalTrials.gov identifiersNCT03046992, NCT04075396.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02286-z.

An updated network meta-analysis of EGFR-TKIs and combination therapy in the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer

ObjectivesTyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI-based combination treatment modes show encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on overall survival (OS).Materials and methodsRandomized controlled trials and meeting abstracts that investigated EGFR-TKIs alone or in combination as front-line care for patients with NSCLC were systematically searched in relevant databases and reviewed. Fixed and random effects network meta-analysis models were used to estimate progression-free survival (PFS), OS, overall response rate, and grade three and higher adverse events (AEs). Surface under the cumulative ranking curves (SUCRAs) were used to rank treatment effects.ResultsEighteen studies covering six treatments and involving a total of 4389 patients were included in this network meta-analysis. On OS, the top three treatment were first-generation EGFR-TKIs (1G EGFR-TKIs) plus chemotherapy (SUCRA, 88.1%), osimertinib (SUCRA, 65.8%) and second-generation EGFR-TKIs (2GEGFR-TKIs) (SUCRA, 63.3%). On PFS, the top three treatments were osimertinib (SUCRA, 96.0%), 1G EGFR-TKIs plus chemotherapy (SUCRA, 67.1%), and 1G EGFR-TKIs plus antiangiogenesis (SUCRA, 48.2%). Two types of TKI-based combination therapy have significantly higher risk of grade three and higher AEs than TKI alone.Conclusion1G EGFR-TKIs plus chemotherapy and osimertinib seem to be the two better options as first-line care in advanced NSCLC patients with EGFR-mutation. Osimertinib caused the lowest incidence of AEs. However, TKIs-based combination therapy significantly increased AEs.

Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

BACKGROUNDIcotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).AIMTo evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODSThis multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups.RESULTSThe median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05).CONCLUSIONA sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.

Abstract LB078: Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study

Abstract Background/Purpose: Osimertinib, a third-generation, irreversible, EGFR tyrosine kinase inhibitor (TKI), is the preferred 1L treatment for pts with EGFRm NSCLC. Unfortunately, most of these pts will eventually develop treatment resistance. ORCHARD is an ongoing Phase II platform study (NCT03944772) enrolling pts with EGFRm NSCLC, whose tumors progressed on 1L osimertinib, to a treatment group based on their tumor molecular profile. This exploratory analysis aimed to further understand the genomic landscape of resistance detected in tumor samples from pts with EGFRm NSCLC post-1L osimertinib, and to evaluate the concordance of resistance mechanisms identified in plasma and tissue. Methods: Pts enrolled on ORCHARD (with advanced EGFRm NSCLC) provided tissue/plasma samples after progression on 1L osimertinib. Samples were analyzed for resistance mechanisms and testing concordance using next generation sequencing (NGS) either centrally (tissue [Foundation Medicine]; plasma [Guardant Health]) or locally. Alterations were determined based on reported results from respective assay. Results: In total, 195 tissue samples (21 local and 174 central NGS) and 69 plasma samples (central NGS) were collected. The 174 central tissue samples were used for the genomic profiling: MET amplification occurred in 24% (42/174) of tumors; EGFR amplifications in 36% (62/174). Secondary EGFR mutations (C797X, L718X) and BRAF fusions were less common, 7% (13/174) and 5% (9/174), respectively, while other potentially actionable genomic alterations were rare: ERBB2 amplified/mutated (2%), ALK fusion (2%), RET fusions (1%), KRAS mutation (1%), BRAF V600E (1%).In the concordance analysis, 69 samples of matched tumor and plasma were used. Concordance was high between tissue and plasma for point mutations, particularly for sensitizing (64 samples; 89% concordance) and uncommon (G719X, L861X, S768I; 5 samples; 100% concordance) EGFR resistance mutations. The majority of EGFR (21/38 samples) and MET (16/30) amplifications were detected via tissue only. For BRAF, concordance was low: 4/5 BRAF fusions were found in tissue only, 1/5 in plasma only; 5/5 BRAF V600E mutations could be identified in plasma but only one of these was also identified in tissue. Conclusions: Genomic profiling of pts with disease progression after 1L osimertinib showed that the most common identifiable resistance mutations were consistent with previous studies, however MET, EGFR amplifications and BRAF fusions were identified at higher rates than expected. Tissue and plasma provided different but potentially complementary results for detecting mechanisms of resistance, with differing levels of concordance across the mutations; further study is required in this area. Further exploration of 1L osimertinib resistance is continuing in the ongoing ORCHARD study. Citation Format: Ryan J. Hartmaier, Aleksandra Markovets, Byoung Chul Cho, Adrianus J. de Langen, Sarah B. Goldberg, Jonathan Goldman, Xiuning Le, Isamu Okamoto, Jonathan W. Riess, Jan Cosaert, Helena Yu, Zofia Piotrowska. Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB078.

Abstract 3362: Multiscale EGFR mutated NSCLC tumor heterogeneity knowledge-based model predicts tumor growth under gefitinib: An avenue to in silico clinical trial

Abstract Introduction: Non-small cell lung cancer (NSCLC) response to gefitinib depends on epidermal growth factor receptor (EGFR) mutational status. Response differs according to tumor heterogeneity, notably through clonal selection according to genetic background. We developed an in silico EGFR mutated lung adenocarcinoma (EGFR+ LUAD) model topredict the effect of EGFR mutations on tumor size in advanced LUAD patients using a mechanistic representation of tumor progression, including response to gefitinib. Tumor heterogeneity, age, gender, initial clinical stage, and smoking status are included as covariates. Methods: 5-step in silico model development: (i) Model Building: Biology of EGFR+LUAD was characterized by extracting biological features and their functional relationships from literature and translating them into ordinary differential equations (ODEs). Mutational burden, EGFR downstream-pathways, tumor growth and heterogeneity, gefitinib-PK/PD, treatment-induced resistance and clinical outcome were modeled in a computational simulation with 43 variables, 170 parameters and 18 to 83 ODEs reflecting intra-tumor heterogeneity. (ii) Calibration: Published spheroid, xenograft and clinical data were used for stepwise calibration. (iii) Virtual populations (VPOP): VPOPs were generated for validation and benchmarking respectively, adapting baseline characteristics of a real population.(iv) Validation: A VPOP with comparable baseline characteristics was tested against published patient data.(v) Benchmarking against a Bayesian reference model : (1) coverage of experimental interquartile range (IQR) with simulated IQR (precision) assesses model fit with experimental data, (2) coverage of simulated IQR with experimental IQR (overlap) assesses model fit with experimental variability. Results: Our model computed in silico data comparable to the reference model without use of original data for calibration (Figure 1B.2: experimental vs. simulated, precision of 68%, overlap of 91%). The reference model reported precision of 72% and overlap of 86%. Therefore, the ISELA model has a better percentage of the literature data area contained in the simulated one while the Bayesian model presents a better percentage of the simulated data contained in the literature one. Conclusion: We simulated tumor growth and treatment response in advanced EGFR+ LUAD patients and successfully validated results with published data, and compared it to an already published model with the same context of use. Both models successfully provide a reliable description of longitudinal tumor size when compared to each other or to observed data. Our model provides a benchmark for future in silico clinical trials. Citation Format: Michael Duruisseaux, Adèle L'Hostis, Emmanuel Peyronnet, Evgueni Jacob, Ben M.W. Illigens, Jim Bosley, Riad Kahoul, Jean-Louis Palgen, Claudio Monteiro. Multiscale EGFR mutated NSCLC tumor heterogeneity knowledge-based model predicts tumor growth under gefitinib: An avenue to in silico clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3362.

Abstract CT198: Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: Initial safety and pharmacokinetic results from the PALOMA study

Abstract Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for patients with advanced EGFR exon 20 insertion non-small cell lung cancer after progression on platinum-based chemotherapy. First-dose intravenous (IV) delivery leads to infusion-related reactions (IRR) among 66% of patients, resulting in dose interruptions and slower infusion restart rates (infusion duration ranges 2-4 hours) and necessitates splitting of the dose over 2 days (Park Ann Oncol 32[suppl_5]:S981). Subcutaneous (SC) administration of amivantamab, which could simplify and accelerate administration, is being investigated in an ongoing phase 1 study (PALOMA; NCT04606381). Preliminary safety (including IRR) and pharmacokinetics (PK) of SC formulations of amivantamab ± recombinant human hyaluronidase (rHuPH20) for enhanced absorption were evaluated. Methods: PALOMA is an ongoing phase 1 dose escalation study of amivantamab SC in patients with advanced solid tumors who may derive benefit from EGFR or MET-directed therapy. Eligible patients must have progressed after standard-of-care therapy for metastatic disease, be ineligible for, or have declined current standard therapies. The study objectives were to evaluate the feasibility of administration, safety, and PK of a low concentration formulation, 50 mg/mL of amivantamab ± rHuPH20 (Part 1) and a high concentration formulation, 160 mg/mL of amivantamab ± rHuPH20 (Part 2). Patients in Part 1 and Part 2 received the currently approved dosage of amivantamab, 1050 mg (1400 mg for bodyweight ≥80 kg) SC (weekly for the first 4 weeks and every other week thereafter). This study also evaluated administering the full dose of amivantamab on the first day. Results: The full safety, PK, bioavailability, and receptor occupancy data of patients enrolled in Part 1 (n=16) and Part 2 (n=17) will be presented. Compared to IV administration, initial SC experience demonstrates the co-formulation of high concentration amivantamab with rHuPH20 shortened the needed infusion time to less than 5 minutes, with initial bioavailability of approximately 65% of IV administration. Saturation of soluble free EGFR and MET was achieved after the first SC dose. The incidence of IRRs was 18.2%, with all events of grade 1-2 severity. The full amivantamab SC dose was safely given at first administration to 14 patients, potentially obviating the need for split dosing. Conclusions: Initial SC amivantamab ± rHuPH20 was well tolerated with improvements in time and ease of administration and associated with a meaningful reduction in IRRs, eliminating the need for split dosing compared with IV administration. Higher SC dose levels and alternative dosing schedules are being explored. Citation Format: Matthew G. Krebs, Melissa L. Johnson, Byoung Chul Cho, Se-Hoon Lee, Rachel Kudgus-Lokken, Donna Zemlickis, Anna Mitselos, Eileen Berkay, Joshua M. Bauml, Roland E. Knoblauch, Peter Hellemans, Anna Minchom. Subcutaneous delivery of amivantamab in patients with advanced solid malignancies: Initial safety and pharmacokinetic results from the PALOMA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT198.