Osimertinib Group Research Articles

Comparison of efficacy of gefitinib and osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer in patients with poor performance status

BackgroundThere is a dearth of studies on the efficacy and safety of the tyrosine kinase inhibitors osimertinib (OSI) and gefitinib (GEF) in treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), even in patients with poor performance status (PS). MethodsWe retrospectively reviewed and compared data of 113 patients with EGFR mutation-positive NSCLC with Eastern Cooperative Oncology Group PS 2–4 who were administered OSI 80 mg/day or GEF 250 mg/day from May 2016 to March 2022. ResultsThe GEF group (39 patients; median age: 74 years) included 20 patients with a PS of 2, 17 with a PS of 3, and 2 with a PS of 4. The OSI group (74 patients; median age: 76 years) included 48 patients with a PS of 2, 24 with a PS of 3, and 2 with a PS of 4. The overall response rates were 69% and 66% in the GEF and OSI groups, respectively. The disease control and PS improvement rates were 89% and 51% in both groups, respectively. The median progression-free survival in the GEF and OSI groups was 6.9 and 9.2 months, respectively (p = 0.15). The OSI group experienced better overall survival than the GEF group (median: 20.9 vs. 13.0 months, p = 0.0031). The incidence of pneumonitis was 10% and 11% in the GEF and OSI groups, respectively. One treatment-related death owing to pneumonitis occurred in the GEF group. ConclusionsOSI may be a useful treatment for untreated EGFR mutation-positive NSCLC with poor PS.

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Comparative effectiveness of lazertinib in patients with EGFR T790M-positive non-small-cell lung cancer using a real-world external control

Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR T790M-positive non-small-cell lung cancer. We evaluated the effectiveness of lazertinib compared with osimertinib using an external control. We obtained individual patient data for the lazertinib arm from the LASER201 trial and the osimertinib arm from registry data at the Samsung Medical Center. In total, 75 and 110 patients were included in the lazertinib and osimertinib groups, respectively. After propensity score matching, each group had 60 patients and all baseline characteristics were balanced. The median follow-up duration was 22.0 and 29.6 months in the lazertinib and osimertinib group, respectively. The objective response rate (ORR) were 76.7% and 86.7% for lazertinib and osimertinib, respectively (p = 0.08). The median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI] 9.5–19.1) and 14.4 months (95% CI 11.8–18.1) for the lazertinib and osimertinib group, respectively (hazard ratio [HR] 0.97; 95% CI 0.64–1.45, p = 0.86). The median overall survival with lazertinib was not reached and that with osimertinib was 29.8 months (HR 0.44; 95% CI 0.25–0.77, p = 0.005). Our study suggests that lazertinib has an ORR and PFS comparable to those of osimertinib and has the potential for superior survival benefits.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

BackgroundOsimertinib is a recommended treatment for advanced non–small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC.MethodsIn this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review.ResultsA total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P=0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged.ConclusionsTreatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.)

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer

BackgroundOsimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME.MethodsWe conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes.ResultsTotally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0–12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97–18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006).The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib.ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1β.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy.ConclusionsIn conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk StudyTORG-TG2101).

Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p=0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p=0.03). Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Abstract 4666: HC-7366, a potent GCN2 kinase activator, augments osimertinib therapy to delay resistance in EGFR mutant NSCLC models

Abstract Despite the efficacy seen with EGFR tyrosine kinase inhibitors (TKIs) in the treatment of EGFR mutant NSCLC, the long-term prognosis remains unfavorable due to resistance. Osimertinib is used as the first- and second-line treatment for EGFR exon 19 deletion, L858R mutation, and acquired T790M mutation. Resistance is driven by both EGFR-dependent and independent events, such as gene amplification and upregulation of HIF1α. Metabolic events also drive resistance by increasing oxidative phosphorylation (OXPHOS) caused by osimertinib-induced glycolysis inhibition. HiberCell has developed HC-7366, a GCN2 activator currently being investigated in a Ph1 clinical trial in patients with solid tumors (NCT05121948). GCN2 activation by HC-7366 drives the integrated stress response (ISR) by inducing the expression of ATF4. This results in translation inhibition, cell cycle arrest, HIF1α suppression, and apoptosis in cancer cells. Our preclinical data suggest HC-7366 can reduce glycolysis, TCA cycle metabolites, and OXPHOS, thereby causing mitochondrial dysregulation. We hypothesized that combination of HC-7366 with osimertinib could reduce resistance by evading the adaptive resistance mechanisms. We treated the NCI-H1975 xenograft model with HC-7366, a clinically relevant dose of osimertinib, and the combination for 21 days and then followed for tumor regrowth. At day 21, the HC-7366 group showed efficacy with tumor growth inhibition (TGI) of 55%, while osimertinib resulted in tumor regression of 97% with 8/10 CRs and 2/10 PRs. The combination had tumor regression of 99% with 10/10 CRs. After treatment cessation for 74 days, tumors in the osimertinib group quickly regrew with 6/10 tumors progressing and 4/10 mice tumor-free. In contrast, the combination group had only 2/10 tumors regrow with 8/10 mice tumor-free. In an EGFR-dependent resistance model NCI-H1975 (EGFR C797S), combination achieved 63% TGI versus 31% with osimertinib. In an EGFR-independent resistant PDX with EGFR exon 19 deletion, combination benefit was seen at 70% TGI compared to 40% for osimertinib, while a PDX with EGFR L858R showed a trend for combination benefit. To understand the mechanism of action, we examined osimertinib-resistance pathways to determine how GCN2 activation could affect them. Combination with HC-7366 reduced the expression of short-lived proteins involved in osimertinib resistance, including HIF1α, MET, cyclin D1, and CDK4. Combination decreased TIM17A and TIM23, proteins essential for mitochondrial protein translocation, potentially causing mitochondrial dysfunction. We found a proliferation reduction by Ki67 and an increase in apoptotic proteins CHOP, PUMA, and cleaved caspase 3. Taken together, these data reveal that combination of HC-7366 and osimertinib, and potentially other EGFR TKIs, may be an effective treatment strategy at targeting adaptive resistance mechanisms. Citation Format: Crissy Dudgeon, Sho Fujisawa, Olivia Funk, Feven Tameire, Takashi O. Kangas, Weiyu Zhang, Eric S. Lightcap, David Surguladze, Nandita Bose. HC-7366, a potent GCN2 kinase activator, augments osimertinib therapy to delay resistance in EGFR mutant NSCLC models [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 4666.

Impact of Folic Acid on the Resistance of Non-small Cell Lung Cancer Cells to Osimertinib by Regulating Methylation of DUSP1

Drug resistance is the main cause of high mortality of lung cancer. This study was conducted to investigate the effect of folic acid (FA) on the resistance of non-small cell lung cancer (NSCLC) cells to Osimertinib (OSM) by regulating the methylation of dual specificity phosphatase 1 (DUSP1). The OSM resistant NSCLC cell line PC9R was establishd by gradually escalation of OSM concentration in PC9 cells. PC9R cells were randomly grouped into Control group, OSM group (5 μmol/L OSM), FA group (600 nmol/L FA), methylation inhibitor decitabine (DAC) group (10 μmol/L DAC), FA+OSM group (600 nmol/L FA+5 μmol/L OSM), and FA+OSM+DAC group (600 nmol/L FA+5 μmol/L OSM+10 μmol/L DAC). CCK-8 method was applied to detect cell proliferation ability. Scratch test was applied to test the ability of cell migration. Transwell assay was applied to detect cell invasion ability. Flow cytometry was applied to measure and analyze the apoptosis rate of cells in each group. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) method was applied to detect the expression level of DUSP1 mRNA in cells. Methylation specific PCR (MSP) was applied to detect the methylation status of the DUSP1 promoter region in each group. Western blot was applied to analyze the expression levels of DUSP1 protein and key proteins in the DUSP1 downstream mitogen-activated protein kinase (MAPK) signaling pathway in each group. Compared with the Control group, the cell OD450 values (48 h, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of extracellular regulated protein kinases (ERK) were obviously increased (P<0.05); the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the DAC group were obviously increased (P<0.05); the apoptosis rate, the expression of p38 MAPK protein, the phosphorylation level of ERK, and the methylation level of DUSP1 were obviously reduced (P<0.05). Compared with the OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously increased (P<0.05). Compared with the FA+OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM+DAC group were obviously increased; the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously reduced (P<0.05). FA may inhibit DUSP1 expression by enhancing DUSP1 methylation, regulate downstream MAPK signal pathway, then promote apoptosis, inhibit cell invasion and metastasis, and ultimately reduce OSM resistance in NSCLC cells.

Economic evaluation of adjuvant therapy with osimertinib in patients with early-stage non-small cell lung cancer and mutated EGFR.

The ADAURA trial demonstrated the superiority of osimertinib over a placebo with regard to disease-free survival, showing it to be indicated as an adjuvant therapy for treatment of non-small cell lung cancer with mutated epidermal growth factor receptor (EGFR). The aim of the present study was to conduct a cost-utility analysis and an analysis of the budgetary impact of adjuvant therapy with osimertinib in patients with non-small cell lung cancer with mutated EGFR who had undergone resection surgery with curative intent. Analyses were based on the outcomes of the ADAURA clinical trial and were conducted through a Spanish National Health Service perspective. The outcome measures used were quality-adjusted life years (QALY). The average overall cost of adjuvant treatment with osimertinib over a period of 100 months in the overall sample of trial patients (stages IB-IIIA) was 220,961 €, compared with 197,849 € in the placebo group. Effectiveness, estimated according to QALY, was 6.26 years in the osimertinib group and 5.96 years in the placebo group, with the incremental cost-utility ratio being 77,040 €/QALY. With regard to the budgetary impact, it was estimated that, in 2021, approximately 1130 patients would be subsidiaries to receive osimertinib. This pertains to a difference of 17,375,330 € over 100 months to fund this treatment relative to no treatment. Taking into account a Spanish threshold of 24,000 €/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 10%, to obtain a cost-effective alternative.

Long QT syndrome after using EGFR-TKIs in older patients with advanced non-small cell lung cancer

ABSTRACT Background Long QT syndrome (LQTS) has been reported in older patients with advanced non-small cell lung cancer (NSCLC) following the use of osimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, there have not been analytic epidemiology studies on this topic. We aimed to compare the risk of LQTS between osimertinib and first/second-generation EGFR-TKIs in older patients with advanced NSCLC. Research design and methods This retrospective observational study used the 2006–2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included older patients with advanced NSCLC who were treated with either osimertinib or first/second-generation EGFR-TKIs during 2007–2017. Inverse probability of treatment weighting (IPTW) was used to balance the two groups with propensity scores estimated based on the patients’ socioeconomic and clinical characteristics. Crude incidence rate (IR) and adjusted hazard ratio (HR) of the primary outcome, incident LQTS, were estimated. Results A total of 545 and 1,135 patients were included in the osimertinib and first/second-generation EGFR-TKI groups, which increased to 1,614 and 1,659, respectively, after IPTW. The osimertinib group had a higher IR of LQTS (2.62 per 100 person-years, 95% CI 2.03–3.38) compared to the first/second-generation EGFR-TKI group (1.33 per 100 person-years, 95% CI 0.92–1.92). After adjusting for covariates, the osimertinib group had a higher risk of LQTS than the first/second-generation EGFR-TKI group, with an HR of 1.94 (95% CI 1.23–3.08). The increased LQTS risk in the osimertinib group was even higher in females, whites and patients aged ≥ 75. Conclusions Given the elevated risk of LQTS associated with osimertinib user, close monitoring for cardiac rhythm irregularities of high-risk patients following initiation of EGFR-TKI is recommended.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC

BackgroundOsimertinib is a third-generation epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI–sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.MethodsIn this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non–small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed.ResultsA total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib–chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib–chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib–chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy — a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.ConclusionsFirst-line treatment with osimertinib–chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.)

Clinicopathological impact of VEGFR2 and VEGF-C in patients with EGFR-major mutant NSCLC receiving osimertinib.

Vascular endothelial growth factor (VEGF) has been identified as one of the resistant mechanisms to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the relationship between the efficacy of osimertinib and protein expression of VEGF family members in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations remains unclear. A total of 76 patients with advanced NSCLC with EGFR major mutations (del19 or L858R) receiving first-line osimertinib were eligible as the osimertinib (Osi) group, whereas 43 patients receiving first- or second-generation EGFR-TKIs were compared with the control group. The expression of vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor C (VEGF-C) in the tumor specimens was analyzed using immunohistochemistry. VEGFR2 and VEGF-C were highly expressed in 65.8% and 51.3% of patients, respectively, in the Osi group, and 69.7% and 76.7%, respectively, in the control group. High VEGFR2 and VEGF-C levels were significantly associated with poor performance status (PS) and female sex, respectively. In the Osi group, patients with co-high expression of VEGFR2 and VEGF-C showed significantly worse progression-free survival (PFS) and overall survival (OS) than those without co-high expression. In del19, VEGFR2 was a significant predictor of PFS and OS and independent predictor of OS in multivariate analysis. In L858R, co-high expression of VEGFR2 and VEGF-C was identified as a significant predictor of PFS and OS and independent predictor of PFS. VEGFR2 and VEGF-C are highly expressed in EGFR-mutant NSCLC cells. Increased expression of VEGFR2 was identified as a significant prognostic factor in patients with EGFR del19 mutation who received osimertinib, whereas co-high expression of VEGFR2 and VEGF-C was a significant predictor for those with EGFR L858R mutation.

Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats.

Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats. The adult male Sprague-Dawley rats were randomly divided into four groups (n=6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0-48 h after osimertinib administration. Osimrtinib's plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min. Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0-t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0-t of osimertinib only increased by 13.91% and 34.80%, respectively. Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals.

Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC

BackgroundAmong patients with resected, epidermal growth factor receptor (EGFR)–mutated, stage IB to IIIA non–small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival.MethodsIn this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety.ResultsOf 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis.ConclusionsAdjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)

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 .

Upfront Use of First-/Second-Generation EGFR-TKI Followed by Osimertinib Shows Better Prognosis than Upfront Osimertinib Therapy in Japanese Patients with Non-small-cell Lung Cancer with Exon 19 Deletion: A Single-Center Retrospective Study.

Clinical evidence on the increased efficacy of sequential epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is limited. This study aimed to compare the efficacy of upfront use of first-/second-generation TKI followed by osimertinib with upfront osimertinib therapy for each representative EGFR mutation in Japanese patients with NSCLC. Patients with EGFR-mutated NSCLC were classified into two groups: first-/second-generation TKI followed by osimertinib (sequential TKI group) and upfront osimertinib groups. The total time to treatment failure (TTF) of TKI therapies, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated. Of the 74 patients included in the analysis, 38 and 34 patients had exon 19 deletion and L858R, respectively, and other two patients had minor mutations. The sequential TKI group had a significantly longer TTF than the upfront osimertinib group in overall patients (33.2 vs. 11.2 months; p = 0.007) and in the subgroup of exon 19 deletion (36.7 vs. 10.0 months; p = 0.004), but not in the subgroup of L858R (22.6 vs. 15.6 months; p = 0.37). The similar tendency was observed in PFS. OS of the sequential TKI group was significantly longer compared with the upfront osimertinib group in overall patients, the subgroup of exon 19 deletion, and the subgroup of L858R. The upfront use of first-/second-generation TKI followed by osimertinib is one of the feasible and effective strategies in Japanese patients with EGFR-mutated NSCLC, especially in patients with exon 19 deletion.

Final Report on Real-World Effectiveness of Sequential Afatinib and Osimertinib in EGFR Positive Advanced Non-Small Cell Lung Cancer: Updated Analysis of the RESET Study.

To report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage EGFR+ non-small-cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group). In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes. The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% CI:14.0-16.1) and 11.9 months (95% CI:8.9-14.6), respectively. The median OS in the osimertinib group was 54.3 months (95%CI:46.7-61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median 59.1, 95% CI:48.7-69.5). This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.

Comparison of Osimertinib versus Almonertinib in T790M+ EGFR Non-Small-Cell Lung Cancer Patients

What is Known and Objective. Almonertinib was newly approved for treating non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, and the therapeutic effect of almonertinib needed to be investigated. This study aims to investigate the efficacy and safety of almonertinib compared with osimertinib in EGFR-T790M+ patients who used earlier-generation EGFR-TKI and experienced disease progression. Methods. Among all 160 patients, 80 received osimertinib, while the other 80 patients took almonertinib once daily. The objective response rate (ORR) and disease control rate (DCR) were analyzed, while overall survival (OS) and progression-free survival (PFS) were estimated. In terms of safety, adverse events (AEs) were compared. Results and Discussions. The ORR and DCR were significantly higher in patients who received almonertinib than those in the osimertinib group (70.0% vs. 47.5%, P = 0.004 ; 90.0% vs. 77.5%, P = 0.032 ). The OS was significantly higher in the almonertinib group than in patients who received osimertinib ( P = 0.031 ), while the PFS was similar between the two groups ( P = 0.226 ). Of 28 patients with brain metastasis, the OS was not raised after using almonertinib compared with the osimertinib group ( P = 0.626 ). The number of AEs was similar between the almonertinib and osimertinib groups (all P &gt; 0.05 ). Treatment-related AEs of grade ≥3 occurred in 20.0% and 15.0% of patients in the osimertinib and almonertinib arms, respectively. What is New and Conclusion. Almonertinib may become an alternative option for EGFR-T790M + NSCLC patients after earlier-generation EGFR-TKI for its promising efficacy and manageable tolerability. However, the treatment option for patients with brain metastasis remains to be explored further.

Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell Lung Cancer Patients with Acquired EGFR T790M Mutation

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

Reaffirming Adverse Events Related to Lung Cancer Survivors' Target Therapies and Their Apparent Effects on Fear of Cancer Progression, Anxiety, and Depression.

Most advanced non-small-cell lung cancer (NSCLC) patients received targeted therapies of epidermal growth factor receptor tyrosine kinase inhibitors. However, few studies reported the relationships between adverse events (AEs) and psychological distress. The aims of this study were to (1) examine the differences in the incidence of AEs, fear of progression (FoP), anxiety, and depression among 3 generations of epidermal growth factor receptor tyrosine kinase inhibitors (first, gefitinib and erlotinib; second, afatinib; third, osimertinib) and (2) examine the difference in levels of FoP, anxiety, and depression between the presence and absence of AEs in NSCLC patients. This study used a cross-sectional study design. Patients with NSCLC (N = 120) were recruited from a medical center in northern Taiwan. Adverse events, FoP, anxiety, and depression were assessed by questionnaires. The incidence rates of photosensitivity, mouth and throat sores, and diarrhea were significantly high in the gefitinib, erlotinib, and afatinib groups, respectively. A lesser proportion of patients experienced AEs in the osimertinib group, compared with those in the gefitinib and erlotinib, and afatinib groups. The incidence rates of FoP, anxiety, and depression were 13.8% to 26.0%, 24.1% to 40.4%, and 17.6% to 40.0%, respectively. Patients with photosensitivity, paronychia, and alopecia had significantly higher levels of FoP, anxiety, and depression. This study confirmed the priorities of care among 3 generations of epidermal growth factor receptor tyrosine kinase inhibitors in NSCLC patients, using both the Common Terminology Criteria for Adverse Events (CTCAE 4.03) and PRO-CTCAE 1.0. Photosensitivity, paronychia, and alopecia were associated with higher levels of FoP, anxiety, and depression. Therefore, these AEs require further management. Our study suggests a follow-up to address AEs and psychological distress.