Osimertinib Group Research Articles

Cost-effectiveness of osimertinib versus placebo in resected EGFR-mutated non-small cell lung cancer in China.

We aim to assess whether osimertinib postoperative adjuvant therapy, compared with placebo, is cost-effective in China. We set up the Markov model that contains three health states over a 20-year period. Data were collected from the ADAURA trial that included transition probabilities and safety data. Through the analysis of literature and local charges, we explore both the cost and utility values. Sensitivity analyses were employed using TreeAge Pro software to access model stability. Patients in the osimertinib group had 1.46 more Quality-adjusted Life Years (8.45 QALYs vs 6.99 QALYs) than the placebo group at an incremental cost of $14098.51($39962.99 vs $25864.48). Compared with the placebo group, the treatment strategy with osimertinib postoperative adjuvant therapy had an incremental cost-effectiveness ratio of $9661.97/QALY. The probability of the osimertinib-assisted therapy strategy being cost-effective will reach 100% if the threshold of willingness to pay is above $15,000/QALY. From the perspective of the Chinese Healthcare System, the treatment strategy with osimertinib postoperative adjuvant therapy is more cost-effective than the placebo strategy.

The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small cell lung cancer. The main objective of the present study was to compare the clinical efficacies between osimertinib and afatinib as first-line treatment in patients with EGFR-mutant non-small cell lung cancer. We retrospectively analyzed patients with advanced and recurrent non-small cell lung cancer who harbored an exon 19 deletion or an exon 21 L858R mutation and were being given either osimertinib or afatinib as first-line treatment from January 2018 to December 2020. A total of 128 patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median follow-up time was 20.1 months in the osimertinib group and 22.7 months in the afatinib group. The median progression-free survival was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (hazard ratio 0.75 [95% confidence interval 0.48-1.18]). The median overall survival was not reached in the osimertinib group and was 41.7 months in the afatinib group (hazard ratio 0.79 [95% confidence interval 0.36-1.72]). In patients without brain metastasis, the median progression-free survival was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (hazard ratio 1.02 [95% confidence interval 0.56-1.85]). In patients with brain metastasis at baseline, the median progression-free survival was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted hazard ratio 0.45 [95% confidence interval 0.21-0.96]). Our research demonstrates that there was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median progression-free survival and overall survival than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median progression-free survival than afatinib in patients with brain metastasis at baseline.

First-line therapy in non-small cell lung cancer patients with EGFR activating mutations: a consideration of the clinical position of osimertinib based on the subset of Japanese patients in the FLAURA study.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been established as the standard first-line treatment for patients with previously untreated advanced non-small cell lung cancer (NSCLC) with an EGFR activating mutation. In the FLAURA study, osimertinib, third-generation EGFR-TKI, resulted in significantly longer progression-free survival and overall survival (OS) than first-generation EGFR-TKIs (gefitinib or erlotinib) in patients with previously untreated advanced NSCLC with an EGFR activating mutation. Osimertinib is now widely used as first-line therapy for those patients. In Japanese subset analysis of the FLAURA study, the median progression-free survival was prolonged by osimertinib (19.1months) relative to gefitinib (13.8months). However, there was no apparent OS benefit, albeit at the level of an exploratory post-hoc analysis. Although the safety profile in the Japanese subset was generally consistent with the overall population, the incidence of liver enzyme increases in the gefitinib group and that of interstitial lung disease/pneumonitis in the osimertinib group was higher among Japanese patients. There is now an increasing number of first-line treatment options for NSCLC with EGFR mutations, including EGFR-TKIs in combination with platinum-doublet chemotherapy or anti-angiogenic drugs. These combinations show progression-free survival benefits similar to osimertinib regardless of the mutation type. Therefore, a first-line combination regimen followed by osimertinib remains an attractive strategy. We review data from the randomized clinical trials of first-line EGFR-TKIs including a subset of Japanese patients and discuss first-line therapies for patients with NSCLC harbouring EGFR mutations.

Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer

BackgroundEGFR-mutant non-small cell lung cancer (NSCLC) is prone to leptomeningeal metastasis (LM) after Tyrosine kinase inhibitors (TKIs) treatment. Our previous study suggested that osimertinib plus bevacizumab was safe and effective in LM from EGFR-mutant NSCLC. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM.MethodsWe retrospectively reviewed the data from 27 LM patients with EGFR-mutant NSCLC who received osimertinib with or without bevacizumab at the Second Affiliated Hospital of Nanchang University. Next, we investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975 (EGFR exon20 T790M and exon21 L858R) cell line. We examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood–brain barrier (BBB) and explored the potential mechanism.ResultsOur retrospective study observed the improved survival of LM patients in osimertinib plus bevacizumab group. The median overall survival (OS) of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib group (n = 11) was 18.0 months versus 13.7 months (log-rank test, p = 0.046, HR = 2.867, 95% CI 1.007–8.162). The median intracranial Progression-free Survival (iPFS) was 10.6 months versus 5.5 months (log-rank test, p = 0.037, HR = 3.401, 95% CI 1.079–10.720). In the LM xenograft model with H1975 cells, the combined treatment significantly increased the effective intracranial concentration of osimertinib, modulated the level of E-cadherin and downregulated the levels of EGFR and downstream signaling pathways including p-AKT and reduced tumor microvessel density (TMD), indicated that combined osimertinib with bevacizumab may exhibit a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin.ConclusionsOur findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC, and more larger sample size research are still needed.

Modeling the Cost-Effectiveness of Adjuvant Osimertinib for Patients with Resected EGFR-mutant Non-Small Cell Lung Cancer.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib was recently approved for resected EGFR-mutant stages IB-IIIA non-small cell lung cancer due to improved disease-free survival (DFS) in this population compared with placebo. This study aimed to evaluate the cost-effectiveness (CE) of this strategy. We constructed a Markov model using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of 3 years of adjuvant osimertinib versus placebo over a 10-year time horizon. An overall survival (OS) benefit of 5% was assumed. Costs and utility values were derived from Medicare reimbursement data and literature. A CE threshold of 3 times the gross domestic product per capita was used. Sensitivity analyses were performed. The incremental cost-effectiveness ratio for adjuvant osimertinib was $317119 per QALY-gained versus placebo. Initial costs of osimertinib are higher in years 1-3. Costs due to progressive disease (PD) are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2388, $379047, and $502937, respectively, in the placebo group, and $505775, $255638, and $800697, respectively, in the osimertinib group. Sensitivity analysis of OS gains reaches CE with an hazard ratio (HR) of 0.70-0.75 benefit of osimertinib over placebo. A 50% discount to osimertinib drug cost yielded an ICER of $115419. Three-years of adjuvant osimertinib is CE if one is willing to pay $317119 more per QALY-gained. Considerable OS benefit over placebo or other economic interventions will be needed to reach CE.

Comparison of Gefitinib in the treatment of patients with non-small cell lung cancer and clinical effects of Osimertinib and EGFR Gene mutation.

Objectives:To compare the clinical effects of Osimertinib and Gefitinib in the treatment of non-small cell lung (NSCLC) complicated with epidermal growth factor receptor (EGFR) gene mutation.Methods:We retrospectively analyzed the clinical data of 102 patients with advanced NSCLC and EGFR gene mutations treated in the Chest Disease Diagnosis and Treatment Center of our hospital from January 2018 to January 2020. We divided the data based on the administered treatments into Osimertinib and Gefitinib groups. The disease control rate (DCR), progression free survival (PFS) and the incidence of adverse events in both groups were analyzed.Results:In the Osimertinib group, there was one patients with complete response (CR), 38 with partial response (PR), eight with stable disease (SD), and two with progressive disease (PD)/ The overall response rate (ORR) was 79.59% (39/49), and the disease control rate (DCR) was 95.92% (47/49). In the Gefitinib group, we found zero patients with CR, 37 patients with PR, 11 with SD, and five with PD. The ORR in the Gefitinib group was 69.80% (37/53) and DCR was 90.57% (48/53). There was no statistical significance between the two groups, ORR was Χ2=0.927 (P=0.336) and the DCR Χ2=0.221 (P=0.638). The median PFS of and Gefitinib groups was significantly higher in the oxitinib group, compared to the Gefitinib group (18.1 months (95% CI 15.4-20.7) and 10.7 months (95% CI 9.9-11.4), respectively, P<0.001). The incidence of adverse reactions in the Osimertinib group was 12.24% (6/49), which was significantly lower than 28.30% (15/53) in the Gefitinib group (P < 0.05).Conclusions:The clinical effect of oxitinib in the treatment of non-small cell lung cancer complicated with EGFR gene mutation is similar to that of Gefitinib. In patients with advanced NSCLC and EGFR gene mutations, oxitinib treatment is associated with significantly longer PFS and lower adverse reaction rate compared with Gefitinib treatment.

Therapeutic effect of osimertinib plus cranial radiotherapy compared to osimertinib alone in NSCLC patients with EGFR-activating mutations and brain metastases: a retrospective study

BackgroundThe study aimed to compare the efficacy of osimertinib plus cranial radiotherapy (RT) with osimertinib alone in advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations and brain metastases (BMs).MethodsThe clinical data of advanced NSCLC patients with BMs who received osimertinib were retrospectively collected. The patients were assigned to one of the two groups according to the therapeutic modality used: the osimertinib monotherapy group or the osimertinib plus RT group.ResultsThis was a retrospective study and 61 patients were included from December 2015 to August 2020. Forty patients received osimertinib monotherapy, and twenty-one patients received osimertinib plus RT. Radiotherapy included whole-brain radiation therapy (WBRT, n = 14), WBRT with simultaneous integrated boost (WBRT-SIB, n = 5) and stereotactic radiosurgery (SRS, n = 2). The median number of prior systemic therapies in the two groups was one. Intracranial and systemic ORR and DCR were not significantly different between the two groups. No difference in iPFS was observed between the two groups (median iPFS: 16.67 vs. 13.50 months, P = 0.836). The median OS was 29.20 months in the osimertinib plus RT group compared with 26.13 months in the osimertinib group (HR = 0.895, P = 0.826). In the L858R mutational subgroup of 31 patients, the osimertinib plus RT group had a longer OS (P = 0.046). In the exon 19 deletion mutational subgroup of 30 patients, OS in the osimertinib alone group was longer than that in the osimertinib plus RT group (P = 0.011). The incidence of any-grade adverse events was not significantly different between the osimertinib plus RT group and the osimertinib alone group (47.6% vs. 32.5%, P = 0.762). However, six patients (28.5%) experienced leukoencephalopathy in the osimertinib plus RT group, and 50% (3/6) of the leukoencephalopathy was greater than or equal to grade 3.ConclusionThe therapeutic effect of osimertinib with RT was similar to that of osimertinib alone in EGFR-positive NSCLC patients with BM. However, for patients with the L858R mutation, osimertinib plus RT could provide more benefit than osimertinib alone.

Osimertinib Improves Overall Survival in Patients with Leptomeningeal Metastases Associated with EGFR-Mutated Non-Small-Cell Lung Cancer Regardless of Cerebrospinal Fluid T790M Mutational Status.

Osimertinib has demonstrated promising efficacy against leptomeningeal metastasis (LM) associated with T790M-positive non-small-cell lung cancer (NSCLC). However, the effect of cerebrospinal fluid's (CSF's) epidermal growth factor receptor (EGFR) T790M mutation on osimertinib efficacy remains unclear.Seventy-eight patients were studied with EGFR-mutated NSCLC and LM. Case data were collected and EGFR mutation status of circulating cell-free DNA from paired CSF, and plasma of 23 patients with LM was detected using droplet digital PCR. The median overall survival (mOS) was 8.08 months (95% CI: 6.07–10.09) in the study. Forty-four osimertinib-treated patients had an improved mOS of 13.15 (95% CI: 5.74–20.57) and a median progression-free survival (PFS) of 9.50 months (95% CI: 6.77–12.23) when compared with patients treated with first- or second-generation EGFR-TKI (mOS = 3.00 months (95% CI: 1.32–4.68) and median PFS = 1.50 months (95% CI: 0.00–3.14)). In the osimertinib group, mOS values for CSF with and without T790M mutation were 22.15 months (95% CI: 9.44–34.87) and 13.39 months (95% CI: 7.01–19.76), respectively, with no statistical differences. Regardless of the CSF T790M mutation status, osimertinib demonstrated significant efficacy against LM associated with NSCLC.

Efficacy of osimertinib for preventing leptomeningeal metastasis derived from advanced EGFR-mutated non-small cell lung cancer: a propensity-matched retrospective study

BackgroundLeptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC). This retrospective study aimed to investigate the potential use of osimertinib for preventing LM in patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC.MethodsPatients with advanced NSCLC harboring EGFR mutations who underwent tyrosine kinase inhibitors (TKIs) therapy for at least 8 weeks between September 2016 and September 2019 were eligible for this study. All included patients were divided into two groups based on whether they received osimertinib, the osimertinib group (patients treated with osimertinib) and the control group (patients not treated with osimertinib). Propensity score matching (PSM, ratio of 1:1) was used to account for differences in baseline characteristics. The cumulative incidence of LM and the overall survival (OS) were evaluated.ResultsA total of 304 patients were included in the study population. Among them, 116 patients received osimertinib, and 188 did not. A total of 112 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two cohorts. LM developed in 11 patients (9.82%) in the osimertinib group and 24 patients (21.42%) in the control group (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19–0.79, p = 0.009). Multivariate analysis indicated that osimertinib was an independent, statistically significant predictor for determining the risk for LM, with an HR of 0.33 (p = 0.042). At present, the OS rate data are too immature for statistical analysis.ConclusionReal-world data demonstrate that osimertinib can significantly reduce the incidence of LM in patients with advanced NSCLC harboring common EGFR mutations. Given this result, osimertinib should be encouraged in clinical practice for specific patient populations.

Abstract 1105: Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR mutant NSCLC

Abstract Osimertinib, the only third-generation EGFR-TKI approved for the treatment of T790M-mutant non-small cell lung cancer, shows robust clinical activity, yet patients inevitably develop secondary resistance. TUSC2, an immunogene therapy, has multifunctional activity, which a) directly blocks downstream signaling through inhibiting MAPK and mTOR, b) arrests growth and proliferation of cancer cells, c) induces direct tumor cell death, and d) activates both innate and adaptive immunity. An osimertinib resistant H1975-OsiR isogenic cell line was developed through continuous exposure to osimertinib, and an osimertinib resistant clone was selected which showed 100 fold higher resistance to osimertinib compared with its parental counterpart (H1975-parental). Xenograft tumors from both H1975-parental and H1975-OsiR cells were developed in NSG mice and were treated with osimertinib. H1975-OsiR tumors were significantly less sensitive than their parental counterparts. To maintain the resistance in H1975-OsiR, the cells were cultured in the presence of osimertinib, and the osimertinib pressure was maintained in vivo throughout the experiments. Synergistic antitumor activity of TUSC2+osimertinib was found in H1975-OsiR tumors where both TUSC2+osimertinib (5mg/kg) and TUSC2+osimertinib (10mg/kg) combinations showed a robust antitumor effect compared with single agent treatment groups. No synergistic effect was observed for H1975-parental tumors. RPPA analysis of residual tumors showed a distinct set of proteins including CD44, VEGFR-2, SHP2, Akt2, and YAP-pS127 overexpressed in H1975-OsiR vs H1975-parental. Among H1975-OsiR tumors, RPPA data showed that PDK1 protein was significantly altered in osimertinib treated groups as compared with controls. PDK1 was also found to be significantly upregulated in the TUSC2+osimertinib group when compared with either control, osimertinib alone, or TUSC2 alone treated H1975-OsiR tumors indicating that PDK1 may be associated with osimertinib resistance. PDK1 was not altered by TUSC2 alone treatment. PDK1 was not altered in any treatment groups in H1975-parental tumors. In order to validate the role of PDK1 in H1975-OsiR, we performed XTT assays of osimertinib and TUSC2+osimertinib combinations in the presence or absence of a PDK1 inhibitor (BX-795). Only the osimertinib and TUSC2+osimertinib groups showed significantly increased sensitivity to osimertinib in the presence of BX-795 as compared with the same treatment without the inhibitor. No PDK1 inhibitor effect was found in the TUSC2 treated group validating the specific role of PDK1 in osimertinib resistance. In conclusion, TUSC2 therapy in combination with osimertinib showed synergistic antitumor efficacy in EGFR mutant osimertinib resistant NSCLC tumors, and upregulation of PDK1 was associated with osimertinib resistance. Citation Format: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Lihui Gao, Meng Feng, Huiqin Chen, Min Jin Ha, Jack A. Roth. Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1105.

A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903

BackgroundFLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear.Patients and methodsWe reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses.ResultsA total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001).ConclusionsTD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

Polyphyllin I reverses the resistance of osimertinib in non-small cell lung cancer cell through regulation of PI3K/Akt signaling

Lung cancer is considered the main cause of cancer mortality worldwide. Osimertinib, a third-generation EGFR-TKI, has been approved and administrated for treating patients with either EGFR T790M mutation or EGFR sensitive mutation. However, resistance to osimertinib emerges and has been considered to be the main obstacle in lung cancer treatment. Polyphyllin I is isolated from the natural herb Paris polyphylla and exhibits anti-cancer activities. In the present study, we identify Polyphyllin I to reverse the resistance of osimertinib in vitro and in vivo. The results showed that Polyphyllin I reversed the resistance of osimertinib through promoting apoptosis, modulating the PI3K/Akt signaling, and regulating the expression of apoptosis-related proteins in osimertinib-resistant cell lines. In vivo study confirmed the results, showing that the tumor growth was significantly suppressed in the Polyphyllin I/osimertinib group compared to the osimertinib group. It has been clarified that Polyphyllin I could reverse the resistance of osimertinib in osimertinib-resistant non-small cell of lung cancer in vitro and in vivo. The underlying mechanism might be related to the downregulation of the PI3K/Akt signaling and increase of the expression of apoptosis-related proteins, suggesting that Polyphyllin I was a promising therapeutic agent for reversing the resistance of osimertinib.

P76.09 A Comparison of Sequential EGFR-TKI Therapy Versus First-Line Osimertinib in NSCLC: A Multi-Center, Retrospective Study

Lung cancer remains the deadliest form of cancer. Several driver mutations have been identified of which targeted tyrosine kinase inhibitors (TKIs) have shown favorable response. Epidermal growth factor receptor (EGFR) is the most common driver mutation and is present in approximately 15% of adenocarcinomas. There are currently several TKIs approved for the use of EGFR mutated lung cancer. The FLAURA trial showed a progression free survival (PFS) and overall survival (OS) benefit with osimertinib compared to first generation EGFR TKIs. There is a paucity of data to support using a first or second generation EGFR TKI after progression on osimertinib. In this study, we aim to assess the outcomes of EGFR mutated lung cancer patients being treated with a first or second generation EGFR TKI compared to osimertinib. An IRB approved, multi-center, retrospective review of lung cancer patients receiving EGFR TKIs between 2014 and 2019 was conducted. Patients were included in this review if they had received an EGFR TKI for metastatic lung cancer in the front line setting. Patients were excluded if they had an active concomitant cancer, de novo T790M mutation, no EGFR mutations, or who were treated with chemotherapy as first line therapy. EGFR TKI was dichotomized as osimertinib vs all other EGFR TKIs. PFS and OS was estimated using the Kaplan-Meier product-limit method and first line EGFR TKI was compared using the log-rank test. A Cox proportional hazards model was used to examine the association between PFS and OS and EGFR TKI and various patient factors. A total of 172 were included in the analysis, 52 (30.2%) received osimertinib and 120 (69.8%) received another EGFR TKI (afatinib=25, gefitinib=1, erlotinib=94) as first line treatment. All but three of these patients (98%) were never or former smokers and 35% of patients had baseline brain metastasis. Sixty percent of patients had an exon 19 deletion, 33% exon 21 mutation and 7% had another EGFR mutation. The PFS rates at 12 and 18 months were 79.5% and 69.8% in the osimertinib group and 64.2% and 39.3% in the other EGFR TKI groups, respectively (p<0.0036). The adjusted Hazard Ratio (HR) for PFS (reference: osimertinib) was 2.59 (95% CI: 1.31 to 5.11) p<0.0064. Estimated OS at 12 and 18 months were 94.2% and 80.2% in the osimertinib group and 93.9% and 84.1% in the other EGFR TKI groups, respectively (p<0.6382). The adjusted HR for OS was 0.95 (95% CI, 0.37 to 2.44) p<0.9128. In this single institution retrospective review, osimertinib demonstrated a greater PFS compared to other EGFR TKIs at 12 and 18 months. Estimated OS were no different between the two groups. Additional follow up is needed to solidify the real world OS benefit of osimertinib to other EGFR TKIs.

Cost-effectiveness analysis of different sequences of osimertinib administration for epidermal growth factor receptor-mutated non-small-cell lung cancer.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is clinically effective in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the use of this treatment is limited by its high cost. A cost-effectiveness analysis of different sequences of osimertinib administration in China and the United States was conducted in the present study. Markov models were established based on data from the FLAURA and AURA3 trials. First-line osimertinib was compared with both first-generation EGFR-TKIs and second-line osimertinib after the failure of first-generation EGFR-TKIs. The analysis also considered different payment modalities available in China. Additionally, one-way and probability sensitivity analyses, with a willingness-to-pay threshold (WTP) of three times the per capita gross domestic product [$27,783/quality-adjusted life year (QALY) for China and $100,000/QALY for the United States], were performed. The first-line osimertinib group displayed higher QALYs and costs than those of the first-generation EGFR-TKI group. The first generation EGFR-TKI group displayed an incremental cost-effectiveness ratio (ICER) of $212,252/QALY in China and $151,922/QALY in the United States. In addition, the ICERs were negative in the second-line osimertinib group, with higher QALYs and lower costs compared with those in the first-line osimertinib group. Furthermore, osimertinib company donation was of benefit in China, with an average cost-effectiveness of $836/QALY. The one-way sensitivity analysis highlighted the influence of utilities in different states. First-line osimertinib could be cost-effective either with higher WTP or a price reduction of 68% in China and 9% in the United States. Although first-line osimertinib therapy could have health benefits, it was not cost-effective compared with first-line first-generation EGFR-TKIs and second-line osimertinib therapy. However, paying via company donation may be a good choice in China.

Cholesterol synthesis disruption combined with a molecule-targeted drug is a promising metabolic therapy for EGFR mutant non-small cell lung cancer.

BackgroundAcquired resistance is a challenge for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. Here, we propose a novel treatment strategy based on recent lipid metabolism work.MethodsWe applied a variety of experimental methods such as immunoblotting, MTT, si-RNA, and animal models, to demonstrate the relationship between EGFR and low-density lipoprotein receptor (LDLR) and the effects of statin monotherapy, and TKI monotherapy, and their combination on cell proliferation at the cell level and animal level.ResultsLDLR has a positive correlation with EGFR, EGFR signaling upregulates LDLR expression through the SREBP-1 dependent pathway, EGFR mutation cells count on lipids to survive and grow. Combined with a molecule-targeted drug, atorvastatin not only enhances the treatment effect in vitro, but also mitigates the growth of NSCLC in vivo. In this animal experiment, the combination medicine (atorvastatin with TKI) has a better tumor suppression effect on NSCLC. In HCC827 cell line, the average tumor shrinkage is about 68% in Gefitinib group, and about 49% in atorvastatin group, but about 89% in combination group. In H1975 cell line, the average tumor shrinkage is about 18% in Osimertinib group, and about 8% in atorvastatin group, but about 44% in combination group.Conclusionsthe combination of an EGFR-TKI and a statin for EGFR mutant NSCLC may be a novel tumor inhibiting treatment.

Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer

BackgroundOsimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation–positive advanced non–small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown.MethodsIn this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation–positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety.ResultsA total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted.ConclusionsIn patients with stage IB to IIIA EGFR mutation–positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)

Preventing Symptomatic Central Nervous System Metastasis in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Comparison of First- and Third-Generation EGFR Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Central nervous system (CNS) metastases, including brain parenchymal metastasis (BM) and leptomeningeal metastasis (LM), are common in the EGFR-TKI treatment failure. The different generation EGFR-TKIs have variant potencies of penetrating into the blood-brain-barrier. This study aims to compare the efficacy of first- and third-generation EGFR-TKIs in preventing symptomatic CNS metastases and to identify their risk factors. Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis and receiving EGFR-TKI treatment were selected. The cumulative incidence of symptomatic CNS metastasis upon treatment failure, and overall survival (OS) of patients who developed CNS metastasis, were measured from the initiation of EGFR-TKIs, using the Kaplan-Meier method. The risk factors for CNS metastasis, and predictors of OS were identified using Cox proportional hazard regression. 935 patients from two academic medical centers were enrolled, with 633, 143 and 35 receiving first-line gefitinib, erlotinib and osimertinib, respectively, the remain 124 patients received osimertinib for acquired T790M mutation. On baseline, 19del, L858R and uncommon mutations were detected in 427, 386 and 122 patients, respectively. At the median follow-up of 10 months, treatment failure was observed in 517 patients, of whom 45 developed symptomatic CNS metastasis, with 37 developing BM, 4 LM, and 4 with both BM and LM. The 1-year, 2-year and 3-year cumulative rate of symptomatic CNS metastasis, were 4.2%, 7.9% and 14.4%, respectively. There was no significant difference in symptomatic CNS metastasis among patients receiving gefitinib or erlotinib, while osimertinib treatment was found to have a lower rate compared to first-generation TKIs (HR 0.45; 95%CI 0.20-0.99, p = 0.049). However, cumulative rate of symptomatic CNS metastasis at 3-year in osimertinib group reached the similar level as the first-generation TKIs. Of interest, the curves of CNS metastasis tend to reached a plateau after three years no matter which generation was used. Patients harboring L858R mutation were at a higher risk of developing CNS metastasis, than other mutations (p = 0.003). Among the 45 patients with CNS metastasis, median OS was 22 months, and patients with single cranial lesion had a significant longer OS (p = 0.011). Compared with first-generation EGFR TKIs, osimertinib significantly delays the development of symptomatic CNS metastasis in the EGFR-mutant advanced NSCLC without baseline CNS metastasis. L858R mutation is a risk factor for CNS failure during EGFR-TKIs treatment.

Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer

BackgroundOsimertinib is the treatment of choice for advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, novel strategies to improve the duration of disease control are still urgently needed. Aspirin has been shown to decrease cancer incidence and improve outcomes in various malignancies. Therefore, we evaluated a cohort of patients who received osimertinib with or without concurrent use of aspirin to assess whether the addition of aspirin may lead to improved clinical outcomes. MethodsMD Anderson Cancer Center GEMINI database was retrospectively queried for EGFR-mutant NSCLC patients who received osimertinib with or without concurrent use of aspirin for progression-free survival (PFS) and overall survival (OS). ResultsA total of 365 patients were identified including 77 which had concurrent use of aspirin. Patients in the aspirin-osimertinib group had significantly improved PFS (21.3 vs 11.6 months; HR, 0.52; 95 % CI, 0.38−0.70) and OS (Not reached vs 32.3 months; HR, 0.56; 95 % CI, 0.35−0.91) compared to osimertinib group. In subgroup analyses, the aspirin-associated PFS benefit was observed in patients with and without central nervous system (CNS) metastases, as well as in osimertinib first-line setting and in subsequent line setting. The median PFS in EGFR 19Del patients was longer than EGFR L858R patients with osimertinib, and when aspirin was added, the median PFS significantly improved in both groups regardless of lines of therapy. The benefit from aspirin was independent of age, gender, TP53 mutational status, or PD-L1 positivity. ConclusionConcurrent aspirin use with osimertinib in EGFR-mutant NSCLC patients was associated with improved survival, regardless of lines of therapy, CNS metastatic status, EGFR mutation type, age, gender, TP53, and PD-L1 status.

Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.

Identification and in silico structural insights of rare recurrent EGFR mutations as resistance mechanisms to osimertinib in EGFR-mutated lung cancer.

9531 Background: Inevitable progression on 3rd-generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib of EGFR-mutated lung cancer patients represents a great challenge in clinic. Previous studies have revealed that one-third of the resistant mechanisms are due to acquired EGFR secondary mutations, mainly on C797, L718 and L792 residues. Our study aims to gain insights into novel mechanisms of acquired resistance to osimertinib. Methods: We performed genomic profiling on a total of 1,058 EGFR-mutated lung cancer patients with progressed disease on osimertinib, and a cohort of 1,803 patients who received only 1st-generation EGFR TKIs upon progression. Recurrent EGFR mutations with a significant enrichment in the osimertinib group were identified. We further established and applied molecular dynamic simulation-based computational model of the mutant EGFR protein to predict its sensitivity to osimertinib. Results: As expected, compared with 1st-TKIs alone group, EGFR mutations, including C797S/G (22.1% vs. 0.5%), L718Q/V (6.2% vs. 0.3%), L792F/H (4.4% vs. 0.3%), were significantly more enriched in the osimertinib cohort. Our computational model has also successfully predicted their sensitivities to osimertinib: WT (-35.19 kcal/mol) &gt; L792F (-34.10 kcal/mol) &gt; L718Q (-30.33kcal/mol) &gt; C797S (-28.02 kcal/mol), which are consistent with our previous in vitro validations. Importantly, a total of 14 low-frequency EGFR mutations were exclusively observed in the osimertinib group, seven of which, including EGFR G796S(n = 6), V802F(n = 3), T725M(n = 2), Q791L/H(n = 2), P794S/R(n = 2), were predicted to dramatically reduce the binding affinity of osimertinib to EGFR. Of note, analysis of the pretreatment samples of two patients supported that EGFR V802F and Q791L/H were acquired during osimertinib treatment. Interestingly, EGFR G796S was predicted to be sensitive to gefitinib, suggesting the possibility of administration of gefitinib in patients with acquired EGFR G796S to first-line osimertinib treatment. Further in vitro functional validations are currently ongoing. Conclusions: Our study represents the largest EGFR-mutated lung cancer cohort so far to investigate osimertinib resistance in a real-world setting, and has uncovered a list of recurrent low-frequency EGFR mutations that may confer acquired resistance to osimertinib. Our in silico structural model was proved to be powerful and robust in the prediction of osimertinib sensitivity of EGFR mutants.