Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment

Su, Po‐Lan; Tsai, Jeng‐Shiuan; Yang, Sheng‐An; Wu, Yi Lin; Tseng, Yau‐Lin; Chang, Chao‐Chun; Yen, Yi‐Ting; Lin, Chia-Ying; Lin, Chien‐Chung; Wang, Chin‐Chou; Lin, Meng-Chih; Su, Wu‐Chou

doi:10.1016/j.lungcan.2021.06.014

Cited by 8 publications

(8 citation statements)

References 30 publications

(25 reference statements)

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“…The negative result presented may be caused by on-targeted resistance not taking into consideration. A retrospective study in T790M-positive osimertinib-refractory patients treated with osimertinib combined with chemotherapy yielded better OS than chemotherapy [119]. The same as IMPRESS study, the COMPEL study is to investigate continued osimertinib combined with chemotherapy versus mono-chemotherapy after first-line osimertinib progresses (NCT04765059) promisingly.…”

Section: Chemotherapy and Antiangiogenic Therapymentioning

confidence: 99%

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Zeng

Tian

et al. 2021

Current Opinion in Oncology

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Purpose of reviewThis review aims to introduce the resistance mechanisms to osimertinib, discuss the therapeutic strategies, and make clinical updates in overcoming resistance to osimertinib. Recent findingsOsimertinib has shown favorable efficacy on second-line and first-line treatments in EGFR-mutant advanced nonsmall cell lung cancer (NSCLC). However, the presence of primary and acquired resistance to osimertinib restricts its clinical benefits. The primary resistance mainly consists of BIM deletion polymorphism and EGFR exon 20 insertions. Meanwhile, the heterogeneous mechanisms of acquired resistance include EGFR-dependent (on-target) and EGFR-independent (off-target) mechanisms. EGFR C797S mutation, MET amplification, HER2 amplification, and small cell lung cancer transformation were identified as frequent resistance mechanisms. Recently, more novel mechanisms, including rare EGFR point mutations and oncogenic fusions, were reported. With the results of completed and on-going clinical trials, the emerging therapeutic strategies of postosimertinib progression are summarized.

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Section: Chemotherapy and Antiangiogenic Therapymentioning

confidence: 99%

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Zeng

Tian

et al. 2021

Current Opinion in Oncology

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“…Osimertinib ( Figure 1 ), is a standard first-line treatment option for patients with advanced EGFR T790 M-mutated NSCLC, effectively extending survival and improving patients’ life quality [ 6 , 7 ]. Subsequently, aumolertinib and furmonertinib ( Figure 1 ) were approved in China for treating advanced EGFR T790 M-mutated NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Li¹,

Ma³

et al. 2022

Molecules

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The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, and furmonertinib represent a new treatment option for patients with EGFR p.Thr790 Met (T790 M)-mutated non-small cell lung cancer (NSCLC). Currently, there are no studies reporting the simultaneous quantification of these three drugs. A simple ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of osimertinib, aumolertinib, and furmonertinib concentrations in human plasma, and it was applied for therapeutic drug monitoring (TDM). Plasma samples were processed using the protein precipitation method (acetonitrile). A positive ion monitoring mode was used for detecting analytes. D3-Sorafenib was utilized as the internal standard (IS), and the mobile phases were acetonitrile (containing 0.1% formic acid) and water with gradient elution on an XSelect HSS XP column (2.1 mm × 100.0 mm, 2.5 µm, Waters, Milford, MA, USA) at a flow rate of 0.5 mL·min−1. The method’s selectivity, precision (coefficient of variation of intra-day and inter-day ≤ 6.1%), accuracy (95.8–105.2%), matrix effect (92.3–106.0%), extraction recovery, and stability results were acceptable according to the guidelines. The linear ranges were 5–500 ng·mL−1, 2–500 ng·mL−1, and 0.5–200 ng·mL−1 for osimertinib, aumolertinib, and furmonertinib, respectively. The results show that the method was sensitive, reliable, and simple and that it could be successfully applied to simultaneously determine the osimertinib, aumolertinib, and furmonertinib blood concentrations in patients. These findings support using the method for TDM, potentially reducing the incidence of dosing blindness and adverse effects due to empirical dosing and inter-patient differences.

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“…Aside from targeted therapy, chemotherapy and the addition of antiangiogenic inhibitors to EGFR-TKI therapy after progression are also alternative strategies. Studies have shown that patients with resistance to osimertinib derived prolonged clinical benefits from the continuous use of osimertinib alone or in combination with radiotherapy or chemotherapy ( Le et al, 2018 ; Su et al, 2021 ; White et al, 2021 ). However, it has not been elucidated whether the combination of osimertinib and bevacizumab is beneficial after the progress of osimertinib.…”

Section: Discussionmentioning

confidence: 99%

Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

Cui

Qing-an

et al. 2022

Front. Pharmacol.

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At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non–small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252–0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266–0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.

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Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment

Cited by 8 publications

References 30 publications

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

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