Safety of osimertinib plus chemotherapy in EGFR-mutant NSCLC.

Piotrowska, Zofia; Liu, Stephen V.; Muzikansky, Alona; Marcoux, Nicolas; Banwait, Mandeep K.; Stevens, Sara E.; Goodwin, Kelly; Lafferty, Tracey E; Ackil, Jennifer; Krueger, Elizabeth; Heist, Rebecca S.; Lin, Jessica J.; Gainor, Justin F.; Hata, Aaron N.; Shaw, Alice T.; Sequist, Lecia V.

doi:10.1200/jco.2018.36.15_suppl.e21231

Cited by 9 publications

(5 citation statements)

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“…96 Furthermore, preliminary results have shown that the addition of platinum-based chemotherapy to osimertinib therapy is well tolerated in EGFR-TKI pre-treated patients. 97,98 A Phase 1 study of carboplatin/etoposide plus osimertinib in EGFR-mutated patients with concurrent RB1 and TP53 alterations-in order to prevent SCLC transformation-is currently ongoing (NCT03567642). Taking into account the positive OS results derived from the addition of chemotherapy to first-generation TKIs for the first-line treatment of patients with EGFR-mutated NSCLC, 99 randomised trials exploring osimertinib combined with chemotherapy in the same clinical setting are needed.…”

Section: Pi3k Pathway Activationmentioning

confidence: 99%

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

et al. 2019

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Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR-dependent as well as EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-line setting, underlying the discrepancies in selection pressure and clonal evolution. This review summarises the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR-mutated NSCLC, including MET/HER2 amplification, activation of the RAS–mitogen-activated protein kinase (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events and histological/phenotypic transformation, as well as discussing the current evidence regarding potential new approaches to counteract osimertinib resistance.

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Section: Pi3k Pathway Activationmentioning

confidence: 99%

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

et al. 2019

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“…The study showed that the addition of chemotherapy to osimertinib was generally well tolerated without producing a significant impact on patients' survival. A retrospective analysis of 18 EGFR-positive advanced NSCLC patients treated with the combination of osimertinib plus different chemotherapy regimens, confirmed a tolerable profile, showing a median duration of treatment comparable to that observed with osimertinib alone within the AURA3 trial (49). Preliminary safety data from the first 30 patients enrolled within the FLAURA2 study did not reveal new toxicity signals, supporting further investigation of osimertinib plus chemotherapy combinations in the upfront setting.…”

Section: Developing Effective and Tolerable Upfront Combinationsmentioning

confidence: 63%

Optimizing the clinical management of EGFR-mutant advanced non-small cell lung cancer: a literature review

Passiglia¹,

Bironzo²,

Bertaglia³

et al. 2022

Transl Lung Cancer Res

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Background and Objective: Despite several steps forward in the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however there are still pending issues and upcoming challenges requiring adequate addressing in order to optimize the clinical management of metastatic patients harboring molecular alterations within the EGFR gene. This review aims to summarize the most recent findings regarding the diagnostic testing and therapeutic strategies of EGFR-mutant advanced NSCLC.

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“…A retrospective study showed that osimertinib-based combination had better overall survival (OS) than cytotoxic chemotherapy (not achieved vs.7.8 months; 95% CI 0.17–0.89, P <0.05) [ 14 ]. However, studies have shown that the median duration of treatment (mDOT) of osimertinib combined with chemotherapy was not significantly longer than that of chemotherapy alone [ 15 , 16 ]. In the phase Ib TATTON study, osimertinib combined with the PD-L1 inhibitor durvalumab was discontinued because of serious adverse effects, such as interstitial pneumonia (38%).…”

Section: Introductionmentioning

confidence: 99%

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

Han,

Guo,

Shi

et al. 2024

BMC Med

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Background Osimertinib 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. Methods We 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. Results Totally 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. Conclusions In 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.

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Safety of osimertinib plus chemotherapy in EGFR-mutant NSCLC.

Cited by 9 publications

References 0 publications

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Optimizing the clinical management of EGFR-mutant advanced non-small cell lung cancer: a literature review

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

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