Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study

Ramalingam, Suresh S.; Cheng, Yi; Zhou, C.; Ohe, Y.; Imamura, Fumio; Cho, B.C.; Lin, Meng-Chih; Majem, Margarita; Shah, Riyaz; Rukazenkov, Yuri; Todd, Alexander; Markovets, Aleksandra; Barrett, J. Carl; Chmielecki, Juliann; Gray, Jhanelle E.

doi:10.1093/annonc/mdy424.063

Cited by 313 publications

(386 citation statements)

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“…The successful suppression of the T790M tumor clone by the front-line use of osimertinib can also be suggested by the subsequent mechanisms of acquired resistance in which the T790Mmediated resistance can no longer be identified. 26 In line with the above mentioned context, an in vitro study has shown that ceritinib was highly active against tumor clones L1196M, G1269A, C1156Y and I1171T/N/S, which were the top four crizotinib-resistant mechanisms associated with the acquired ALK mutations. [27][28][29] Therefore, the early eradication of these tumor clones by the front-line administration of ceritinib may explain the better therapeutic efficacy, especially a favorable control of systemic progression, than the front-line use of crizotinib.…”

Section: Discussionmentioning

confidence: 81%

“…Given osimertinib is a highly active agent for the treatment of gefitinib/erlotinib‐resistant T790M tumor clone, the front‐line administration of osimertinib allows the early eradication of T790M part within an EGFR ‐mutated tumor and thereby significantly improves tumor control relative to the front‐line use of gefitinib/erlotinib. The successful suppression of the T790M tumor clone by the front‐line use of osimertinib can also be suggested by the subsequent mechanisms of acquired resistance in which the T790M‐mediated resistance can no longer be identified …”

Section: Discussionmentioning

confidence: 99%

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Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Huang

Wang

et al. 2019

Thoracic Cancer

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BackgroundApproximately 3%–5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum‐based chemotherapy as front‐line treatment for patients with ALK‐positive advanced non‐small cell lung cancer (NSCLC). However, the direct comparison between them in the front‐line setting remains lacking.MethodsA total of 48 patients with ALK‐positive, previously untreated advanced NSCLC, who received crizotinib and ceritinib as front‐line treatment were retrospectively investigated. The efficacy and pattern of disease progression were analyzed.ResultsPatients receiving ceritinib treatment were significantly younger than those receiving crizotinib treatment (52.0 vs. 63.0, P = 0.016). The median progression‐free survival (PFS) was significantly longer with ceritinib than with crizotinib treatment (32.3 vs. 12.9 months; log‐rank P = 0.020); the hazard ratio for disease progression or death, 0.27 (95% CI, 0.08–0.90; P = 0.033). An objective response was noted in all patients in the ceritinib group and in 23 patients in the crizotinib group (74.2%; 95% CI, 59.0 to 88.5). The rate of systemic progression was significantly lower over time with ceritinib treatment compared to crizotinib treatment (cause‐specific hazard ratio, 0.21; 95% CI 0.06–0.73; P = 0.014). Serious adverse events were noted in one (2.9%) patient showing elevated liver function in the crizotinib group and three (23.1%) patients showing diarrhea in the ceritinib group. Dose reduction was needed in five out of 13 (38.5%) patients receiving ceritinib treatment.ConclusionCeritinib showed higher efficacy associated with a better control of systemic progression compared to crizotinib for the front‐line treatment of ALK‐positive advanced NSCLCs.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Huang

Wang

et al. 2019

Thoracic Cancer

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“…This is underpinned by concerns on the potential impact of selective pressures imposed by 3G TKI, best revealed by emerging understanding of resistance mechanisms. Multiple studies have attempted to characterize resistance to osimertinib, with a range of different mechanisms described to date [16][17][18][19][20]. These include EGFR dependent mechanisms and non-canonical mechanisms such as alternative bypass pathway activation and histological changes.…”

Section: Should All Patients Receive Upfront 3 Rd Generation Egfr Tki?mentioning

confidence: 99%

Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

Tan

Teh

Lai

et al. 2019

Expert Review of Anticancer Therapy

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“…This is important, as third-generation inhibitors such as osimertinib are therapeutic options in first-line therapy for EGFR-mutant patients [66]. Using liquid biopsy, MET amplifications (15%) and EGFR mutations such as C797S (7%) have been reported as the major resistance mechanisms to osimertinib and this finding can enable clinical trials with targeted therapies according to the genomic profile during progression using NGS [67].…”

Section: Detecting Resistance Mechanismsmentioning

confidence: 99%

Liquid biopsy in oncology: a consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

et al. 2019

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The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is growing considerably. The diagnosis of these genomic alterations can lead to tailored treatment at the onset of disease or on progression and to obtaining additional predictive information on immunotherapy efficacy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, which includes liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and captures intra-patient genomic heterogeneity as well. To date, there are several diagnostic techniques available for use in liquid biopsy, each one of them with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology is to evaluate the viability and effectiveness of the different methodological approaches in liquid biopsy in cancer patients and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures, to ensure reproducibility and generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular boards to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.

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Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study

Cited by 313 publications

References 0 publications

Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

Liquid biopsy in oncology: a consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

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