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AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials.

ABSTRACT: Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) constitute the standard of care for stage IV EGFR mutated non-small cell lung cancer (NSCLC) patients initiating first-line systemic treatment. Despite the initial remarkable activity of targeted treatment in these patients rendering objective response rates (ORR) of 50-80% and progression-free survivals (PFS) of 9-12 months, most patients present disease progression during the first 12 to 24 months. Although the activity of platinum-based doublets has been shown in EGFR mutated NSCLC patients after progression to first-line TKIs, PFS is rather short. Drug development companies have more recently focused their attention on the molecular basis of EGFR TKIs acquired resistance. Secondary resistance mutations have proven to be the most frequent cause of acquired resistance. Among them, T790M mutation in exon 20 seems to be the leading responsible for that resistance. Several agents have shown preliminary preclinical and clinical activity in overcoming acquired resistance to firstline EGFR TKIs. To date, however, only AZD9291, an oral, potent, irreversible EGFR TKI that is selective for EGFR tyrosine kinase inhibitor-sensitizing mutations and the T790M resistance mutation has shown to be not only highly active but also fairly tolerable in a large cohort of patients. Here we present a critical analysis of this trial in its clinical setting and propose some future directions.

SUBMITTER: Gil-Bazo I

PROVIDER: S-EPMC4758983 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials.

Gil-Bazo Ignacio I Rolfo Christian C

Translational lung cancer research 20160201 1

Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) constitute the standard of care for stage IV EGFR mutated non-small cell lung cancer (NSCLC) patients initiating first-line systemic treatment. Despite the initial remarkable activity of targeted treatment in these patients rendering objective response rates (ORR) of 50-80% and progression-free survivals (PFS) of 9-12 months, most patients present disease progression during the first 12 to 24 months. Although the activity ...[more]

PMID: 26958497

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Project description:PurposeThe great efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been identified in patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, it has not yet been established in postoperative adjuvant therapy.Patients and methodsTo compare the prognosis and toxicity of EGFR-TKI-based adjuvant therapy and non-EGFR-TKI-based adjuvant therapy in resected NSCLC with sensitive EGFR mutations, we performed this meta-analysis of all eligible randomized controlled trials (RCTs).ResultsA comprehensive literature search of electronic databases (from inception to December 31, 2017) was performed. Additionally, abstracts presented at the American Society of Clinical Oncology conferences and World Conference on Lung Cancer held between January 2000 and November 2017 were searched to identify relevant trials. Disease-free survival (DFS), overall survival (OS), and grade 3 or 4 toxicities were analyzed. Five RCTs were selected, and 560 participants were included. This meta-analysis demonstrated that EGFR-TKI-based adjuvant therapy was associated with better DFS compared with non-EGFR-TKI-based therapy (HR =0.52, 95% CI 0.34-0.78, P=0.002). Pooled estimate has showed the trend of superiority of EGFR-TKI-based therapy in the aspect of OS (HR =0.65, 95% CI 0.22-1.91, P=0.43); however, the difference was not significant. The incidence rate of grade 3-4 toxicities of EGFR-TKI-based regimens was significantly higher for rash (OR =10.17, 95% CI 2.37-43.63, P=0.002) but lower for vomiting (OR =0.08, 95% CI 0.01-0.61, P=0.02).ConclusionEGFR-TKI-based therapy was associated with better DFS compared with non-EGFR-TKI-based adjuvant therapy in patients with NSCLC harboring EGFR mutations. A trend was found that EGFR-TKI-based regimen improved the OS, though the difference was not significant. Although more OS data are needed, EGFR-TKI-based treatment has the potential to be an alternative of adjuvant therapy for NSCLC with a sensitive EGFR mutation.

Project description:BackgroundResults of several randomized clinical trials (RCTs) testing the combination of an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus an anti-angiogenic drug in advanced EGFR-mutated non-small cell lung cancer were reported.MethodsWe first report a systematic review and meta-analysis of all RCTs to estimate effectiveness and toxicity of this new therapeutic approach compared with first-generation EGFR-TKI monotherapy. Subsequently, we present a network meta-analysis comparing the combination of an EGFR-TKI plus an anti-angiogenic drug with 2 new treatment options: combination of an EGFR-TKI plus chemotherapy or new EGFR-TKIs of second or third generation as monotherapy.ResultsFive RCTs were included in the first meta-analysis. The progression-free survival (PFS) was statistically significantly larger in patients treated with an EGFR-TKI plus an anti-angiogenic drug compared with EGFR-TKI monotherapy: the pooled PFS-hazard ratio (HR) was 0.59 (95% confidence interval [CI] = 0.51 to 0.69). The pooled median-PFS was 17.8 months (95% CI = 16.5 to 19.3 months) for the combination vs 11.7 months (95% CI = 11.1 to 12.7 months) for EGFR-TKI as monotherapy. No statistically significant differences between the 2 treatment arms were observed in overall survival or objective response rate. The rate of grade equal or higher than 3 adverse events was statistically significantly higher in patients treated with EGFR-TKI plus an anti-angiogenic drug: the pooled-relative risk was 1.72 (95% CI = 1.43 to 2.06). Ten RCTs were included in the network meta-analysis. All 3 experimental treatments were associated with a statistically significant improvement in PFS compared with first-generation EGFR-TKIs. When compared to each other, none of the 3 experimental treatments were statistically significantly associated with larger PFS or lower rate of grade 3 or higher adverse events.ConclusionPatients with EGFR-mutated non small-cell lung cancer derived clinically meaningful larger PFS benefit from the addition of an anti-angiogenic drug to a first-generation EGFR-TKI at the cost of an increase of toxicities.

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AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials.

Publications

AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials.

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