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Pasi A Jänne1, James Chih-Hsin Yang, Dong-Wan Kim
1From the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston (P.A.J.); National Taiwan University and National Taiwan University Hospital (J.C.-H.Y.) and Cheng Kung University Hospital (W.-C.S.) - both in Taipei, Taiwan; Seoul National University Hospital (D.-W.K.), Samsung Medical Center (M.-J.A.), Asan Medical Center (S.-W.K.), and Yonsei Cancer Center, Yonsei University Health System (J.-H.K.) - all in Seoul, South Korea; Institut Gustave Roussy, Villejuif, France (D.P.); National Cancer Center Hospital, Tokyo (Y.O.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Vanderbilt Ingram Cancer Center, Nashville (L.H.); Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC (D.H.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (E.F.); and AstraZeneca, Macclesfield (P.F., M.C., K.H.B., P.A.D., S.G.), and University of Manchester, Christie Hospital, Manchester (M.R.) - both in the United Kingdom.
Background:
The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations.
Methods:
We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy.
Results:
A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients.
Conclusions:
AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).
Insights
AZD9291 shows high activity in patients with lung cancer harboring the EGFR T790M mutation. This EGFR inhibitor is effective in treating resistance mutations after prior EGFR tyrosine kinase inhibitor therapy.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- The EGFR T790M mutation is a primary cause of resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated lung cancer.
- Preclinical studies indicated AZD9291's efficacy against both sensitizing and T790M resistance mutations.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and efficacy of AZD9291 in patients with advanced lung cancer who progressed on prior EGFR tyrosine kinase inhibitors.
- To assess AZD9291's activity in relation to EGFR T790M mutation status.
Main Methods:
- A phase I/II study involving dose-escalation and dose-expansion cohorts.
- AZD9291 administered at doses of 20-240 mg once daily.
- Tumor biopsies were used for central EGFR T790M mutation status determination.
Main Results:
- 253 patients were treated; no dose-limiting toxicities observed in dose-escalation.
- Overall objective response rate was 51%.
- Response rate was 61% in EGFR T790M-positive patients versus 21% in EGFR T790M-negative patients. Median progression-free survival was 9.6 months vs. 2.8 months, respectively.
Conclusions:
- AZD9291 demonstrated high activity in EGFR T790M-positive lung cancer patients progressing on prior EGFR tyrosine kinase inhibitors.
- The drug is effective in patients with acquired resistance mutations.
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