Frontline Osimertinib Approaches 80% Response in EGFR+ NSCLC

Jason M. Broderick @jasoncology
Published: Thursday, Apr 14, 2016

Suresh S. Ramalingam, MD

Suresh S. Ramalingam, MD

First-line treatment with single-agent osimertinib (Tagrisso) induced a response rate of 77% in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to phase I data1 presented at the 2016 European Lung Cancer Conference (ELCC).

The median progression-free survival (PFS) was 19.3 months for patients receiving osimertinib at 160 mg once daily (n = 30) and was not yet reached for patients receiving the third-generation EGFR TKI at a dose of 80 mg once daily (n = 30). The median duration of response was 16.7 months with 160 mg and non-calculable in the 80-mg group.

“The overall response rate was among the best reported for first-line therapy of EGFR-mutated NSCLC,” lead author Suresh Ramalingam, MD, professor of Hematology and Medical Oncology at Emory School of Medicine and deputy director of Winship Cancer Institute, said in a statement.

“The PFS results are exciting, well exceeding the historical control rates of 10 to 13 months with first or second generation drugs. Many of the patients have not had disease progression on the study and are still benefitting from treatment.”

Osimertinib (80 mg once daily) is currently approved by the FDA for patients with advanced EGFR T790M mutation–positive NSCLC following progression on an EGFR TKI. Updated data2 were also presented at the ELCC for the drug in this setting.

The frontline findings came from a study comprising 60 treatment-naïve patients with locally advanced or metastatic EGFR+ NSCLC from 2 phase I expansion cohorts of the phase I/II AURA trial. Seventy-five percent of patients were female and 72% were Asian. Patients had a WHO performance status of 0 to 1 and were still eligible if they had asymptomatic brain metastases.

EGFR mutation status was determined through local and/or central laboratory testing (cobas EGFR Mutation Test). Forty percent of patients had EGFR exon 19 deletions and 42% had L858R mutations. There were 5 patients with EGFR T790M mutations at the start of the study.

The median follow-up was 16.6 months at the January 4, 2016, data cutoff. The overall response rate (ORR) was 67% (95% CI, 47-83) and 87% (95% CI, 69-96) in the 80- and 160-mg groups, respectively. The overall disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) was 97% (95% CI, 88.5-99.6), including 93% (95% CI, 78-99) and 100% (95% CI, 88-100) in the 80- and 160-mg cohorts, respectively.

Overall, 72% of patients were alive and progression-free at 12 months, including 75% of patients in the 80-mg arm and 69% of patients in the 160-mg arm. Fifty-five percent of patients were progression-free at 18 months, including 57% and 53% in the lower- and higher-dose cohorts, respectively.

Outcomes were also reported for the 5 patients with T790M mutations at diagnosis. All 5 patients had a PR with a response duration ranging from 12.2 to 20.7 months. Ramalingam said these data may help explain the favorable efficacy of frontline osimertinib, which targets the T790M mutation. “We may be changing the biology of the disease with the use of first-line osimertinib.”

Dose reductions to manage AEs were needed for 3 patients (10%) in the lower-dose arm and 14 patients (47%) in the higher-dose cohort. “Overall, we found that the 80-mg dose was better tolerated than the 160-mg dose,” Ramalingam said at a press conference held during the ELCC by AstraZeneca, the manufacturer of osimertinib.

The most common all-grade adverse events (AEs) were rash (70% with 80 mg; 87% with 160 mg), diarrhea (60%, 87%), dry skin (57%, 60%), stomatitis (43%, 50%), and paronychia (37%, 63%). Grade ≥3 AEs for the 160-mg arm included diarrhea (7%), paronychia (7%), rash (3%), and stomatitis (3%). One patient in the 80 mg-arm had grade ≥3 nausea.

The ongoing phase III FLAURA study is further examining these early-stage findings. In the double-blind trial, treatment naïve patients with EGFR+ locally advanced or metastatic NSCLC will be randomized to either osimertinib (80 mg or 40 mg orally once daily) or a standard of care EGFR TKI—erlotinib (Tarceva) or gefitinib (Iressa).

“The results with osimertinib in the first-line look promising. The ongoing randomized trial will define the role of osimertinib in the treatment of EGFR mutated patients who are treatment-naïve,” Enriqueta Felip, MD, PhD, a medical oncologist at Vall d`Hebron University Hospital in Barcelona, Spain, who was not directly involved with the study, commented in an ELCC release.

Update Confirms Results in Pretreated Patients

New osimertinib data presented at ELCC confirmed the drug’s efficacy for its approved indication in patients with EGFR T790M mutation–positive NSCLC who progressed on an EGFR TKI.

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