Frontline Osimertinib Approaches 80% Response in EGFR+ NSCLC

First-line treatment with single-agent osimertinib (Tagrisso) induced a response rate of 77% in patients with EGFR-mutated non–small cell lung cancer.

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).

Update Confirms Results in Pretreated Patients

“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.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.

At the 80-mg recommended dose in this setting, the ORR was 71% (95% CI, 57-82) in a phase I dose expansion cohort (n = 63) and 66% (95% CI, 61-71) in a pooled analysis of 411 patients from 2 phase II studies. The median PFS was 9.7 months (95% CI, 8.3-13.6) and 11 months (95%, CI 9.6-12.4) for the expansion cohort and pooled results, respectively.

“In this mature pooled analysis for T790M-positive EGFR-mutant patients who have progressed on prior EGFR TKI, we were able to show a high overall response rate, encouraging duration of response, and good tolerability profile. PFS was long compared to the 4 to 5 months provided by chemotherapy,” lead author James Yang, MD, PhD, said in a statement.

“This is good news for patients with EGFR mutations who have failed EGFR TKI, for whom osimertinib is now standard of care. Molecular diagnosis for T790M must now be the standard, as well,” added Yang, who is director of the Department of Oncology and Department of Medical Research in the National Taiwan University Hospital, Taipei.

The pooled cohort included 210 patients from the phase II AURA2 study and 201 patients from the phase II part of the phase I/II AURA trial. The initial data for these 411 patients were evaluated by the FDA in granting the accelerated approval to osimertinib in the pretreated setting. The 63-patient group was an expansion cohort from the phase I part of the AURA trial.

All 474 patients in the analysis had T790M-positive advanced NSCLC and had progressed on an EGFR TKI. Over 60% of the patients were female and over two-thirds were never-smokers. The median age was 60 and 63 years in the phase I and phase II groups, respectively.

The disease control rate (CR + PR + SD + progressive disease) was 93% (95% CI, 84-98) in the phase I group and 91% (95% CI, 88-94) in the pooled phase II cohort. The median duration of response was 9.6 months and 12.5 months, respectively. The maximum duration of response was 26.3+ months in the phase I group and 15.3+ months in the pooled phase II analysis.

In the phase I cohort, 41, 29, and 17 patients were progression-free at 12, 18, and 24 months, respectively. In the pooled analysis, 48 patients were progression-free at 12 months and results were not reported for 18 or 24 months.

The most common all-grade AEs included rash (37% in the phase I group; 41% in the pooled phase II group), diarrhea (35%, 38%), paronychia (29% each), and dry skin (22%, 30%). In the phase I group, grade ≥3 AEs included diarrhea (n = 2) and paronychia (n = 2). Grade ≥3 AEs in the pooled analysis included rash (n = 3) and diarrhea (n = 2).

“Of note, is that some of these patients [receiving osimertinib] developed interstitial lung disease, which is a class effect for this kind of drug, and some patients developed QT prolongation,” Yang said when presenting at the AstraZeneca press conference. He added that the occurrence of these events was infrequent and similar to rates reported in previous analyses.

Commenting on the findings, Felip said in statement, “The study confirms the good results with osimertinib in this setting. Nowadays, in patients with an EGFR mutation who progress after an EGFR TKI, there is a clear need for T790M testing since we now have a highly active agent, osimertinib, for this situation.”

  1. Ramalingam S, Yang JC, Lee CK, et al. Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two phase I expansion cohorts. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract LBA 1.
  2. Yang JC, Ramalingam S, Jänne PA, et al. Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated phase 1 (p1) and pooled phase 2 (p2) results. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract LBA 2.


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