Osimertinib Improves Response in T790M+ NSCLC With CNS Metastases

Marina Chiara Garassino, MD

Patients with T790M-positive non—small cell lung cancer (NSCLC) had superior outcomes when treated with osimertinib (Tagrisso) for central nervous system (CNS) metastases, according to phase III results presented at the 2017 ASCO Annual Meeting.

Marina Chiara Garassino, MD, chief of the thoracic oncology unit at the National Cancer Institute of Milan, Italy, presented data from a subset analysis of patients with CNS metastases participating in the AURA3 trial. AURA3 is a randomized, international, open-label trial evaluating osimertinib in patients with T790M-positive advanced NSCLC who progressed after first-line EGFR-TKI therapy.

“The majority of patients had shrinkage in the brain metastases,” she said. “Despite the small number of patients, you can observe, that in the osimertinib group, responses are more frequent and deeper compared to chemotherapy.”

In patients with CNS evaluable for response (n = 46), CNS overall response rate (ORR) was 70% with osimertinib compared with 31% for patients treated with platinum-based doublet chemotherapy (odds ratio [OR], 5.13; 95% CI, 1.44-20.64; P = .015). In the full analysis population (N = 416), CNS progression-free survival (PFS) also favored the osimertinib group, 11.7 months versus 5.6 months (HR, 0.32; 95% CI 0.15-0.69; P = .004).

Median time to response was 6.1 weeks in both treatment groups, but overall duration was significantly greater in the osimertinib group, 8.9 months versus 5.7 months. Disease control rate was 93% (95% CI, 78-99) in the experimental group compared with 63% (95% CI, 35-85) in the control group.

CNS metastases are common in patients with EGFR-positive NSCLC—Garasinno said up to 40% of patients will develop such metastases over the course of their disease. She added that prognosis is poor for these patients, with a median PFS of 3 months to 6 months.

In AURA 3, patients were assigned to 80 mg of oral osimertinib daily or platinum-pemetrexed chemotherapy every 21 days for up to 6 cycles. In the group of patients with ≥1 measurable CNS metastasis, termed the CNS evaluable for response set (cEFR), 30 patients received osimertinib and 16 received chemotherapy.

In what Garassino called the CNS full analysis set (cFAS), 75 patients were assigned to the experimental group and 41 were assigned to chemotherapy. Data cutoff was April 15, 2016.

In the cFAS group, CNS ORR was 40% (95% CI 29-52) with osimertinib and 17% (95% CI 7-32) with chemotherapy (OR, 3.24; 95% CI 1.33-8.81; P = .014).

Among patients in the cFAS population who had radiotherapy to the brain within 6 months of entering the trial, CNS ORR was 64% (95% CI, 35-87) for patients assigned to osimertinib (n = 14) compared with 22% (95% CI, 2-60) for patients assigned to chemotherapy (n = 9).

For cFAS patients who did not have radiotherapy or had radiotherapy ≥6 months before enrollment, CNS ORR was 34% (95% CI, 23-48) for patients assigned to osimertinib (n = 61) versus 16% (95% CI, 5-33) for those assigned to chemotherapy (n = 32).

“If we overlap the curves of patients with CNS metastases, you can observe that for chemotherapy, patients with brain metastases fair worse, as expected,” Garassino said. “But you can observe that the curves of patients with brain metastases treated with osimertinib are very similar to those without brain metastases, suggesting that osimertinib is able to convert the prognosis of patients with brain metastases to similar to patients without brain metastases.”

In 2015, the FDA granted osimertinib an accelerated approval in this patient population based on data from 411 patients in two single-arm studies.

In the first study, AURA2, ORR was 61% (95% CI, 54-68) for patients with pretreated EGFR T790M-mutant NSCLC assigned to osimertinib (n = 210). In the second trial, an extension to the AURA study, ORR was 57% in 201 patients. In a pooled-analysis of the 2 studies, the ORR with osimertinib was 59% and duration of response was 12.4-months.

In February 2016, the European Commission (EC) granted a conditional marketing authorization to osimertinib for patients regardless of prior treatment with EGFR TKI.

Mok T, Ahn M, Han J, et al. CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3). J Clin Oncol. 2017;35 (suppl; abstr 9005).