OSIMETRINIB FOR T970M+ NSCLC

VIENNA — For patients with non-small cell lung cancer (NSCLC) carrying the specific T790M mutation in the epidermal growth factor receptor (EGFR) gene, there is now a new standard of care, say experts.

The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso, AstraZeneca Pharmaceuticals) is now the standard of care for patients with NSCLC and the acquired genetic resistance who had previously been treated with an EGRF inhibitor, experts said here at the International Association for the Study of Lung Cancer's 17th World Conference on Lung Cancer (WCLC).

They were discussing results from the AURA3 trial, presented at the meeting and published simultaneously in The New England Journal of Medicine, which show that in these patients, osimertinib improved progression-free survival (PFS) by 5.7 months compared with chemotherapy.

Osimertinib was approved in Europe earlier this year for the treatment of patients with locally advanced or metastatic NSCLC that is positive for the EGFR T790M mutation, which is found in 40% of Asian patients and 15% of Western patients. The drug was also approved in the United States in November 2015 on the same basis.

The current results from AURA 3 build on those from the AURA extension and AURA2 studies that formed the basis of those approvals. As previously reported by Medscape Medical News, these studies showed that osimertinib was highly active when used both as a first-line treatment in locally advanced or metastatic NSCLC and as a second-line treatment in NSCLC.

Discussing the new results here at a press conference, Vassiliki A. Papadimitrakopoulou, MD, Department of Thoracic–Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, said that the findings were "very exciting news for our patients."

"It is the confirmatory trial," she said. "It is the first trial of its kind to actually compare standard-of-care chemotherapy with a third-generation EGFR-TKI, [and] there was an overwhelming benefit from osimertinib."

Specifically, the drug achieved an "impressive benefit" in terms of PFS, at a hazard ratio of less than 0.5 across all predefined subgroup analyses, including Asian versus non-Asian ethnicity and by EGFR-TKI sensitizing status before the start of treatment.

Dr Papadimitrakopoulou added: "There was an overwhelming benefit for patients with central nervous system [CNS] metastasis. The hazard ratio for these patients was 0.32, and for patients without CNS metastasis, it was 0.40."

She said, "There should be no question, based on [an overall] PFS hazard ratio of 0.30 and PFS of 10.1 months, 5.7 months more than chemotherapy, what we should be giving to our patients in this setting…. In the setting of CNS metastasis, it is also very impressive, and we can now officially call this the 'standard of care' for these patients."

However, Dr Papadimitrakopoulou emphasized that the benefit can be realized only if patients undergo tumor or liquid biopsy to determine their T790M mutation status.

"What is most important, and what oncologists need to remember, is that to actually deliver this treatment, you need to do the test," she said. "You need to find the T790M to offer the best therapy to your patients, so that should be an impetus for us to test the tumor or the plasma.

Discussing the study after its presentation, Tetsuya Mitsudomi, MD, PhD, Department of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan, agreed that osimertinib is now 'officially' the standard of care for patients with acquired resistance via T790M.

He highlighted the more than doubling of median PFS with the drug and the activity in patients with brain metastases, as well as its relatively low toxicity.

Dr Mitsudomi also agreed with Dr Papadimitrakopoulou that rebiopsy of patients with NSCLC is important but noted that it "is not always very easy." Citing a recent paper from Japan, he pointed out that of 120 patients eligible for rebiopsy and EGFRmutation analysis, "only about 50% had the mutation test."

"So the importance of liquid biopsy is evident and it's imperative that it should be encouraged," he said.

Dr Mitsudomi also noted some other issues that will have to be addressed in the future. These include the optimal sequence of different EGFR-TKIs, as well as the development of a "strategy to cope with acquired resistance against osimertinib" because "even with osimertinib, cancer cells become resistant in the end."

Study Details 

AURA3 was a randomized, open-label, phase 3 trial conducted in 419 patients with T790M-positive advanced NSCLC and disease progression after first-line EGFR-TKI therapy. They were randomly assigned in a 2:1 ratio to oral osimertinib (80 mg once daily) or intravenous pemetrexed (500 mg/m² body surface area) plus carboplatin (at a target area under the curve of 5) or cisplatin (75 mg/m²) every 3 weeks for up to 6 cycles.

A total of 419 patients were randomly assigned, with 279 patients given osimertinib and 140 treated with standard-of-care chemotherapy. The median age of the patients was 62 and 63 years, respectively; 62% and 69% were female; and 65% and 66% were of Asian ethnicity.

One third (33%) of patients receiving osimertinib and 36% receiving chemotherapy had CNS metastases, and most patients had received just one prior anticancer treatment regimen (96% in both groups).

The median duration of PFS on investigator assessment was significantly longer with osimertinib than with chemotherapy, at 10.1 months vs 4.4 months, with a hazard ratio of 0.30 (P < .001).

The objective response rate also significantly improved with osimertinib vs chemotherapy, at 71% and 31%, respectively, and an odds ratio of 5.39 (P < .001). The mean duration of objective response was 9.7 months and 4.1 months, respectively.

When the investigators looked at patients with CNS metastases, the median duration of PFS was 8.5 months with osimertinib vs 4.2 months with chemotherapy, with a hazard ratio of 0.32. Among patients without CNS metastases, the median PFS was 10.8 months and 5.6 months, respectively, with a hazard ratio of 0.40.

Crucially, osimertinib was associated with a significant survival benefit over chemotherapy in both Asian and non-Asian patients (at respective hazard ratios of 0.32 and 0.48) and in patients with the Exon 19 deletion EGF-TKI–sensitizing mutation and in those with the L858R EGF-TKI–sensitizing mutation before study entry (at respective hazard ratios of 0.34 and 0.46).

The authors, led by Tony Mok, MD, PhD, from the Chinese University in Hong Kong, also report that the proportion of patients with grade 3 or higher adverse events was lower with osimertinib than with chemotherapy, at 23% vs 47%, and the study drug was linked to a lower rate of adverse events leading to discontinuation, at 7% vs 10%.

The most commonly reported adverse events with osimertinib were diarrhea (41%), rash (34%), and dry skin (23%). With chemotherapy, the most commonly reported events were nausea (49%), constipation (35%), and anemia (30%).

An important aspect of the study was that patients were screened for the T790M mutation using a liquid biopsy measuring plasma circulating (ct)DNA. The team writes: "The findings of AURA3 support the feasibility of detecting EGFR T790M from plasma ctDNA samples, in line with previous reports.

"However, because of the high false negative rates with plasma ctDNA T790M testing, the analysis of a biopsy sample is recommended for patients with a plasma T790M-negative result who have disease progression after receiving first-line EGFR-TKI," they add.

The study was funded by AstraZeneca. Dr. Papadimitrakopoulou reports personal fees from AstraZeneca outside the submitted work, alongside consultancy work for AstraZeneca, ARIAD, BMS, Genentech, and Biothera, among others, and the receipt of numerous grants and/or research support. Other authors report several disclosures. Dr Mitsudomi also reports the receipt of grants/research support and honoraria from AstraZeneca, as well as acting in and advisory role for the company, among other disclosures. 

17th World Conference on Lung Cancer (WCLC). Abstract PL03.03. Presented December 6, 2016.

N Engl J Med. Published online December 6, 2016. Abstract