Conference Coverage

VIDEO: Pivotal results nail osimertinib’s role in NSCLC

Publish date: December 7, 2016
By
Mitchel L. Zoler, PhD
MDedge News

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Osimertinib now standard of care

Osimertinib overcomes the T790M mutation, which is the cause of about half of the non–small-cell lung cancers that are EGFR positive and develop resistance to a first- or-second generation tyrosine kinase inhibitor. The AURA3 results officially make osimertinib the standard of care for these patients.

Osimertinib’s performance in AURA3 was consistent with what it did in the earlier studies, producing an overall response rate of about 60%-70% and extending progression-free survival out to a median of 10-11 months.

Dr. Tetsuya Mitsudomi Mitchel L. Zoler/Frontline Medical News

Dr. Tetsuya Mitsudomi

Osimertinib also features high activity against brain metastases and is far less toxic than both standard chemotherapy and first- and second-generation EGFR tyrosine kinase inhibitors. Getting biopsies to identify tumors with T790M mutations now becomes critically important. The next question is whether to use osimertinib as the first-line EGFR tyrosine kinase inhibitor.

Tetsuya Mitsudomi, MD, is professor of thoracic surgery at Kindai University in Osaka-Sayama, Japan. He has been a consultant to, and has received honoraria and research support from, AstraZeneca and several other companies. He was principal investigator for AURA2, one of the phase II studies of osimertinib. He made these comments as designated discussant for AURA3.


 

VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.

During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

Dr. Vassiliki A. Papadimitrakopoulou Mitchel L. Zoler/Frontline Medical News

Dr. Vassiliki A. Papadimitrakopoulou

In addition, osimertinib clearly surpassed standard chemotherapy for safety by cutting the rate of serious adverse events that were at least possibly drug related from 13% with chemotherapy to 4% on osimertinib, said Dr. Papadimitrakopoulou, professor of medicine and chief of thoracic medical oncology at MD Anderson Cancer Center in Houston. Concurrently with her report, the findings also appeared online (N Engl J Med. 2016 Dec 6. doi: 10.1056/NEJMoa1612674).The key to osimertinib’s activity is targeting it to patients with non–small-cell lung cancer (NSCLC) that breaks through treatment with a first- or second-generation EGFR TKI because a clone grows out with a T790M mutation, which osimertinib was developed to address. “This new information should be a deterrent against complacency about testing” for T790M mutations in all similar NSCLC patients who progress on first-line treatment, Dr. Papadimitrakopoulou said in a video interview at the meeting sponsored by the International Association for the Study of Lung Cancer.

The AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) trial enrolled 419 patients at 126 international sites during 2014 and 2015. The trial’s primary endpoint was investigator-assessed progression-free survival, which occurred after a median of 10.1 months with osimertinib and 4.4 months with standard chemotherapy, a statistically significant 70% relative risk reduction (P less than .001) in the hazard for death or progressive disease. The drug was as effective for patients with central nervous system metastases as it was for the other patients, which Dr. Papadimitrakopoulou attributed to osimertinib’s good penetration across the blood-brain barrier. The drug’s overall performance in AURA3 was completely consistent with the results of earlier studies that led to its U.S. approval.

Despite that approval, routine testing for T790M mutations and routine prescribing of osimertinib to positive patients “has not fully penetrated U.S. practice,” Dr. Papadimitrakopoulou said, but she hoped that these new confirmatory data will now firmly establish it as standard of care for the tested population.

Osimertinib is now under testing as first-line TKI treatment for EGFR-positive NSCLC regardless of the tumor’s T790M status. It’s going head to head with two first-generation EGFR TKIs, gefitinib and erlotinib, in the FLAURA trial, which should have reportable results in 2017. “We are very encouraged by the AURA3 data that osimertinib could beat the first-generation TKIs” for first-line treatment, she said.

AURA3 was sponsored by AstraZeneca, which markets osimertinib (Tagrisso). Dr. Papadimitrakopoulou is a consultant to, and has received research support from, AstraZeneca and several other companies.

On Twitter @mitchelzoler

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