Osimertinib Shows Promise in EGFR T790M-Mutant NSCLC Trials

Mature data from both the phase I and phase II portions of the AURA study paints a bright, hopeful future for the use of third-generation TKI osimertinib (AZD9291) in patients with EGFR T790M-mutant non-small cell lung cancer.

James Yang, MD, MPH

Mature data from both the phase I and phase II portions of the AURA study paints a bright, hopeful future for the use of third-generation TKI osimertinib (AZD9291) in patients withEGFRT790M-mutant non—small cell lung cancer (NSCLC), according to James Yang, MD, MPH.

Both studies employed an 80 mg dose of osimertinib in patients withEGFRT790M-mutant NSCLC following resistance to frontline anti-EGFR therapy. The phase I portion of the AURA study, which enrolled 63 patients, showed a 71% response rate, while the pooled data from the 411 patients enrolled in two phase II studies showed a 66% response rate. Progression-free survival was 9.7 months in the phase I study and 11 months in the pooled data from the phase II study.

In an interview withTargeted Oncology, Yang, director of the Department of Oncology and Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, discusses the future osimertinib and its possible toxicities in patients.

TARGETED ONCOLOGY:What were the most significant findings from the AURA studies?


We recently presented the AURA phase I and phase II pool analysis inT790Mpositive tissue diagnosed patients who had been treated with EGFR TKI and failed. In the phase II pool analysis, we have a total of 411 patients. This is a mature, progression-free analysis. The progression-free survival for these patients was 11 months, and the response rate in the independent review was 66%. The duration of response in these responding patients was 12.5 months, and the same number was shown similarly in the phase I, 63-patient portion of the study.

We believe that osimertinib in this study was part of very important events in terms of our treatment for advanced NSCLC withEGFRandT790Mmutations who had progressed on prior EGFR TKIs.

TARGETED ONCOLOGY:Were there any toxicities that oncologists should be aware of?


Yes. Osimertinib has all these similar side effects compared to previous EGFR TKIs, so-called ‘class side effects.’ That includes skin rash, diarrhea, and paronychia, but the frequency of these side effects with osimertinib was much less compared to the previous ones. Most of these patients only experienced grade 1 toxicities. Only less than 2% of the patients had grade 3 toxicities of these kinds.

In particular, osimertinib also induced lung disease in several patients and QTc prolongation in several patients, but these are pretty rare.

TARGETED ONCOLOGY:What do you think the impact of these positive results might be on this patient population?


Previously for patients withEGFRmutations, the standard treatment is first-generation or second-generation EGFR TKI. Once they progress, they have only one choice and that is to receive chemotherapy. Of these patients, 60% of them hadT790M, that resistant mutation, in their tissue biopsy samples. Osimertinib certainly provides a good targeted therapy for these patients who hadT790Min the tissue, and provides roughly 1 year of good, quality treatment for these resistant patients.

This is really good news for those patients who had progressed on prior EGFR TKIs.


At this point, isT790Msomething that's easily identified?


In AURA phase I and phase II, we used tissue diagnosis as an inclusion criteria. So one needs to do a re-biopsy of the progression tumor and get thisT790Msequencing done in the laboratory. We also collect plasma for the diagnosis. Plasma is a good source forT790Mdetection. We also show that 60% of the patients in this phase II study who are able to detectT790Musing the standard test, plasma tests can be an alternative for those who had problems getting a tissue biopsy or had to replace some of the procedures.

In the future, perhaps we may be able to do plasma tests first, and for those patients whoT790Min their plasma, we could do a tissue test to confirm that is truly active.


In the future, do you think there might be a role for osimertinib in an earlier line?


At the European Lung Cancer Congress Dr. Ramalingham presented on 60 of our patients who had never received any EGFR TKIs, but who hadEGFRmutations and received osimertinib at 2 doses. These patients had a very long progression free survival time at 19.3 months. We are still observing their subsequent treatment effects, because the data is not fully mature yet. I'm sure there will be some efforts in this regard.

A study called FLORA is ongoing that collects patients withEGFRmutations and randomizes them to osimertinib or erlotinib. This study will tell us whether osimertinib is better compared to the current standard of care, which is erlotinib.


Where are we at in understanding the causes of TKI resistance?


The resistance to the first generation and second generation TKI has been studied extensively. The majority of them developT790M, so roughly 60%. In addition to that, some patients developed CMET amplifications. Some of them developed small-cell transformations, and others develop additional mutations. For the rest of the 40% of the patients who don’t haveT790Mmutations, we are still working on whether there are targeted therapies responding to their genomic alterations.

Before any treatments are confirmed to be effective, chemotherapy is still the best choice for them at this moment.