Anticipated Osimertinib Data Could Transform Frontline NSCLC Treatment

Jamie E. Chaft, MD

The oncology community is eagerly awaiting the pivotal data from the phase III FLAURA trial, which will determine the benefit of osimertinib (Tagrisso) in the frontline setting for patients with EGFR-mutated non—small cell lung cancer (NSCLC) who harbor the acquired resistance mutation T790M.

Earlier findings from the phase I AURA trial, which investigated the agent in the first-line setting in 60 patients across 2 different dose cohorts, demonstrated a 77% objective response rate (95% CI, 0.64-0.87).¹ Moreover, the median progression-free survival (PFS) was 19.3 months; 55% of patients remained progression-free at 18 months, and the median duration of response was non-calculable at the time of data cutoff.

The phase III findings would also follow the updated results of the phase III AURA3 trial, which showed that treatment with osimertinib reduced the risk of disease progression by 70% versus a chemotherapy doublet regimen for patients with EGFR T790M-mutant NSCLC who progressed after first-line targeted therapy.² The AURA3 results led to the recent conversion of the accelerated approval of osimertinib in this setting to a full approval.

OncLive: You lectured on EGFR TKIs at this meeting. How has this space evolved?

What are some of the most recent advances with TKIs in NSCLC?

Jamie E. Chaft, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, shared insight on the available EGFR TKIs in lung cancer during the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer. In an interview, she spoke to the effectiveness of osimertinib and what the future holds for patients with EGFR-mutant NSCLC. Chaft: We currently have 4 EGFR TKIs that are FDA-approved for the treatment of NSCLC in the United States. There are 2 first-generation drugs, 1 second-generation drug, and a third-generation drug, osimertinib, which is the newest addition. The second-generation drugs are for newly diagnosed cancers, and osimertinib is indicated to be administered at the time of progression in patients whose tumors have a T790M mutation. The most recent advance is still osimertinib’s approval. It was approved in November 2015 for EGFR-mutant lung cancer with a T790M mutation. More recently, there was the publication of the AURA3 data, which really confirm osimertinib’s drastic superiority over chemotherapy in this setting.

An additional major advance has been the investment of the industry to have the ability to detect EGFR mutations in the blood. This is both faster and safer than a re-biopsy, small biopsies, or insufficient tissue for tumor tissue analysis in many of our patients who are diagnosed with NSCLC.

What are the current challenges we face with sequencing therapies, if any?

It really does open up a line of therapy to a percentage of patients who would not have otherwise had it. Today, there is not much of a challenge. The treatment algorithm is fairly obvious, in terms of approvals. The third-generation drug will follow either a first- or second-line agent.

At this meeting, we talked about the controversy over the superiority of first- versus second-generation drugs. My interpretation of the data is that the second-generation drug afatinib (Gilotrif) has more toxicity and does not have an obvious therapeutic advantage over the first-generation drugs.

What clinical trials are anticipated in this space?

What do you envision for the future of EGFR TKIs?

What are the main ideas that community oncologists who attended your presentation should take away?

However, the sequence will become more challenging depending on the data that’s forthcoming with the FLAURA study, which is looking at first-line osimertinib versus first-generation inhibitors, as well as the similar designs of other companies in this space. It is, really, the first-line osimertinib versus erlotinib (Tarceva) and gefitinib (Iressa) study that most people are eagerly anticipating. Although, interestingly, it’s a PFS endpoint and I do wonder whether or not it will have an overall survival advantage. It is unclear to us if we will be then able to utilize a first- or second-generation drug after osimertinib; or, will there be new drugs available that are specifically targeted at the time of progression on osimertinib? We certainly know that T790M has a resistance mechanism, but the drugs to inhibit it are still a ways off. While the EGFR space was here before the ALK space, the number of drugs in the ALK space has exploded. Therefore, I would imagine or hope that we have more and more targeted therapies in patients who are really treated with 2, 3, or 4 lines of EGFR inhibitors before having to face chemotherapy. The main points that have come about in the last 2 years are, first, that we have a blood test for first-line detection of EGFR mutations now. Therefore, for patients who have a small biopsy or insufficient tissue, you do not have to send them for a new biopsy. You can send a blood test and very quickly know whether these drugs are appropriate.

Additionally, for patients who are known to have EGFR mutations, the superiority of osimertinib over chemotherapy is not comparable to anything else we've seen. It is really important to go that extra mile and test patients for T790M, and with the blood test first. If the blood test is negative, then we’ll follow up with a tumor biopsy. We need to keep doing more research to keep these advances going.

References

1. Ramalingam, SS. Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two phase I expansion cohorts. In: Proceedings from the 2016 European Lung Cancer Congress; April 13 to 16, 2016; Geneva, Switzerland. Abstract LBA1_PR.
2. Mok TS, Wu YL, Ahn MJ, et al. The AURA3 Investigators. Osimertinib or platinum—pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017; 376:629-640.