Expert Discusses Frontline Osimertinib Approval and Next Steps in EGFR+ NSCLC

Helena A. Yu, MD

The FDA approval of osimertinib (Tagrisso) as a frontline therapy for patients with non—small cell lung cancer (NSCLC) whose tumors harbor EGFR mutations, specifically exon 19 deletions or exon 21 L858R substitution mutations, has provided physicians with an alternative and more potent treatment for this patient population.

The April 2018 decision wass based on findings from the double-blind, phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard tyrosine kinase inhibitor (TKI) therapy with erlotinib (Tarceva) or gefitinib (Iressa). Data showed that the median progression-free survival (PFS) was 10.2 months for standard therapy and 18.9 months with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).¹

The agent has also seen benefit in patients with central nervous system (CNS) metastases. Real-world clinical data presented at the 2018 European Lung Cancer Congress demonstrated that patients with advanced NSCLC and baseline CNS metastasis showed control of their metastasis after osimertinib treatment. The CNS clinical benefit was observed in 7 patients with brain metastasis at baseline with osimertinib; the objective response rate by RECIST was 70%, including partial responses in 50% and stable disease in 20%.²

Next steps after the approval of osimertinib as the frontline standard of care include how to treat patients who develop resistance to the third-generation EGFR TKI, explains Helena A. Yu, MD.

The regulatory approval is not the only exciting development in the EGFR-mutant space. Dacomitinib was granted a priority review designation by the FDA in April 2018 for the frontline treatment of patients with EGFR-positive locally advanced or metastatic NSCLC. The application is based on the phase III ARCHER 1050 trial, in which frontline dacomitinib reduced the risk of disease progression or death by 41% and was associated with an average 6.5-month improvement in response duration versus gefitinib.³

OncLive: You lectured on sequencing EGFR-targeted therapies in NSCLC. Can you provide an overview?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Yu, a medical oncologist at Memorial Sloan Kettering Cancer Center, highlighted sequencing strategies in EGFR-mutant NSCLC, the impact of osimertinib in the frontline setting, and the questions surrounding dacomitinib’s intriguing data in this landscape.Yu: I spoke about treatments for EGFR-mutant lung cancer. The first part focused on what data are out there. The real key is the news of osimertinib in the first-line setting. The FLAURA study read out late last year, which showed that osimertinib had a doubling of median PFS compared with what was previously the standard of care. I see osimertinib being the standard of care for first-line treatment.

Then, I spoke about resistance mechanisms. That is a key with targeted therapy; these treatments are very effective and they work for a long time, but at some point all patients have progression. It’s key to re-biopsy patients at that point, and to look and see what the different resistance mechanisms are.

With osimertinib, there are patterns that are emerging; off-target resistance is going to be a more dominant factor. Osimertinib is an excellent EGFR inhibitor, so we are seeing less-acquired EGFR mutations. We sometimes see the EGFR mutation C797S, but it is probably more like 15% rather than the 60% we saw with T790M [after treatment with] erlotinib, afatinib (Gilotrif), and gefitinib.

We need to see what is prevalent and what is common, and the key is looking at combinations to sort of prevent those resistance mechanisms.

Anecdotally, how do TKIs compare with chemotherapy in EGFR-mutant patients?

When these patients are told they do not need chemotherapy but an oral agent, is there apprehension involved?

With regard to EGFR inhibitors, is there an optimal choice for patients with brain metastases?

Other small focuses, in terms of managing EGFR-mutant NSCLC is the ability to treat beyond progression. There is a subset of patients who have more indolent progression, where things are starting to grow but they are growing slowly; the patient is asymptomatic and can sometimes continue an EGFR TKI for a significant period of time. There is also the unique but not completely uncommon situation where you see that most of the disease is stable and continues to be controlled, but there is one growing lesion. That is a perfect candidate for doing some local treatment, like radiation therapy or surgery. You are able to eradicate the subclone that is growing on the TKI and then continue the EGFR inhibitor. There have been multiple prospective randomized studies looking at EGFR inhibitors compared with chemotherapy. It has been pretty clear, mostly with the early-generation TKIs, that there is a doubling of response rate, doubling of PFS, and there is just less toxicity. These are oral drugs that people take once daily compared with coming in continually for intravenous treatment. With a better toxicity profile and better efficacy, it is sort of a no-brainer to give these EGFR inhibitors to these patients first. Yes; it’s a double-edged sword. These patients are usually never smokers who are young and shouldn’t have gotten lung cancer, so there is a total overwhelming factor to these first visits. But people get used to the ease and the minimal toxicity with these EGFR inhibitors. The bigger issue I see with my patients is that they are on TKIs for 2 or 3 years, and then I want to switch them to chemotherapy. Then, I get a lot of resistance. However, it’s key to remember that for these patients, and all patients, it is a journey and there are appropriate treatments for each segment along the way. However, chemotherapy is a key part of these patient treatment regimens, too. All EGFR inhibitors are effective when somebody has brain metastases. When someone presents with stage IV lung cancer and has brain metastases, universally, all of the TKIs work in the brain. Therefore, local therapies to the CNS, like whole-brain radiation or stereotactic radiosurgery, can be deferred. I feel confident with all of the EGFR inhibitors to treat those lesions, but where the different TKIs sort of separate from each other is the prevention of new brain metastases. With the earlier-generation inhibitors, the CNS was a sanctuary site where there was less drug getting in. Although there was enough to treat brain metastases that were there, there was not enough concentration to prevent brain metastases from emerging.

If dacomitinib is approved, how would you incorporate it into treatment management? What data do we have with that agent?

The data with osimertinib, which isn’t fully fleshed out, shows that there is definitely less CNS progression on that. There is really full penetration; that is definitely an asset for osimertinib. ARCHER 1050 was presented at the 2017 ASCO Annual Meeting and that looked at dacomitinib versus gefitinib and it looked really good. The median PFS with dacomitinib was 16 months compared with 10 months with gefitinib. Among the earlier-generation EGFR TKIs, if it had come out a little earlier, it would be a clear winner. If approved, I would certainly think about using that compared with gefitinib or erlotinib. It is challenging; you do cross-trial comparisons, but when you look at the numbers, osimertinib is better in terms of the median PFS of 19 months.

Is there anything else you would like to emphasize in this space?

It is also better tolerated. As second-generation EGFR TKIs, afatinib and dacomitinib have more EGFR wild-type effects, so you are going to see more diarrhea and mucositis. That is a consideration, too. It is challenging to say definitively what I would do because of that lack of head-to-head comparison. The key moving forward is understanding the mechanisms of resistance to osimertinib. It will be challenging with erlotinib, gefitinib, and afatinib; two-thirds of patients had T790M, so it was sort of an easy next step—find a T790M inhibitor, develop that, and give that to patients.

However, with osimertinib, it will definitely be more personalized treatment. Anecdotally, I have seen different acquired mutations, different protein amplification, and it’s more of a piecemeal thing where you have to personalize treatment for your patient. What [are we finding] that was acquired and how can we target that? That will be a real challenge for clinical trials because it will be harder to collectively be able to test these rarer combinations, but it’s important to do.

References

1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.
2. Devjak R, Turnsek Hitij N, Mohorcic K, Rajer M, Cufer T. CNS response to osimertinib in patients with EGFR mutated lung adenocarcinoma: Real world data. In: Proceedings from the 2018 European Lung Cancer Congress; April 11-14, 2018; Geneva, Switzerland. Abstract 154P.
3. Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase 3 trial. J Clin Oncol. 2017;35(suppl; abstr LBA9007).