Osimertinib Now Standard in Frontline EGFR+ NSCLC, But Potential for Progress Remains

Mary J. Fidler, MD

Long-awaited overall survival (OS) data have established osimertinib (Tagrisso) as the standard frontline agent for patients with EGFR-mutant non—small cell lung cancer (NSCLC), explained Mary J. Fidler, MD, adding that more work lies ahead for the third-generation TKI.

“Osimertinib remains the standard first-line agent for newly diagnosed, EGFR-mutated patients. That's based on the OS data and better central nervous system (CNS) penetration,” Fidler said. “There's room to improve upon osimertinib, as these patients are young and healthy and their lifespan, unfortunately, is likely to be limited by their lung cancer. Strategies that may work are adding antiangiogenic agents into the mix and also potentially adding back chemotherapy.”

Updated data from the phase III FLAURA trial demonstrated a median OS for osimertinib of 38.6 months (95% CI, 34.5-41.8) versus 31.8 months (95% CI, 26.6-36.0) for erlotinib (Tarceva) or gefitinib (Iressa) in patients with metastatic EGFR-mutant NSCLC (HR, 0.799; 95% CI, 0.647-0.997; P = .0462).¹ At 3 years of follow-up, 54% of patients who received osimertinib were alive compared with 44% of patients treated with erlotinib or gefitinib, despite crossover between arms.

Additionally, the RELAY trial examined the combination of ramucirumab and erlotinib, and results found a significant and clinically meaningful improvement in progression-free survival (PFS) versus erlotinib alone in treatment-naïve patients with EGFR-mutant NSCLC. The ramucirumab plus erlotinib combination was associated with a median PFS of 19.4 months versus 12.4 months with erlotinib plus placebo, showing a 41% reduction in the risk of disease progression or death (HR, 0.59; 95% CI, 0.46-0.76; P <.0001) at a median follow-up of 20.7 months.²

In an interview&#8239;during the 2019 OncLive^® State of the Science Summit^™ on Lung Cancer, Fidler, an associate professor at Rush University Medical Center, discussed how recent research has impacted the EGFR-mutant NSCLC landscape.

OncLive: What is the state of EGFR-mutant NSCLC treatment?

Fidler: The treatment landscape has evolved from our first-generation TKIs to using the second-generation TKIs, with data suggesting that some mutations benefited more [from TKIs] than others. Osimertinib then became approved as a frontline option. That has dramatically changed prescribing patterns in the United States, based on improved PFS and now also improved OS, compared with earlier-generation gefitinib or erlotinib.

What is interesting to note about the RELAY trial?

The RELAY trial is studying the potential benefit of adding an angiogenic inhibitor to frontline TKIs. We saw some signals using bevacizumab; there was a negative US phase II trial, but there was a positive trial in Japan. The RELAY trial used erlotinib and the randomization was ramucirumab compared with placebo. [Ramucirumab] is a bit different than bevacizumab because it's a monoclonal antibody targeting the receptor instead of the circulating VEGF protein. In the RELAY trial, we saw improvement in PFS. That trial excluded patients with brain metastases. However, erlotinib, at least in the United States prescribing patterns, is not the first go-to drug right now.

It was a significant trial, and it shows that adding angiogenic agents to TKIs may add some benefit to patients. It's definitely worth further study, and there is some work in combining ramucirumab with osimertinib. We look forward to those trials and we are going to be participating in that trial at Rush University.

Could you give an overview of the FLAURA trial and its findings?

The FLAURA trial was a frontline trial in patients with EGFR-mutant lung cancer. It was unique because the trial included patients who had brain metastases. [Patients] had to be asymptomatic, but they didn't have to be treated with radiation. The randomization was to osimertinib, which is a third-generation TKI, versus one of the first-generation inhibitors, investigator’s choice of erlotinib or gefitinib.

The trial generated a huge amount of excitement with PFS significance. In the OS data, we saw that patients who were randomized to osimertinib over erlotinib or gefitinib had a longer OS. This was at about the 3-year mark, which is exciting for our patients with lung cancer. Unfortunately, this is usually a young, healthy patient population. Therefore, 3 years sounds great for physicians who have been treating lung cancer for many years, but we still have some work to do to change lung cancer into a chronic illness.

How is osimertinib different from other available TKIs, specifically regarding brain penetration?

In the early studies, when we treated patients with osimertinib after they have progressed on earlier TKIs, we saw a signal of brain activity. We have seen it be beneficial to patients with leptomeningeal disease, which is a very hard patient population to treat. In the FLAURA trial, where patients were randomized to osimertinib or erlotinib or gefitinib, about 20% of those patients had untreated brain metastases. We saw disease control in the brain mirror what we saw in the body from the neck down, suggesting good central nervous system penetration in patients who were less likely to develop new brain metastases if they received osimertinib compared with one of the first-generation agents.

Where does dacomitinib (Vizimpro) fit in this paradigm?

Dacomitinib is a second-generation irreversible binder to the TKI for EGFR, and it was shown, compared with a first-generation agent, to prolong PFS and OS. [Dacomitinib] is a little more toxic, and two-thirds of patients required dose reductions. They did a follow-up study measuring blood levels of the dacomitinib-treated patients, and it seems like those who were able to maintain the original dose had less blood levels. Therefore, it may be a metabolism issue for those patients. Having dose reductions didn't correlate with inferior outcomes. The PFS and OS were very similar, whether patients required a dose reduction or not.

[Dacomitinib] is not designed to treat T790M, and it would be used likely in a sequential fashion—in which dacomitinib would be followed by T790M mutation testing, and then patients would receive osimertinib if [T790M] is noted upon progression. The FLAURA trial showed that about 30% of patients in both arms were not able to go on to receive any subsequent therapy. That is the inherent risk of playing the crossovers design with the T790M mutation.

Are there other emerging agents or treatment approaches that you would like to highlight?

We can talk about adding chemotherapy to TKIs as a strategy. A large trial that was conducted in India showed a benefit to adding carboplatin and pemetrexed to gefitinib as a frontline treatment. Those data are also trying to be replicated with our later-generation osimertinib, but it's too soon to tell if adding chemotherapy would also help patients with newly diagnosed EGFR [mutations].

References

1. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30(suppl_5). doi: 10.1093/annonc/mdz394.076.
2. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial [published online ahead of print October 4, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30634-5.