Lead FLAURA Researcher Discusses Frontline Osimertinib in EGFR+ NSCLC

Suresh S. Ramalingam, MD

The much-anticipated progression-free survival (PFS) findings from the phase III FLAURA trial did not disappoint the lung cancer community, as the third-generation EGFR inhibitor osimertinib (Tagrisso) demonstrated a significant improvement in PFS over current first-line therapies for patients with EGFR-mutant non—small cell lung cancer (NSCLC).

Results showed that frontline osimertinib was associated with a 54% reduction in the risk of progression or death versus standard therapy, which included erlotinib (Tarceva) or gefitinib (Iressa). In the double-blind study, the median PFS was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

Though overall survival (OS) data remain immature, there is an encouraging trend that favors osimertinib. Additionally, the trial’s findings highlighted a benefit with osimertinib in patients who also had brain metastases.

“We showed activity in the brain, a robust PFS benefit, almost a two-fold improvement in duration of response, and a promising survival trend, which is why we are excited about the results of the FLAURA study,” explained Suresh A. Ramalingam, MD.

OncLive: Please share your insight on the FLAURA findings?

In an interview with OncLive during the 2017 ESMO Congress, Ramalingam, deputy director of Winship Cancer Institute of Emory University, discussed the practice-changing FLAURA findings and his thoughts on sequencing should the FDA approve osimertinib in the frontline setting.Ramalingam: The FLAURA study was a phase III clinical trial that compared, head to head, osimertinib—a new, third-generation EGFR inhibitor&mdash;to standard of care, which are presently used drugs such as erlotinib and gefitinib. Osimertinib is approved in the United States by the FDA for the second-line treatment of EFGR-mutated patients in those who have developed a T790M mutation as a resistance mechanism to the first-generation drug.

What we tried to do with the FLAURA study is move osimertinib to the first-line setting and compare it head to head. The hypothesis is that it shuts off the resistance pathway. Therefore, we compared osimertinib in a cohort of 556 patients with a double-blind, placebo-controlled, randomized, phase III trial. It was a 1:1 randomization between osimertinib versus either erlotinib or gefitinib. The primary endpoint of the trial was PFS as assessed by the investigator. What we found was that there was a clear superiority for osimertinib over standard of care.

Here are the numbers: the median PFS with standard of care was 10.2 months; the median PFS with osimertinib was 18.9 months. The hazard ratio was 0.46, and the P value was highly significant. Therefore, this means a 54% reduction in the risk of death or progression with osimertinib.

The second efficacy point to make is that the duration of response was more than two-fold higher for patients treated with osimertinib. For standard of care, it was 8.5 months; for osimertinib, it was 17.2 months. The third point is OS. We found that even though the data are very immature at this point—at only 25%&mdash;the hazard ratio for OS is 0.63, with a P value of .0068.

Though not statistically significant at this time, it is a very promising trend. That is important because we allowed crossover from the control arm for patients who develop progression in T790M.

What is the safety profile of osimertinib?

We also found activity in the brain. Patients with brain metastases that came into the study had a very similar hazard ratio, at .47, as the overall population.Osimertinib is a mutation-specific EGFR inhibitor. What that tells you is that it has a more profound effect on the mutant receptor than the wild-type receptor, which means the toxicities tend to be lower. We have seen this in trials done already with osimertinib, where the skin toxicities and overall toxicity burden is much lighter on the patients.

In FLAURA, we saw a similar picture. If you look at grade 3/4 adverse events, it was considerably lower with osimertinib compared with standard of care. When you look at skin toxicity, it was almost half as common with osimertinib as it was with standard of care.

Are there subgroups of patients who may be ideal for frontline osimertinib versus a first-generation EGFR-targeted agent?

When you look at liver transaminase elevation, that was almost one-third of what we saw in the standard-of-care arm versus osimertinib. That is 25% with standard of care compared with 9% for osimertinib. When you look at gastrointestinal toxicities, it was comparable. What is important is that the duration of exposure to osimertinib was much longer because patients stay on the drug longer—close to 16.5 months&mdash;compared with only approximately 11 months with standard of care. Despite having a longer duration of therapy, patients did much better with osimertinib in terms of safety. That adds the other important factor for patients, which is that you have an efficacious option with a better safety profile. FLAURA is the largest study conducted for patients with EGFR-mutation—positive or advanced-stage disease. We were able to look at some of the key subsets to see if there were any differences in efficacy. What was exciting here was, whether it was exon 19 or exon 21 mutation, the efficacy of osimertinib was superior to standard of care with similar hazard ratios. When you look at patients who had brain metastases or without them, we once again saw similar hazard ratios.

Once survival findings of FLAURA become available, what would be optimal second-line treatment—would first-generation TKIs still be effective?

Across all of the key subgroups—age, performance status, and stage&mdash;we saw very similar hazard ratios favoring the use of osimertinib. We were happy to see that osimertinib seemed to benefit all of the key subgroups of patients enrolled in this trial. Therefore, it is a new standard option for first-line treatment of patients with either EGFR exon 19 or 21 mutations. The survival results for FLAURA, at this time, are premature and the hazard ratio is promising at 0.63. We will follow these patients closely and we will report the mature survival results as soon as they are available.

For the time being, the standard of care is first- and second-generation EGFR inhibitors in the first-line setting. FLAURA positions osimertinib in the first-line space, and if a patient receives osimertinib as first-line therapy after progression of disease we would envision them receiving platinum-based chemotherapy as a second-line approach for the immediate future.

However, work is already being done to understand what the mechanisms of resistance to osimertinib are and what can be done proactively to prevent it.

We have now an exciting new option in osimertinib that provides the ability to completely shut off the T790M escape pathway. Surely, the cancer cells will have other pathways that they will develop for resistance, and our goal will be to proactively try, once again, to prevent those and move the field forward in order to extend the benefits of osimertinib even to the next higher level.

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. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.