Wakelee Highlights Latest Treatment Strategies in EGFR+ NSCLC

Heather A. Wakelee, MD

Novel treatments and strategies continue to emerge in the treatment paradigm for patients with EGFR—positive non–small cell lung cancer (NSCLC), explained Heather Wakelee, MD.

For example, osimertinib (Tagrisso) has demonstrated superiority to standard EGFR tyrosine kinase inhibitors (TKI) with a similar safety profile and lower rates of serious adverse events (AEs) in the frontline treatment of patients with advanced EGFR-positive disease, according to data from the FLAURA study.

Results from the study showed that the median PFS was 18.9 months (95% CI, 15.2-21.4) on the osimertinib arm versus 10.2 months (95% CI, 9.6-11.1) for standard therapy with erlotinib (Tarceva) or gefitinib (Iressa; HR, 0.46; 95% CI, 0.37-0.57; P <.0001). Median OS has not yet been reached.

The objective response rate with osimertinib was 77% compared with 69% for erlotinib and gefitinib. The median duration of response with osimertinib was 17.6 months versus 9.6 months in the comparator arm.

Based on these data, the FDA approved osimertinib in April 2018 for the first-line treatment of patients with EGFR—positive NSCLC (exon 19 deletions or exon 21 L858R substitution mutations).

Moreover, the pan-human EGFR inhibitor dacomitinib has also shown superiority over gefitinib in the phase III ARCHER 1050 trial. Data showed that dacomitinib led to a 40% reduction in the risk of disease progression or death versus gefitinib in the frontline setting for EGFR-mutant patients. The FDA granted a priority review designation to dacomitinib based on these findings.

OncLive: Can you highlight some of the latest advances in EGFR-positive lung cancer?

In an interview with OncLive, Wakelee, an associate professor of oncology at Stanford University School of Medicine, shared insight on emerging treatment strategies in EGFR¬positive NSCLC.Wakelee: There is a lot happening in the EGFR space. We now have several first-generation drugs and a couple of second-generation drugs. Third-generation osimertinib has also been FDA approved. Most of the recent data that have been very interesting are the direct comparisons. Until very recently, we went for many, many years without having direct comparisons of different TKIs in the first-line setting.

We had the FLAURA data, which was first-line osimertinib compared with either gefitinib or erlotinib. That has shown a clear improvement in PFS. The OS data at this time are still not significant, but it's trending in favor [of osimertinib]. Osimertinib is becoming the first-line standard [of care]. At the 2018 ASCO Annual Meeting, the data with dacomitinib were very interesting. We saw the [findings from the] ARCHER 1050 trial, which compared this TKI with gefitinib. There was a clear OS benefit presented this year. The problem with dacomitinib is the toxicity. What we are now struggling with is where dacomitinib fits in. We're now using osimertinib in the frontline setting, so we're not sure where to sequence dacomitinib.

There have also been some combination data with erlotinib and bevacizumab (Avastin); that has been looked at particularly in Japan. There was a significant PFS benefit to the combination, while the OS benefit was not as compelling. There was a randomized phase III trial looking at the same combination and it confirmed the PFS benefit. That PFS benefit, if you add erlotinib and bevacizumab, gets awfully close to what we see with frontline osimertinib. Again, the question becomes, “Where do we fit this into treatment?” We're still not sure what to do with this setting.

Will there ever be a head-to-head comparison with osimertinib and dacomitinib?

When the EGFR TKI were first developed—before we even knew about EGFR mutations—we did trials of EGFR TKIs plus chemotherapy, which were negative. That left everyone with the idea that we shouldn't do that. It took a long time before those questions were asked again. Japanese researchers did a great study looking at first-line chemotherapy plus an EGFR TKI. The OS was in excess of 15 months. This was statistically significant, and it goes away from what we thought to be the truth.There might be, but it's not likely. This is just because dacomitinib is unlikely to beat osimertinib for that PFS endpoint. It certainly won't win from a toxicity standpoint. I can't imagine they would do this trial. The better trial would be starting with osimertinib, and then after progression going over to dacomitinib. We could work chemotherapy into the mix, as well, and see how this impacts PFS and OS. This kind of study would probably be hard to accrue to, at least in the United States. There is the potential for a global study.

References

1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et all. Osimertinib in untreated EGFR-mutated advanced non—small-cell lung cancer. N Engl J Med. 2018; 378:113-125. doi: 10.1056/NEJMoa1713137.
2. 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).