Differentiating Among EGFR Inhibitors in NSCLC

Chul Kim, MD, MPH

The frontline setting of patients with EGFR-positive non— small cell lung cancer (NSCLC) is a crowded space, said Chul Kim, MD, MPH, but there are some considerations for thoracic oncologists to help distinguish among the available TKIs.

Kim, an attending physician at MedStar Health and an assistant professor of medicine at Georgetown University, encouraged making cross-trial comparisons between these agents, but with caution. However, in terms of progression-free survival (PFS) data, osimertinib (Tagrisso) seems to be superior, he said.

In the phase III FLAURA study, the median PFS was 18.9 months (95% CI, 15.2-21.4) in patients with EGFR-mutant NSCLC who were on the osimertinib arm versus 10.2 months in those who received standard therapy with erlotinib (Tarceva) or gefitinib (Iressa; HR, 0.46; 95% CI, 0.37-0.57; P <.0001).¹ Median overall survival (OS) has not yet been reached. Based on these findings, 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).

Further, the second-generation pan-human EGFR inhibitor dacomitinib (Vizimpro) showed superiority over gefitinib in the phase III ARCHER 1050 study. Dacomitinib reduced the risk of disease progression or death by more than 40% and resulted in an average 6.5-month improvement in duration of response (DOR) compared with gefitinib.²

The median PFS for patients who received dacomitinib was 14.7 months compared with 9.2 months for those who received gefitinib (HR, 0.59; 95% CI, 0.47- 0.74; P <.0001). The median DOR was 14.8 months with dacomitinib versus 8.3 months with gefitinib (HR, 0.40; 95% CI, 0.31-0.53; P <.0001).

OncLive: Please provide an overview of your presentation on EGFR-mutant NSCLC.

In an interview with OncLive^® at the 2018 State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Kim discussed the additions of these EGFR inhibitors to the armamentarium and how to best select therapy for these patients.Kim: We have seen a great number of advances made this year in the field of EGFR-positive NSCLC. Two additional EGFR TKIs were approved for the frontline treatment of these patients: osimertinib and dacomitinib. Osimertinib, a third-generation TKI, was approved based on data from the FLAURA trial. This study compared osimertinib with gefitinib or erlotinib, and osimertinib showed superior PFS versus the earlier-generation TKIs. Also remarkable about this study was that patients with central nervous system (CNS) disease at baseline benefited at a lower dose; this suggests that osimertinib is probably the way to go for patients with CNS disease.

Dacomitinib was approved based on data from the ARCHER 1050 study, in which dacomitinib was again compared with gefitinib. This was another big development in the field. Now, we have 5 different EGFR TKIs in the frontline setting. One practical question is, “How do we select among these treatments?” You have to do a number of things. First, you should compare PFS data with each agent. Osimertinib provides the best PFS, but you have to take caution when making cross- trial comparisons. Osimertinib is also associated with a more favorable toxicity profile.

Another unanswered question is whether there is a subset of patients who may benefit from a sequential approach. For example, if you start with dacomitinib, it will give you about 15 months of PFS, followed by osimertinib in the second-line setting. If you combine these 2, that is about a 25-month PFS. We need more research [in that space].

Following treatment with a first-generation EGFR TKI, we see development of T790M, which is a mechanism of resistance; this occurs in about 50% to 60% of cases. We also see other forms of resistance, such as HER2 amplification. We have to understand this better. Broadly speaking, there are 3 categories of mechanisms of resistance; MET amplification is another big one. After first-line use of osimertinib, we saw a presentation at the 2018 ESMO Congress that used data from FLAURA. Using a circulating tumor DNA analysis, researchers showed the most common mechanisms of resistance to osimertinib in the first-line setting. One remarkable thing was that there was no development of T790M, showing that osimertinib is effective in suppressing this.

We did see fusion events. For example, a recent publication described 3 fusions that arose when treating patients with osimertinib in the second-line setting. There was a RET fusion, FGFR fusion, and BRAF fusion. Three out of 41 patients presented with these. I don’t think these fusions have been well documented in this space, so we have to better understand this. It was quite striking to see those fusion events.

In terms of overcoming resistance to TKIs, we can circumvent or overcome these mechanisms in several ways. The major finding this year was that if you use chemotherapy and combine it with gefitinib, there was a significant OS benefit compared with the use of gefitinib alone. What if we combine pemetrexed with osimertinib? Ongoing studies are looking at this. This is a very relevant question and can be applied to other oncogenes as well.

How do you distinguish among these TKIs?

What would be your take-home message?

The second strategy is to pinpoint the exact mechanism of resistance in each patient because now we have advanced technologies to do that. One presentation at the 19th World Conference on Lung Cancer was that researchers found RET fusions with second-line osimertinib. They treated these patients with osimertinib plus a RET inhibitor. The combination achieved partial responses, which were ongoing at 4 months. Because the mechanisms are so diverse, we need an umbrella-type trial with multiple arms. For example, if you have an ALK fusion, you might be able to get osimertinib plus alectinib (Alecensa) or brigatinib (Alunbrig).I look at the data from their respective trials. There have been some head-to-head studies. For example, ARCHER 1050 looked at dacomitinib versus gefitinib. You want to look at the median PFS, and osimertinib provided the best PFS. We also have to consider patient factors. For a patient with CNS metastases, my first choice would be osimertinib. As far as I know, the FLAURA study was the only one that showed equivalent benefit with patients who had CNS involvement.The first-line EGFR setting is quite crowded, as I mentioned, with 5 TKIs. I would want community oncologists to understand the attributes of each, and understand certain patient factors to determine which patients get each agent. You can distinguish between each generation of TKIs. For example, osimertinib is an irreversible EGFR inhibitor but also binds to T790M from the get-go. That is a main advantage of osimertinib. In the United States, osimertinib seems to be the favored drug.

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; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.
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 (AR- CHER 1050): a randomized, open-label phase III trial. J Clin Oncol. 2017;35(18 suppl; abstr LBA9007). doi: 10.1200/JCO.2017.35.18_suppl.LBA9007.