Progress Continues in EGFR+ NSCLC Paradigm

Charu Aggarwal, MD, MPH

Charu Aggarwal, MD, MPH

Recent progress in the treatment paradigm for EGFR-mutant non—small cell lung cancer (NSCLC) includes the FDA’s frontline approval of osimertinib (Tagrisso) and priority review designation for dacomitinib, both of which have demonstrated longer progression-free survival (PFS) and overall survival (OS) outcomes versus standard therapy, said Charu Aggarwal, MD.

“This is such an exciting time to be a lung cancer oncologist because we are making tremendous progress in the treatment of the subset of patients with EGFR-mutant lung cancer,” said Aggarwal.

The FDA approved osimertinib in April 2018 as a frontline treatment for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations), based on results from the phase III FLAURA trial.¹

At the 2018 ASCO Annual Meeting, OS data with dacomitinib were presented from the phase III ARCHER 1050 trial. In the study, the median OS was 34.1 months in patients randomized to dacomitinib versus 26.8 months in those randomized to gefitinib (Iressa).² Based on results from the ARCHER 1050 trial, dacomitinib was granted an FDA priority review designation in April 2018 as a first-line agent for patients with EGFR-positive NSCLC.

Moreover, regimens are being explored with antiangiogenic inhibitors for this patient population, primarily combinations with bevacizumab (Avastin).

OncLive: Can you discuss recent advances in EGFR-mutant NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Lung Cancer, Aggarwal, an assistant professor of Medicine at University of Pennsylvania, discussed the latest developments in EGFR-mutant lung cancer.Aggarwal: I spoke about the preferential use of osimertinib (Tagrisso), which is our third-generation tyrosine kinase inhibitor (TKI) in the first-line setting. That offers patients a tremendous opportunity to live longer, as well as avoid some of the other side effects with first- or second-generation TKIs.

I also discussed new data from the 2018 ASCO Annual Meeting. There were data on dacomitinib, which is an oral TKI. Patients were randomized against the use of gefitinib, which is one of our first-generation TKIs. PFS data were presented at the 2017 ASCO Annual Meeting. This year, we heard about OS data, which was simultaneously published in the Journal of Clinical Oncology. The data show an improvement in OS compared with gefitinib. However, in my opinion, it's being compared with a nonrelevant first-line therapy. I'm not sure if there is a clear role [for dacomitinib] moving forward. Still, it was an interesting and well-conducted trial.

There were a couple of trials that evaluated the use of antiangiogenic agents in the treatment of patients with EGFR-mutant NSCLC, mainly with bevacizumab. These trials looked at combinations in the upfront setting in chemotherapy-naïve and previously untreated patients with EGFR-mutant NSCLC. There were improvements in PFS. One of the trials reported consistent benefit across all subtypes. However, it's being compared with lorlatinib, which is not our current favorite and most-used agent in the United States.

I wanted to highlight the trial [from the meeting] that looked at triplet therapy. We have become so used to using triplet therapy in the upfront treatment of lung cancer, but that's a different triplet of chemotherapy plus immunotherapy. What if we were to use chemotherapy in combination with a TKI for EGFR-mutant lung cancer?

In fact, the authors of this Japanese study showed that you can delay progression by more than 20 months and make a dent in OS. The OS improvement was quite significant at 52 months. These are definitely data that should be looked at more carefully. It added more toxicity as we can imagine. There was more myelosuppression and the usual chemotherapy-related side effects, but they combined it with gefitinib which is well tolerated. These are data worth looking at.

I also highlighted some of the data with regard to emerging resistance mechanisms. We all know about T790M, but as we start using osimertinib upfront, T790M may no longer be an escape mechanism of resistance. We are finding different resistance mechanisms, such as MET amplification, small cell transformation, and HER2. We are even finding mutations such as C797S, which resensitizes patients to the use of first- and second-line EGFR TKIs. It underscores the importance of rebiopsy to best figure out the next approach. It also begs the question of what is going on with these patients at the time of resistance.

For MET amplification, MET inhibitors are being used. For small cell lung cancer, we recommend chemotherapy. There are interesting combination approaches that are being evaluated.

How do the data with dacomitinib compare with osimertinib?

There is no clear role of immunotherapy [in EGFR-mutant NSCLC] just yet, even if patients have high PD-L1 expression. At the 2018 ASCO Annual Meeting, we saw an abstract that showed that despite high PD-L1 expression, pembrolizumab (Keytruda) was associated with a 0% response rate. I would not recommend routine use [of immunotherapy for these patients].I spoke about how we are going to sequence these therapies. One approach is to use osimertinib upfront, which we do already. Although that gives us a PFS of about 18.9 months, it doesn't leave the option of T790M-directed therapy. [Upfront] dacomitinib may result in a PFS of about 14.5 months and allows us to perhaps use osimertinib for a subset of patients who develop the T790M resistance mutation. If we do that, can we then prolong the PFS as well as the OS?

What is the role of the first-generation TKIs?

How would the approval of bevacizumab and erlotinib (Tarceva) shift the landscape even more so?

The data from dacomitinib show considerable toxicity. There is significant diarrhea, and a greater majority of patients had to reduce their dose. It didn't look like it was a well-tolerated drug compared with osimertinib; it will be very hard to sell dacomitinib to a patient who is otherwise feeling well. The data with CNS metastases are best [with] osimertinib, and that needs to be emphasized. One of the ways that these patients do poorly is by developing brain metastases, and the data are strongest with the use of osimertinib.I don't think we will be using them that often unless we start believing in the chemotherapy plus gefitinib trial. Though it has some relevance, osimertinib is going to take center stage.There is a role for angiogenesis inhibitors. There have been data in the second-line setting that have shown that you can improve OS by coming in with antiangiogenic agents and VEGF as an escape pathway. In the future, as we start moving up the combination of a TKI and chemotherapy, or a TKI, there will be a role in the second-line setting for antiangiogenic agents.

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. Mok T, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study comparing dacomitinib with gefitinib in patients with advanced non-small cell lung cancer harboring EGFR-activating mutations. J Clin Oncol. 2018;36(suppl; abstr 9004).