Osimertinib Spearheads Progress in EGFR-Mutant NSCLC

Suresh S. Ramalingam, MD

Following a frontline approval for patients with EGFR-mutant non—small cell lung cancer (NSCLC), future directions for the third-generation EGFR TKI osimertinib (Tagrisso) include overcoming acquired resistance mechanisms with optimal combination partners, explained Suresh A. Ramalingam, MD.

Osimertinib was granted a first-line indication in April 2018, based on findings from the double-blind, phase III FLAURA trial, in which the TKI led to a 54% reduction in the risk of disease progression or death versus erlotinib (Tarceva) or gefitinib (Iressa). In the double-blind study, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).¹

Most recently, it was announced that frontline osimertinib also significantly improved overall survival (OS) compared with the first-generation EGFR TKIs in the FLAURA study.² The OS data will be presented at an upcoming medical meeting.

Now, studies have been exploring acquired resistance mechanisms to osimertinib, such as C797S, in order to determine what agents can help overcome them. Combination strategies with osimertinib have included the MET inhibitor savolitinib as well as the MEK inhibitor selumetinib, both regimens of which have showcased intriguing preliminary activity and need to be further explored, Ramalingam said.

In an interview during the 2019 OncLive^® State of the Science Summit on Non—Small Cell Lung Cancer, Ramalingam, deputy director of Winship Cancer Institute, Emory University School of Medicine, discusses recent updates in EGFR-mutant NSCLC and the next steps for osimertinib and other agents in this patient population.

OncLive: How would you define the state of EGFR-mutant NSCLC treatment?

Ramalingam: EGFR mutations account for approximately 15% of lung adenocarcinomas. For patients who have these mutations, we now know very well that EGFR TKIs are standard of care for patients with stage IV disease. We have seen a lot of excitement in this area; we have multiple generations of the drugs that target the EGFR pathway. Osimertinib is the newest [addition] to that list.

We are also beginning to see knowledge about resistance mechanisms to osimertinib and the emergence of combination approaches that specifically can help overcome resistance to third-generation EGFR inhibition. We know that checkpoint inhibition is still not an effective therapy for patients with EGFR-mutant disease, so we still need to do a lot of work on that, but the good news is that the outcomes for patients with EGFR-mutant lung cancer are very good. We have drugs that can prolong PFS, drugs that can improve survival, and also drugs that can have sufficient and substantial activity against brain metastases.

The FLAURA trial has been a practice-changing study. How would you describe the impact of osimertinib?

The FLAURA study led to the approval of osimertinib for frontline therapy for EGFR-mutated patients. We randomized patients to either osimertinib or gefitinib or erlotinib, and it showed that the median PFS was close to 19 months for patients treated with osimertinib compared with approximately 10.2 months in the control group. Not only did we see a two-fold improvement in efficacy in median PFS and hazard ratios, we also saw a two-fold improvement in median duration of response (DOR) for patients with osimertinib. We also saw a favorable toxicity profile with osimertinib, and finally we also saw substantial activity against brain metastases.

Based on all of these favorable outcomes, osimertinib has emerged as the preferred EGFR TKI for patients with exon 19 or 21 [deletions in EGFR-mutant] NSCLC. National Comprehensive Cancer Network guidelines recommend osimertinib as the preferred first-line therapy for patients. We are in a new era as a new agent has become first-line therapy, and we’re beginning to think about what is next for our patients.

Are there patients with EGFR-mutant NSCLC who, at this point, are not the optimal candidates to receive osimertinib?

For patients with exon 19 and 21 deletions, I believe that osimertinib has established itself as the most effective therapy out there. For those with exon 20 insertion mutations, the first-, second-, and third-generation drugs are not very effective. There are some promising drugs—poziotinib and TAK-788—that have shown some preliminary evidence of activity. We eagerly await larger cohorts of patients being treated with these agents, so we can finally have a targeted therapy for those with exon 20 insertion mutations.

Could you highlight the data that have been presented looking at acquired resistance mechanisms to osimertinib?

When we serially looked at plasma samples in the FLAURA study, we were able to conduct cell-free DNA testing, and that provided some preliminary insights into the resistance mechanisms to osimertinib. The good news is that we don’t see any T790M mutations in patients treated with osimertinib, which tells us that that drug has an on-target effect in preventing the escape pathway mediated by T790M.

We do see some cases of secondary EGFR mutations in the form of C797S mutations, probably in about 8% to 10% of patients. We see alternative pathway activations in the form of MET amplification in about 15% of patients. These are some preliminary leads that we are getting; these are results from plasma that are ongoing efforts to look at tissue samples, to see if resistance mechanisms will read out a little differently in tissue. However, the good news is that this is the next question that the field has already focused on addressing.

How would you describe the activity that has been reported with osimertinib in combination?

As we understand resistance mechanisms to osimertinib in the form of activation in the MET pathway, and activation of MEK, we’re beginning to combine osimertinib with some of the specific inhibitors against MET and MEK.

At the 2019 AACR Annual Meeting, there were 2 presentations; Dr Lecia Sequist of Massachusetts General Hospital [presented on] combining osimertinib with a MET inhibitor, and we presented on data with osimertinib with a MEK inhibitor. Even though the numbers of patients treated so far are small…the good news is that we see the response rates in these patients ranging from 25% to 45%, and the median DOR seems to be in the upper 7 to 8 months. Therefore, these combinations can help salvage resistance to osimertinib and needs to be studied further.

What other novel strategies are in the pipeline for EGFR-mutant patients?

When we talk about EGFR inhibition, we have focused primarily on single-agent therapy for patients with EGFR mutations. At the 2019 ASCO Annual Meeting, there was a study combining erlotinib with ramucirumab (Cyramza), which resulted in a median PFS of approximately 19.2 months. The survival results are not mature, but it shows that the combination has promising activity.

There was also a study that combined chemotherapy with gefitinib in EGFR-mutated patients, which showed superiority with PFS and OS compared with gefitinib alone. There is a lot of interest looking at EGFR inhibitors with VEGF inhibition or with chemotherapy. What specific settings do we study them in? Do we give it to all patients, or do we select patients who are less likely to benefit from monotherapy? Those are key questions we need to investigate further. At this point, I don’t think we would use any of these in the United States in the frontline setting.

As chair of this State of the Science Summit™, could you emphasize the importance of having these types of events?

As new advances come in, it’s clinically important that those are applied in the clinic in a real-time basis. We all know there is a knowledge gap across various segments of people who provide care for patients with lung cancer. The purpose of this [State of the Science Summit™] was to reduce that and increase the likelihood of proven evidence-based approaches applied to every patient with lung cancer.

For instance, screening for lung cancer is very effective, but a very small percentage of patients at risk are getting screened; therefore, we want to make sure we educate our colleagues the critical importance of screening for early detection of disease. We want to make sure patients are getting molecular testing for stage IV disease, and PD-L1 testing [to determine if they can] have appropriate therapy with checkpoint inhibition. We want to make sure each patient with locally advanced stage III disease gets durvalumab (Imfinzi) as consolidation therapy. We provided updates on key developments in lung cancer and had engaging conversations with our community oncologists about complicated medical situations. It is really [important] to have ongoing conversations with our colleagues to make sure that every patient is getting top notch therapy for lung cancer.

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. Presented at: 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.
2. Tagrisso Significantly Improves Overall Survival in the Phase III FLAURA Trial for 1st-Line EGFR-Mutated Non-Small Cell Lung Cancer. AstraZeneca. Posted August 9, 2019. https://bit.ly/2ZGF7gZ. Accessed August 9, 2019.