Novel Approaches Seek to Enhance Efficacy of Osimertinib in EGFR+ NSCLC

Jeffrey M. Clarke, MD

Despite the sequential efficacy of some of the FDA-approved EGFR TKIs, frontline osimertinib (Tagrisso) confers the greatest progression-free survival (PFS) advantage for patients with EGFR-positive non—small cell lung cancer (NSCLC), explained Jeffrey M. Clarke, MD.

“At this point, we have been selecting osimertinib for most of our treatment-naïve patients given the improvement in PFS relative to the first- and second-generation agents, as well as [enhanced tolerability] compared with dacomitinib (Vizimpro),” said Clarke.

Even so, patients will progress, making the pursuit of rational combination approaches a top priority in the field. To date, combinations of VEGF- and EGFR-targeted therapies have shown consistent PFS benefit, but clinically meaningful improvements in overall survival (OS) have yet to be observed. Additionally, acquired resistance mechanisms, such as MET amplification, offer the opportunity to explore other combinations, which was done in the phase Ib TATTON trial with the combination of savolitinib and osimertinib.

Additional insight from a subgroup analysis of the phase III IMpower150 trial suggests that immunotherapy may also have a role upon progression in patients with nonsquamous NSCLC who harbor an EGFR mutation. In the trial, patients with untreated nonsquamous NSCLC, not excluding patients with an EGFR or ALK mutation, were randomized to receive the combination of atezolizumab (Tecentriq), carboplatin, and paclitaxel (ACP); bevacizumab (Avastin), carboplatin, and paclitaxel (BCP); or atezolizumab plus BCP (ABCP).

Although initially excluded from the intent-to-treat analysis, patients with EGFR mutations (n = 58) experienced a median PFS of 6.1 months with ABCP, reflecting a 59% reduction in the risk of progression or death compared with either BCP or ACP alone. Notably, the median OS had not yet been reached in these patients.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Clarke, assistant professor of medicine, Duke Cancer Institute, discussed the optimal targeted therapies for the frontline treatment of patients with EGFR-positive NSCLC and sequencing beyond progression.

OncLive^®: What are the available EGFR TKIs in the frontline setting for patients with EGFR-positive NSCLC?

Clarke: Currently there are a total of 5 FDA-approved TKIs for frontline treatment of EGFR- positive NSCLC. These include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), dacomitinib, and osimertinib. We have seen a lot of exciting data over the past couple years with regard to these agents.

Most excitingly, we saw the results of the FLAURA study last year and the FDA approval that resulted from the trial. The FLAURA study was a large phase III trial in which patients were randomized to receive either osimertinib, gefitinib, or erlotinib. There was a significant improvement in PFS in patients who received osimertinib. Overall, the therapy was well tolerated; we're still waiting on the OS data. Even so, the study was practice-changing. Clinically, we see that there are lower rates of significant rash with this therapy.

We've also seen the recent FDA approval of dacomitinib, which shows higher rates of grade 3/4 diarrhea and rash compared with gefitinib. However, there was an improvement in PFS as well as OS seen with dacomitinib. At this point, most people feel that osimertinib remains the preferred frontline therapy based on tolerability and PFS; however, there are multiple options.

How else do these agents compare with one another?

The PFS with osimertinib is somewhat longer than what we see with dacomitinib. Osimertinib is a third-generation agent, which spares EGFR wild-type, whereas dacomitinib is a potent irreversible pan-HER inhibitor. At this point, we know that dacomitinib improves OS; we're still waiting on that data for osimertinib. As far as the toxicity profiles, osimertinib has a clear advantage with lower rates of grade 3/4 toxicity, primarily driven by improvements in rash and potentially diarrhea, as well.

Are there any ongoing trials with other TKIs or combination approaches?

There have been several studies conducted over the past several years looking at anti-VEGF therapies in combination with anti-EGFR therapies. We've seen a consistent improvement in PFS in those studies of at least several months. However, one study that came out of Japan last year showed that there was no improvement in OS [with the combination of VEGF- and EGFR-targeted agents]. Patients were randomized to receive the combination of bevacizumab and erlotinib compared with erlotinib alone. It does somewhat call into question what should be expected from these agents moving forward.

Additionally, we're eagerly awaiting data with ramucirumab (Cyramza) in combination with erlotinib in this patient population, [a combination] that is reportedly positive for PFS. Moreover, there have been studies looking at different therapies following progression on osimertinib. We've seen exciting data from the TATTON study, which showed response rates ranging from 30% to 50% with the combination of savolitinib and osimertinib and a duration of response of 7 months in one study, and I believe 9 months in the other study. We definitely have exciting data targeting MET amplification in those patients. We're looking to studies that are looking at the rationale for combinations following progression on osimertinib.

Could you discuss ongoing work regarding immunotherapy in EGFR-mutant patients?

We now have several published reports and studies investigating immunotherapy for patients with EGFR and ALK alterations and demonstrating suboptimal clinical benefit. We've seen studies enrolling [EGFR-mutant] patients with high PD-L1 scores that show no responses with immunotherapy. That’s really striking evidence to support the fact that immunotherapy, at least in treatment-naïve patients with EGFR mutations, does not have any activity.

We've seen data from the IMpower150 study, in which patients could receive 1 of 3 regimens following progression on their TKI, one of which included chemotherapy plus bevacizumab and atezolizumab. There, we saw a significant improvement in PFS compared with chemotherapy/bevacizumab or chemotherapy/atezolizumab. The combination of those drugs is a regimen that many people are excited about for patients with EGFR mutations and potentially patients with ALK mutations as well. We need additional data regarding its use in that patient population, although there is a high response rate and a meaningful improvement in PFS.

Could you expand on the role of chemotherapy upon progressive disease?

Those data come from the IMpower150 study. Patients with EGFR and ALK mutations were allowed to be enrolled in the study although they were not included in the intent-to-treat analysis. In the subgroup analysis looking at those patients, we saw a very high response rate approaching 70% with chemotherapy, bevacizumab, and atezolizumab. There was also an improvement in PFS upwards of 10 months, whereas the patients who did not receive that regimen had a PFS of around 6 months. These are exciting data that everyone is enthusiastic about. Everyone wants immunotherapies to work in this patient population—it's a matter of finding the right combination.

Where is research headed?

Novel combinations, certainly targeting VEGF. We'll see several studies moving forward with results reported out in the coming year or 2. There are exciting ongoing studies targeting MET following progression on osimertinib. I would look toward novel approaches that are trying to enhance the activity of osimertinib by targeting other oncogenic pathways in combination with anti-EGFR therapy.

Reck M, Mok TSK, Nishio M et al. Atezolizumab plus bevacizumab and chemotherapy in non-small cell lung cancer (IMpower150): key subgroup analysis of patients with EGFR mutations or liver metastasis in a randomised, open label phase 3 trial. Lancet Respir Med. 2019;7(5):387-401. doi: 10.1016/S2213-2600(19)30084-0.