Expert Outlines Opportunities With Osimertinib in EGFR-Mutant NSCLC

Elaine Shum, MD

Osimertinib (Tagrisso) is the standard of care in the frontline treatment of patients with EGFR-mutant non–small cell lung cancer (NSCLC), according to Elaine Shum, MD, and the agent may also be on its way to becoming a key player in the adjuvant setting and a promising option to include with novel combinations.

Results from the phase 3 ADAURA trial, presented during the 2020 ASCO Virtual Scientific Programshowed that adjuvant osimertinib resulted in a significant and clinically meaningful improvement in disease-free survival (DFS) in patients with EGFR-mutated, stage I, II, and IIIA disease. The DFS with osimertinib had not been reached versus 20.4 months with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). These data, according to Shum, underscore the importance of identifying whether patients harbor an EGFRmutation as early as possible.

“First, we need to find the EGFR mutation. We still hear many reports of patients who undergo chemotherapy and immunotherapy in the metastatic setting, without knowing whether or not they have an EGFR mutation. Testing, with liquid biopsy to begin with, followed by NGS testing on tissue, is certainly very important,” said Shum. “I believe osimertinib is really here to stay; it still is my first-line choice for these patients. The question of whether we can improve osimertinib with other agents such as VEGF inhibitors, does remain to be seen.”

In an interview with OncLive during the International Perspectives in Cancer webinar on Lung Cancer,Shum, an associate professor in the Department of Medicine at NYU Grossman School of Medicine, discussed exciting data with osimertinib and other emerging approaches in EGFR-mutated NSCLC.

OncLive: Could you provide a brief overview of the key developments made in EGFR-mutant lung cancer?

Shum: In the past few months, we’ve seen exciting data. Some agents have been FDA approved, although, not all of them have received regulatory approval just yet. These developments have certainly been discussion generating and exciting for the field of lung cancer.

Specifically, the ADAURA trial was discussed during the 2020 ASCO Virtual Scientific Program. FLAURA is another key trial and it’s important to put that into context with the RELAY trial, which led to the recent FDA approval [of ramucirumab (Cyramza) and erlotinib (Tarceva)] for patients with EGFR-mutated disease.

The ADAURA trial generated a good deal of excitement at this year’s ASCO meeting. What is the significance of this trial?

The data are very exciting. A hazard ratio (HR) of 0.17 is almost unheard of in most of the studies that we have seen thus far. It’s still very early on and we are awaiting the OS data. However, with the encouraging DFS demonstrated, it's hard to believe that there won’t be an OS benefit. Even more importantly, the fact that EGFR TKIs are moving into the early-stage space is also exciting; this definitely presents our patients with new options that will hopefully help them live longer.

Given that trial, are you inclined to use osimertinib in all patients or just specific subsets?

The primary end point was looking at stage II and III disease, but investigators also looked at patients with stage IB disease. An impressive HR was also observed in that group of patients, but, again, it’s a much earlier stage of disease compared with stage II and III disease.

Right now, this trial is definitely something that I'm discussing with my patients who have had resected lung cancer with an EGFR mutation. For patients with stage II and III disease, it's definitely [an option] that I would encourage them to pursue. For those with stage IB disease, even with just the use of adjuvant chemotherapy, there's no set standard on who receives it and who does not. In the clinic, we have this discussion about whether to use osimertinib for 3 years in patients with stage IB resected disease.

Other trials have shown a DFS benefit with EGFR TKIs that did not translate into an OS benefit. Does this impact your decision making?

During this year’s ASCO meeting, the OS data for the adjuvant [CTONG 1104] trial was discussed as a prime example of how we saw a DFS advantage that did not translate into an OS advantage. This trial definitely differs from the ADAURA trial. A different EGFR TKI was used and the design of the study was also different in that patients were randomized to either receive the TKI or chemotherapy.

I believe many do consider osimertinib to be the more superior drug over some of the earlier generation TKIs, so that's something to bear in mind. This study definitely makes us pause in terms of rushing to give this [option] to patients until we see OS data. However, again, with such an impressive HR observed in ADAURA, it would be really [surprising] to not see some form of benefit here.

How do you believe next-generation sequencing (NGS) will be impacted?

This is a great advantage of the study coming out. Right now, many insurance companies only cover NGS for late stages of lung cancer. However, with the ADAURA data, more people should definitely be interested to know whether their patients have these mutations or not.

Liquid biopsies are an easy and somewhat painless way to get this information. The timing of the liquid biopsy will be important. With earlier stage disease, you can argue the burden of disease might be less. However, the advantage of having a resected specimen is that there should be plenty of tissue that's available that could be sequenced; that provides a wealth of information.

If we can get a buy-in from many companies to ensure that NGS is covered by insurance so that we can get this information, it would not only help the patients, but it would help the field. This is especially true in terms of looking at other mutations that might benefit from adjuvant therapies.

Shifting to the FLAURA trial, if osimertinib is being brought into the adjuvant setting, how will it affect its use in the metastatic setting?

That’s another big question: If you use osimertinib in the early-stage setting and the patient develops progression, what are you going to use next? For all stages of disease, when someone progresses, each situation is a little different, whether it's oligometastatic disease or more widespread progression. This should be taken into account.

Right now, the standard of care would be to try to see what kind of resistance mechanisms develop after osimertinib at the time of progression. Treatment that is tailored to that resistance mechanism should also be looked into. However, without a known resistance mechanism, chemotherapy is commonly used; the majority of patients will most likely receive this treatment. Hopefully some of our studies looking at these resistance mechanisms and treatments will pan out by that time so we can present more options to patients.

For patients coming in with metastatic disease, is osimertinib the standard? How are you integrating the results of the RELAY trial into practice?

Even with data from the RELAY trial, osimertinib is still the standard of care for first-line, metastatic, EGFR-mutated NSCLC. When comparing data from FLAURA with those reported from RELAY, it’s important to note that the RELAY trial did not include patients with central nervous system (CNS) disease, which is a huge factor. Patients often develop CNS metastases either at diagnosis or at the time of progression. Whether you use osimertinib or the combination of erlotinib and ramucirumab, the progression-free survival data are similar. This being said, patients should consider taking the oral medication osimertinib alone versus having to come in for infusions of ramucirumab in terms of quality of life; the potential benefits with the combination should be weighed against osimertinib alone.

Are any agents or approaches emerging in the EGFR space that you wanted to highlight?

As mentioned earlier, looking at the resistance mechanisms that develop after progression with osimertinib is definitely an exciting space. We're hoping that we will have standard-of-care agents soon, but most of these efforts are still ongoing. Many different trials are examining different combinations of MET inhibitors with osimertinib to overcome some of these resistance mechanisms.

There is also JNJ-6372 [in metastatic NSCLC with EGFR exon 20 insertion mutations and efforts] looking at patients with MET amplification and C797S resistance mutation, which is well known to develop after osimertinib. Promising data are coming out but only time will tell what we should do next with our patients.

Reference

Herbst RS, Tsuoboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5