EGFR TKIs for Curative Intent Among Patients With Early-Stage Non-Small Cell Lung Cancer

At the 2022 Great Debates & Updates in Lung Cancer meeting in New York, Helena Yu, MD, Memorial Sloane Kettering Cancer Center, New York, discussed how to treat patients with early-stage EGFR-mutated lung cancer.

In her presentation, Dr Yu focused on treatments in the adjuvant setting, covering platinum-doublet chemotherapy and the EGFR TKI osimertinib.   

Transcript

Hi everyone. My name's Helena Yu. I am a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. I gave a talk at Great Debates and Updates in Lung Cancer discussing exporting EGFR inhibitors to the curative setting. To begin this topic and this talk, I think it's important to highlight that we don't do great for early-stage lung cancers. Even stage 2 lung cancers, which are early-stage lung cancers, only about half of patients are alive at 5 years. Even for EGFR-mutant lung cancer, when you look at early-stage cancers, only about 40% are cancer-free at 4 to 5 years. A lot of people have recurrent disease, and a lot of people end up dying of their disease. EGFR-mutant lung cancer has a similar prevalence or frequency in early-stage lung cancer, and there is some data to suggest that, stage-for-stage, EGFR-mutant lung cancer does worse. So this is really an important subset to look at.

The only kind of established adjuvant treatment for all-comers based on stage is platinum-doublet chemotherapy. Large prospective randomized studies, including meta-analyses, have shown a small but real benefit in overall survival with the addition of adjuvant chemotherapy for the appropriate patients. This is still a mainstay and important to offer our patients. When we think about adjuvant therapies, it’s important to think about what we're trying to do with adjuvant therapy. The ultimate goal would be to eliminate any micrometastatic residual disease with adjuvant therapy after surgery, and consequently, cure more patients. Another potential possibility is that adjuvant therapies can suppress or control residual disease but not eradicate disease. This would lead to disease control and improved disease-free survival, and delaying recurrence, but not improving overall survival oftentimes. Adjuvant therapies can also do neither. They can be ineffective or intolerable. Of course, in that situation, we don't want to use them.

The areas besides chemotherapy where we think there is potential in improving outcomes for patients is the addition of targeted therapies, as well as immunotherapies. Both have been looked at in the adjuvant and perioperative setting to look to improve survival. The big study for targeted therapy was the ADAURA study. This was a large, almost 700-patient study of patients with resected EGFR-mutant lung cancers with stage 1B through 3A disease. And those patients were randomized 1-to-1 to receive osimertinib or placebo for a total of 3 years. These patients had the common EGFR mutations [exon 19 deletion] ex19del/L858R, and they were stratified by type of EGFR mutation, race, and stage.

Based on the ADAURA positive data in December 2020, osimertinib was approved by the FDA for adjuvant therapy. There was an update at ASCO in September 2022 that provided an additional 2 years of follow-up that again showed a marked improvement in disease-free survival with the use of adjuvant osimertinib. This benefit deepened in higher stages but remained across all stages, all subgroups, and with or without the use of adjuvant chemotherapy. Importantly, there was a significant reduction in [central nervous system] CNS recurrences, which of course have significant morbidity and mortality for our patients and set the stage for the use of osimertinib as adjuvant therapy. They did not yet provide an update on overall survival data, which we are still awaiting, but the data makes a convincing case based on the risk reduction of disease recurrence to utilize this for the appropriate patient.

In my practice, I offer adjuvant osimertinib for patients with stage 1B through 3 EGFR-mutant lung cancer. I think some questions that are outstanding are, of course, is there going to be an overall survival benefit? How long to continue the EGFR inhibitor?

There was the interesting suggestion of potential narrowing of the curves after 3 years, after the completion of osimertinib. We'd like to see further data on that, as well as data on treatments upon recurrence, but osimertinib is an important treatment option that we have for our patients. Regarding upcoming or novel studies in the perioperative space, osimertinib is being looked at in the neoadjuvant setting in neoADAURA, just like some of the immunotherapy chemotherapy studies. There could be greater benefit with these treatments given upfront to lead to a more effective complete surgery.

Because a lot of the mutation subsets within lung cancer are quite small, there are these basket studies largely led by the Lung Cancer Mutation Consortium, LCMC, where patients are getting biopsied. And when we see their PD-L1 expression and what mutations are present, they can be allocated to the appropriate perioperative study, such as a study for chemotherapy-immunotherapy or adjuvant selpercatinib for a RET-positive lung cancer, focused on personalized perioperative care.

Finally, in terms of novel studies, we're going to be using ctDNA to help us understand who's at risk in the perioperative setting. There's good data that the presence of ctDNA in plasma after curative surgery demonstrates who's at risk for recurrence. I envision future studies to utilize ctDNA positivity as a biomarker to help stratify patients and randomize them to certain treatments based on their risk of recurrence. We will see a slew of studies like that next.

In conclusion, it's important to test all patients in the early stage setting for these different predictive biomarkers. Adjuvant chemotherapy still definitely has a role for the appropriate patient because it has a small but real survival benefit. Osimertinib is established a standard of care in the adjuvant setting for early-stage lung cancers. We await a lot of these new studies to see what's next in this space. Improving outcomes in the early stage is important because that is of course our opportunity to cure our patients. Thanks for listening. Bye.

Source

Yu, H. Exporting EGFR TKIs to the Curative Setting. Presented at: Great Debates & Updates in Lung Cancer; Oct 14-15, 2022; New York, New York.