Osimertinib Plus Chemo Adds Combination Strategy to Advanced EGFR+ NSCLC Armamentarium

Pasi A. Jänne, MD, PhD

After osimertinib (Tagrisso) plus platinum-based chemotherapy was approved for the treatment of patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC), determining if the regimen generates an overall survival (OS) benefit vs osimertinib alone will be the next key step, according to Pasi A. Jänne, MD, PhD, who added that additional research could help better identify subgroups of patients who would most benefit from the addition of chemotherapy to the EGFR inhibitor.

On February 16, 2024, the FDA approved osimertinib in combination with platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.¹

The regulatory decision was supported by data from the phase 3 FLAURA2 trial (NCT04035486), an open label, randomized trial that enrolled 557 patients with EGFR exon 19 deletion– or exon 21 L858R mutation–positive locally advanced or metastatic NSCLC who received no prior systemic therapy for advanced disease.

Findings showed that osimertinib plus chemotherapy demonstrated a statistically significant improvement in progression-free survival (PFS) compared with osimertinib monotherapy (HR, 0.62; 95% CI, 0.49-0.79; 2-sided P < .0001). The median PFS was 25.5 months (95% CI, 24.7–not estimable [NE]) and 16.7 months (95% CI, 14.1-21.3) in the combination and monotherapy arms, respectively. OS data remained immature.

“[There are] several different types of benefits of the combination over osimertinib alone. We’re excited to see this move forward and have the combination available to treat our patients,” Jänne said.

In an interview with OncLive®, Jänne expanded on the significance of the FDA approval of osimertinib plus platinum-based chemotherapy for patients with advanced EGFR-mutant NSCLC and discussed the key findings from the FLAURA2 trial that supported the decision.

Jänne serves as a senior physician, director of the Lowe Center for Thoracic Oncology, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, and the David M. Livingston, MD, Chair at the Dana-Farber Cancer Institute and is a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: Why is the FDA’s approval of osimertinib plus chemotherapy for EGFR-positive NSCLC significant?

Janne: The [FLAURA 2] trial demonstrated that the addition of chemotherapy to osimertinib, compared with osimertinib alone, as first line therapy for advanced EGFR-mutant lung cancer, led to an [8.8-month] improvement in PFS. That is a clinically significant and meaningful improvement in outcomes of patients. Although there were some added [adverse] effects [AEs] of adding chemotherapy to osimertinib, most patients tolerated the therapy very well.

In addition to the improvement in PFS, there was an also an improvement in patients who had brain metastases at baseline. There was an improvement in intracranial PFS, and more patients who received the combination of chemotherapy and osimertinib have had complete clearance of their brain metastases compared with those who have received osimertinib alone.

Osimertinib is a mutant-selective EGFR inhibitor, meaning that it’s more potent against the mutant form of EGFR that's found in cancers and less potent against the normal form of EGFR, which is found in normal tissues. Hence, it has a pretty wide therapeutic index. Most patients tolerate the drug very well. It also crosses the blood-brain barrier and gets into the brain effectively. [Since] it's a fairly well tolerated medicine, it lends itself to study combinations like chemotherapy in combination with osimertinib.

Are there any safety signals to note regarding the combination of osimertinib and chemotherapy?

With the combination of osimertinib and chemotherapy, most of the added AEs of the combination occur early on in the treatment, because that's when combination chemotherapy is administered. Once patients transition into the maintenance part of chemotherapy, which is just pemetrexed by itself, the combination of osimertinib and pemetrexed it is well tolerated. Overall, the AEs lessen over time because of the changes from combination chemotherapy to maintenance chemotherapy with osimertinib.

Where do you see osimertinib plus chemotherapy fitting into the treatment landscape for patients with EGFR-mutated NSCLC?

[Osimertinib monotherapy] is the standard of care for patients with newly diagnosed, advanced EGFR-mutant lung cancer. For patients who've had surgery for early-stage, EGFR-mutant lung cancer, [single-agent osimertinib] is also given in the adjuvant setting. Chemotherapy adds to osimertinib, but we still need to continue to develop improvements in this field. It was too early in the trial to know if [osimertinib plus chemotherapy] improves patients’ OS. We are eagerly awaiting for that piece of information. If [the combination] does not [improve OS], we need to try to understand why and how to continue to improve upon this combination [to allow] patients with newly diagnosed, advanced EGFR-mutant NSCLC to live longer and better lives.

What is your view on making treatment decisions between osimertinib monotherapy and combination therapy with osimertinib and chemotherapy?

[Osimertinib plus chemotherapy] is more effective than osimertinib alone. It doesn't mean that everybody needs to receive chemotherapy and osimertinib, and one of the areas of future research for all of us is to try to understand which of our patients truly need the more intensified combination therapy and which patients can be treated with osimertinib by itself. However, the approval clearly demonstrates that there is a benefit to adding chemotherapy to osimertinib as initial treatment. We'll need to continue to study how patients do and try to better understand who needs chemotherapy, because it does come with some associated increase in AEs.

Reference

FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed February 28, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer