Osimertinib Plus Chemotherapy Moves One Step Closer to EU Approval in EGFR+ Advanced NSCLC

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of osimertinib (Tagrisso) for use in combination with pemetrexed and platinum-based chemotherapy as frontline treatment for adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R mutations.¹

The positive opinion was based on data from the phase 3 FLAURA2 trial (NCT04035486), which demonstrated a 38% reduction in the risk of disease progression or death with the combination vs osimertinib alone (HR, 0.62; 95% CI, 0.49-0.79; P <.0001). The median investigator-assessed progression-free survival (PFS) was 25.5 months (95% CI, 24.7–not evaluable [NE]) in the combination arm vs 16.7 months (95% CI, 14.1-21.3) with osimertinib alone. Overall survival (OS), though immature at the second interim analysis with 41% maturity, displayed a positive trend in favor of the combination vs osimertinib alone (HR, 0.75; 95% CI, 0.57-0.97).²

“The FLAURA2 results build on the established efficacy of osimertinib monotherapy in patients with EGFR-mutated lung cancer, demonstrating a meaningful 9-month improvement in PFS with the addition of chemotherapy,” David Planchard, MD, PhD, thoracic oncologist at Gustave Roussy Institute of Oncology and principal investigator for the trial, stated in a news release.¹ “Today’s positive recommendation is a vital step toward providing patients in Europe with an additional treatment option capable of extending the time before their disease progresses. This expands on the already approved use of osimertinib as monotherapy, providing physicians with options to tailor treatments that best suit their patients' specific disease needs.”

In February 2024, the FDA granted approval to the combination of osimertinib and platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.³

FLAURA2 is a randomized, open-label, multi-center, global phase 3 trial evaluating the activity of osimertinib plus chemotherapy vs osimertinib alone in patients with newly diagnosed, locally advanced stage IIIB to IIIC or metastatic stage IV EGFR-mutated NSCLC.¹ Patients who were randomly assigned to the investigational arm received 80 mg of osimertinib via oral tablets plus pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin at area under the curve 5 every 3 weeks for four cycles, followed by osimertinib with pemetrexed maintenance every 3 weeks.

To be eligible for enrollment, patients could not have previously received systemic therapy for advanced disease. Patients also needed to have measurable disease by RECIST 1.1 criteria and a World Health Organization performance status of 0 or 1.

The primary end point of the trial is investigator-assessed PFS. OS, a key secondary end point, will continue to be evaluated as the trial is ongoing. Other secondary end points include objective response rate (ORR) and duration of response (DOR).

Regarding responses, osimertinib plus chemotherapy led to an ORR of 77% (95% CI, 71%-82%) vs 69% (95% CI, 63%-74%) with osimertinib alone, with median DORs of 24.9 months (95% CI, 22.1-NE) and 17.9 months (95% CI, 15.2-20.9), respectively.

“Today’s news reinforces the importance of [osimertinib] as the backbone therapy in EGFR-mutated lung cancer. If approved in Europe, patients will have the option to be treated with [osimertinib] alone, or with chemotherapy, which is especially important when caring for patients whose disease has spread to the brain or those with L858R mutations,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, said.¹

The safety profile of the combination was mostly manageable and comparable with the known adverse effect (AE) profiles of each agent alone.1 The most common AEs that occurred in the combination arm were diarrhea (any grade, 43%; grade ≥3, 2.9%), stomatitis (31%; 0.4%), rash (49%; 2.5%), nail toxicity (27%; 0.7%), dry skin (24%; 0%), and pruritus (8%; 0%). The rate of serious and fatal AEs with osimertinib plus chemotherapy was 38% and 7%, respectively. AEs leading to dose interruptions or reductions were required by 44% of patients in the combination arm vs 10% of patients in the monotherapy arm. Treatment discontinuation owing to AEs occurred in 11% of patients in the combination arm vs 6% of those in the osimertinib monotherapy arm.²

References

1. Tagrisso with the addition of chemotherapy recommended for approval in the EU by CHMP for patients with EGFR-mutated advanced lung cancer. News release. AstraZeneca. June 3, 2024. Accessed June 4, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-plus-chemo-recommended-for-approval-in-eu.html
2. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
3. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed June 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer