Frontline Osimertinib Plus Chemo Wins Canadian Approval for EGFR+ Advanced NSCLC

Health Canada has approved osimertinib (Tagrisso) in combination with pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R mutations.¹

The regulatory decision was supported by data from the phase 3 FLAURA2 trial (NCT04035486), which showed that osimertinib plus chemotherapy led to a statistically significant improvement in progression-free survival (PFS) compared with osimertinib alone (HR, 0.62; 95% CI, 0.49-0.79; P < .001). Per investigator assessment, the median PFS was 25.5 months (95% CI, 24.7-not calculable [NC]) for osimertinib plus chemotherapy (n = 279) vs 16.7 months (95% CI, 14.1-21.3) for osimertinib alone (n = 278).

Per blinded independent central review (BICR) assessment, osimertinib plus chemotherapy led to a median PFS of 29.4 months (95% CI, 25.1-NC) compared with 19.9 months (95% CI, 16.6-25.3) with osimertinib alone (HR, 0.62; 95% CI, 0.48-0.80).

“The FLAURA2 trial showed results demonstrating that patients experienced a significantly longer time without progression than those patients on standard of care,” Barbara Melosky, MD, FRCPC, medical oncologist and clinical professor of medicine at the University of British Columbia, stated in a news release.1 “This approval is great news for physicians and patients and further helps us to match the right patient to the right treatment to get the best possible outcomes.”

In February 2024, the FDA approved osimertinib plus platinum-based chemotherapy for use in patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.3 The European Commission approved osimertinib plus pemetrexed and platinum-based chemotherapy in the same indication on July 5, 2024.⁴

Both of those regulatory decisions were supported by data from FLAURA2, which enrolled patients at least 18 years of age (or at least 20 years of age in Japan) with previously untreated locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations. Patients were required to have a World Health Organization performance status of 0 or 1. Those with central nervous system (CNS) metastases were allowed to enroll if they were neurologically stable.²

The international, open-label study randomly assigned patients 1:1 to receive 80 mg of osimertinib per day plus 500 mg/m² of pemetrexed and either 75 mg/m² of cisplatin or area under the curve 5 of carboplatin on day 1 of each 21-day cycle for 4 cycles; or 80 mg of osimertinib per day alone. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Investigator-assessed PFS per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate, depth of response, and time to second progression.

Additional data showed that in patients who had CNS metastases at baseline, osimertinib plus chemotherapy (n = 116) resulted in a median PFS of 24.9 months (95% CI, 22.0-NC) vs 13.8 months (95% CI, 11.0-16.7) with osimertinib alone (n = 110; HR, 0.47; 95% CI, 0.33-0.66). In patients without CNS metastases, the median PFS was 27.6 months (95% CI, 24.7-NC) for osimertinib plus chemotherapy (n = 163) vs 21.0 months (95% CI, 16.7-30.5) for osimertinib alone (n = 168; HR, 0.75; 95% CI, 0.55-1.03).

Patients in the osimertinib/chemotherapy arm achieved an ORR of 83% (95% CI, 78%-87%) compared with 76% (95% CI, 70%-80%) for those in the osimertinib monotherapy arm per investigator assessment. The BICR-assessed ORRs were 92% (95% CI, 88%-95%) and 83% (95% CI, 78%-87%), respectively. The investigator-assessed median DOR was 24.0 months (95% CI, 20.9-27.8) for osimertinib plus chemotherapy vs 15.3 months (95% CI, 12.7-19.4) for osimertinib alone.

At the time of the analysis, OS data were at 27% maturity, and a trend favoring osimertinib plus chemotherapy was observed (HR, 0.90; 95% CI, 0.65-1.24; P = .52). The respective 12- and 24-month OS rates were 89% (95% CI, 84%-92%) and 79% (95% CI, 73%-83%) in the osimertinib plus chemotherapy arm. These rates were 92% (95% CI, 88%-95%) and 73% (95% CI, 67%-78%), respectively, in the osimertinib monotherapy arm.

Regarding safety, any-grade adverse effects (AEs) occurred in all patients in the osimertinib plus chemotherapy arm vs 97% of those in the osimertinib monotherapy arm. The rates of grade 3 or higher AEs were 64% and 27%, respectively. The respective rates of serious AEs were 38% and 19%.

AEs led to discontinuation of osimertinib in 11% of patients in the experimental arm vs 6% of patients in the control arm. The rates of AEs leading to dose interruptions of osimertinib were 43% and 19%, respectively. The respective rates of AEs leading to dose reductions of osimertinib were 10% and 3%.

References

1. Health Canada approves Tagrisso with the addition of chemotherapy for patients with EGFR-mutated advanced lung cancer. News release. AstraZeneca. July 12, 2024. Accessed July 12, 2024. https://www.biospace.com/article/releases/health-canada-approves-tagrisso-and-174-with-the-addition-of-chemotherapy-for-patients-with-egfr-mutated-advanced-lung-cancer
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 with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed July 12, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer
4. Tagrisso with the addition of chemotherapy approved in the EU as new 1st-line treatment for patients with EGFR-mutated advanced lung cancer. News release. AstraZeneca. July 5, 2024. Accessed July 12, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-with-the-addition-of-chemotherapy-approved-in-the-eu-as-new-1st-line-treatment-for-patients-with-egfr-mutated-advanced-lung-cancer.html