Osimertinib Combo Receives FDA Priority Review in Advanced EGFR+ NSCLC

A supplemental new drug application of osimertinib (Tagrisso) plus chemotherapy has been granted priority review by the FDA for patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer, according to a press release from AstraZeneca, the developer of the EGFR inhibitor.¹

The application is based on results from the phase 3 FLAURA2 trial (NCT04035486), with results previously presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.² Findings via investigator assessment included improved progression-free survival (PFS) in the combination arm of 25.5 months (95% CI, 24.7-not calculable [NC]) vs 16.7 months (95% CI, 14.1-21.3) in the osimertinib monotherapy arm (HR, 0.62; 95% CI, 0.49-0.79; P <.0001). At 12 months, the PFS rate was 80% in the combination arm vs 66% in the monotherapy arm, and at 24 months it was 57% and 41%, respectively.

The PFS via blinded independent central review (BICR) was 29.4 months (95% CI, 25.1-NC) vs 19.9 months (95% CI, 16.6-25.3) in the combination and monotherapy arms, respectively (HR, 0.62; 95% CI, 0.48-0.80; P = .0002). At 12 months, the PFS rate was 80% in the combination arm and 67% in the monotherapy arm vs 62% and 47%, at 24 months, respectively.

“The FLAURA2 results reinforce [osimertinib] as a backbone of the standard of care in first-line EGFR-mutated non–small cell lung cancer, providing patients with an additional 9 months of median progression-free survival when combined with chemotherapy,” Susan Galbraith, executive vice president of oncology research and development at AstraZeneca, said in the press release. “This option is particularly important for patients with a poorer prognosis such as those with brain metastases. We look forward to working with the FDA on an accelerated timeline to bring this treatment regimen to patients as quickly as possible.”

A total of 587 patients were enrolled on the trial and were given the combination therapy (n = 279) of osimertinib at 80 mg once daily plus pemetrexed at 500 mg/m² and carboplatin at an area under the curve 5 or cisplatin at 75 mg/m² given once every 3 weeks for 4 cycles, or maintenance osimertinib at 80 mg once daily plus pemetrexed every 3 weeks. A total of 278 patients received osimertinib monotherapy.

The primary end point included PFS by BICR via RECIST 1.1, and the secondary end points were overall survival, PFS, and duration of response (DOR).

Baseline characteristics in the combination vs monotherapy arms included patients having a median age of 61 vs 62 years (range, 26-85), respectively, a majority of patients being women (62% vs 61%), 25% in both arms were Chinese Asian, and non-Chinese Asian were 39% vs 38% of patients. Additional characteristics showed that the World Health Organization performance status was 1 (62% vs 63%), patients were never smokers (67% vs 65%), had metastatic disease (95% vs 97%), and central nervous system metastases (42% vs 40%) in the combination and monotherapy arms, respectively. Additionally, EGFR mutations in the combination and monotherapy arms included exon 19 deletions (61% vs 60%), and L858R (38% vs 38%).

A total of 56% of patients in the combination arm and 45% in the monotherapy arm were still receiving treatment at the data cutoff. Discontinuation rates for osimertinib were 44%, platinum therapy was 23%, and pemetrexed was 75%. For the monotherapy arm, 55% of patients discontinued osimertinib.

For patients who received the combination, CNS metastases were present in 116 patients, and the median PFS was 24.9 months (95% CI, 22.0-NC) vs 110 patients with CNS metastases in the monotherapy arm and a median PFS of 13.8 months (95% CI, 11.0-16.7; HR, 0.47; 95% CI, 0.33-0.66). For those without metastases in the combination arm (n = 163), the median PFS was 27.6 months (95% CI, 24.7-NC) and 21.0 months (95% CI, 16.7-30.5) in the monotherapy arm (n = 168; HR, 0.75; 95% CI, 0.55-1.03).

The median PFS for patients with EGFR exon 19 deletions in the combination arm (n = 172) was 27.9 months (95% CI, 25.1-NC) vs 19.4 months (95% CI, 16.5-27.6) with osimertinib monotherapy (n = 169; HR, 0.60; 95% CI, 0.44-0.83). For those with an L858R mutation, the median PFS in the combination arm (n = 106) was 24.7 months (95% CI, 19.5-27.4) vs 13.9 months (95% CI, 11.1-19.4) in the monotherapy arm (n = 107; HR, 0.63; 95% CI, 0.44-0.90).

The objective response rate in the combination arm was 83.2% (95% CI, 78.2%-87.4%) vs 75.5% (95% CI, 70.1%-80.5%) in the monotherapy arm (OR, 1.61; 95% CI, 1.06-2.44). A complete response was observed in less than 1% and 83% had a partial response compared with 1% and 75% in the combination and monotherapy arms, respectively. The median DOR was 24.0 months (95% CI, 20.9-27.8) in the combination arm and 15.3 months (95% CI, 12.7-19.4) in the monotherapy arm.

All patients in the combination arm experienced any-grade adverse effects (AEs) vs 97% in the monotherapy arm, with 64% vs 27% experiencing grade 3 or higher AEs. The most common grade 1/2 AEs in the combination arm included nausea (42%), diarrhea (41%), anemia (27%), and constipation (29%). In the monotherapy arm, the most common grade 1/2 AEs were diarrhea (40%), paronychia (26%), dry skin (24%), and rash (21%).

In the combination arm, interstitial lung disease was reported in 3% of patients vs 4% in the monotherapy arm.

References

1. Tagrisso plus chemotherapy granted Priority Review in the US for patients with EGFR-mutated advanced lung cancer. News release. AstraZeneca. October 16, 2023. Accessed October 16, 2023. https://bit.ly/3ZUDUm9
2. Jänne PA, Planchard D, Cheng Y, et al. Osimertinib with / without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract PL03.13.