First-Line Osimertinib Plus Chemo Approved in Japan for EGFR+ Advanced NSCLC

First-line osimertinib (Tagrisso) plus pemetrexed and platinum-based chemotherapy has been approved by the Japanese Pharmaceuticals and Medical Device Agency (PMDA) for the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R mutations.¹

This regulatory decision was based on data from the randomized, open-label, multicenter, phase 3 FLAURA2 study (NCT04035486), which demonstrated that the addition of osimertinib to chemotherapy reduced the risk of disease progression or death reduced by 38% compared with osimertinib monotherapy (HR, 0.62; 95% CI, 0.49-0.79; P < 0.0001). The investigator-assessed median progression-free survival (PFS) was 25.5 months (95% CI, 24.7–not calculable [NC]) for patients treated with the combination (n = 279) vs 16.7 months (95% CI, 14.1-21.3) for those given osimertinib alone (n = 278).²

Moreover, blinded independent central review assessment showed that the median PFS was 29.4 months (95% CI, 25.1-NC) with osimertinib plus chemotherapy vs 19.9 months (95% CI, 16.6-25.3) with osimertinib alone (HR, 0.62; 95% CI, 0.48-0.80).

Although overall survival (OS) data remained immature at the second interim analysis, a trend was observed favoring osimertinib plus chemotherapy vs osimertinib alone (HR, 0.90; 95% CI, 0.65-1.24; P = .52). The 12- and 24-month OS rates for osimertinib plus chemotherapy were 89% (95% CI, 84%-92%) and 79% (95% CI, 73%-83%), respectively. Those respective rates were 92% (95% CI, 88%-95%) and 73% (95% CI, 67%-78%) in the osimertinib monotherapy group.

“The FLAURA2 results showed [that] osimertinib [plus] chemotherapy provided a nearly 9-month improvement in PFS vs osimertinib monotherapy. This approval brings an important new treatment option for this aggressive form of lung cancer, the leading cause of cancer death in Japan," principal trial investigator Kunihiko Kobayashi, MD, PhD, professor at Saitama Medical University International Medical Center, in Hidaka, Japan, stated in a news release.¹

In February 2024, the FDA approved osimertinib plus platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. This regulatory approval was also based on data from FLAURA2.³

FLAURA2 enrolled patients at least 18 years of age (or at least 20 years of age in Japan) with newly diagnosed locally advanced or metastatic NCSLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation who did not have prior exposure to systemic treatment for advanced disease; a World Health Organization performance status of 0 or 1; and a life expectancy greater than 12 weeks.⁴

Exclusion criteria included those with unstable brain metastases; a history of interstitial lung disease; radiation pneumonitis needing steroids; severe or uncontrolled systemic diseases; and active infections. Additional exclusion criteria include inadequate bone marrow reserve or organ function; refractory nausea and vomiting; chronic gastrointestinal diseases; and significant prior bowel resection.

Eligible patients were randomly assigned to receive 80 mg of oral osimertinib once per day in combination with pemetrexed at 500mg/m² and cisplatin at 75mg/m² or carboplatin area under the curve 5 every 3 weeks for 4 cycles, followed by osimertinib once per day plus pemetrexed at 500 mg/m² once every 3 weeks as maintenance; or oral osimertinib at 80 mg once per day.

The primary end point was PFS, and key secondary end points included OS, objective response rate, duration of response, depth of response, disease control rate, time to second progression, and safety.

The safety profile of osimertinib combined with chemotherapy was consistent with the known profiles of the individual medications, although adverse effect (AE) rates were higher in the osimertinib plus chemotherapy group. This was primarily due to well-characterized chemotherapy-related AEs. Discontinuation rates of osimertinib due to AEs were 11% for the combination therapy group and 6% for the monotherapy group.¹

“Today's approval in Japan solidifies [osimertinib] as the backbone therapy for patients with EGFR-mutated lung cancer either in combination with chemotherapy or as monotherapy, now providing 2 effective first-line treatment options," Dave Fredrickson, executive vice president of the Oncology Business Unit at AstraZeneca, added in a news release. "The opportunity to combine osimertinib with chemotherapy is especially important for those patients with a poorer prognosis, such as those whose disease has spread to the brain or those with L858R mutations."

References

1. Tagrisso with the addition of chemotherapy approved in Japan as new 1st-line treatment for patients with EGFR-mutated advanced lung cancer. News release. AstraZeneca. June 25, 2024. Accessed June 25, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-addition-chemotherapy-approved-japan-new-first-line-treatment-patients-egfr-mutated-advanced-lung-cancer.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 with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. February 16, 2024. Accessed June 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer
4. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2) (FLAURA2). ClinicalTrials.gov. Updated February 14, 2024. Accessed June 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04035486