On June 25, 2024 AstraZeneca reported that Tagrisso (osimertinib) with the addition of pemetrexed and platinum-based chemotherapy has been approved in Japan for the 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose tumours have exon 19 deletions or exon 21 (L858R) mutations (Press release, AstraZeneca, JUN 25, 2024, View Source [SID1234644510]).

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The approval by the Japanese Pharmaceuticals and Medical Device Agency (PMDA) was based on the results from the FLAURA2 Phase III trial, which were also published in The New England Journal of Medicine.

Results showed Tagrisso with the addition of chemotherapy reduced the risk of disease progression or death by 38% by investigator assessment compared to Tagrisso monotherapy, which is the 1st-line global standard of care (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). Median progression-free survival (PFS) was 25.5 months for patients treated with Tagrisso plus chemotherapy, an 8.8-month improvement versus Tagrisso monotherapy (16.7 months).

PFS results by blinded independent central review were consistent with results by investigator assessment, showing 29.4 months median PFS with Tagrisso plus chemotherapy, a 9.5-month improvement over Tagrisso monotherapy (19.9 months) (HR 0.62; 95% CI 0.48-0.80; p=0.0002).

While the overall survival (OS) remained immature at the second interim analysis (41% maturity), an encouraging trend towards an OS benefit was observed with Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.75; 95% CI 0.57-0.97), presented at the 2024 European Lung Cancer Congress (ELCC) in Prague, Czech Republic (abstract #4O). The trial continues to assess OS as a key secondary endpoint.

Lung cancer is the most common cause of cancer-related deaths both globally and in Japan.1-2 Lung cancer is the second most prevalent cancer type in Japan with more than 135,000 patients diagnosed each year.2 Among those with NSCLC, the most common form of lung cancer, approximately 36% of patients in Japan have tumours with an EGFR mutation.3 Additionally, the majority of patients with NSCLC are diagnosed with advanced disease.4

Kunihiko Kobayashi, MD, PhD, Professor at Saitama Medical University International Medical Center and a principal investigator in the trial, said: "The FLAURA2 results showed osimertinib with the addition of chemotherapy provided a nearly nine-month improvement in progression-free survival versus 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."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Today’s approval in Japan solidifies Tagrisso as the backbone therapy for patients with EGFR-mutated lung cancer either in combination with chemotherapy or as monotherapy, now providing two effective first-line treatment options. The opportunity to combine Tagrisso 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."

The safety profile of Tagrisso plus chemotherapy was consistent with the established profiles of the individual medicines. Adverse event (AE) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Discontinuation rates of Tagrisso due to AEs were 11% for Tagrisso plus chemotherapy and 6% for monotherapy.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFRm NSCLC. Tagrisso with the addition of chemotherapy is also approved in the US and several other countries for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.1 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.4-6

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.7-9 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.10

FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once-daily oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes in early-stage disease in the ADAURA Phase III trial, locally advanced stages in the LAURA Phase III trial and late-stage disease in the FLAURA Phase III trial and FLAURA2 Phase III trial.

As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial.

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.