Osimertinib (Tagrisso) Nears Approval for NSCLC Adjuvant Therapy in China as New Indication Enters Final Regulatory Stage

By Dopine

[Image] Recently, AstraZeneca’s registration application (Class 2.4) for osimertinib mesylate tablets (brand name: Tagrisso), with relevant acceptance numbers JXHS2000150/151, has entered the administrative approval phase. It is expected to be approved in China shortly for its third indication: adjuvant treatment of adult patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) sensitizing mutations following tumor resection.

Osimertinib Mesylate (osimertinib; Tagrisso) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It was approved by the FDA in 2015 for the treatment of previously treated non-small cell lung cancer (NSCLC), approved by the FDA in 2018 as first-line therapy for metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations, and approved by the FDA in December 2020 for adjuvant treatment of patients with EGFR-mutated NSCLC following surgical resection.

According to the latest 2020 global cancer burden data released by the International Agency for Research on Cancer (IARC) of the World Health Organization, lung cancer ranks second in incidence and first in mortality worldwide, with approximately 80%–85% of cases classified as non-small cell lung cancer (NSCLC). EGFR is a major driver gene in NSCLC; approximately 20% of NSCLC patients harbor this mutation, with a higher prevalence of up to 40% observed in Asian populations. Although most NSCLC patients are diagnosed at an advanced, inoperable stage, around 30% are diagnosed at an early stage and can undergo curative surgery. However, nearly half of patients with stage IB NSCLC and more than three-quarters of those with stage IIIA NSCLC experience recurrence within five years.

Reducing the risk of recurrence and improving the quality of life in patients with lung cancer after surgery have always been the goals of clinical research. At the 2020 ASCO Annual Meeting, results from the ADAURA study on osimertinib as adjuvant therapy for EGFR-mutated stage IB–IIIA non-small cell lung cancer (NSCLC) showed that, compared with placebo, osimertinib significantly prolonged median disease-free survival (DFS) in patients with stage II–IIIA disease, reducing the risk of disease recurrence or death by 83%. In the overall population, osimertinib reduced the risk of disease recurrence or death by 80%. Notably, the 2021 NCCN Clinical Practice Guidelines in Oncology (Version 1) recommend osimertinib for postoperative adjuvant treatment in patients with stage IB–IIIA EGFR-mutated NSCLC, regardless of whether they have received prior adjuvant chemotherapy or are intolerant to chemotherapy.

Since its approval and market launch in 2015, osimertinib has evolved from a second-line to a first-line therapy for advanced non-small cell lung cancer (NSCLC), and from treatment for advanced-stage to early-stage NSCLC, thereby reshaping the therapeutic landscape for EGFR-targeted agents. With the expansion of its approved indications and target patient populations, annual sales of osimertinib have risen steadily. Starting in 2019, it topped AstraZeneca’s core product sales rankings for two consecutive years, reaching $4.328 billion in 2020.

In China, osimertinib was first approved by the National Medical Products Administration (NMPA) in March 2017 for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had experienced disease progression during or after prior EGFR-TKI therapy and whose tumors tested positive for the EGFR T790M mutation. Marketed under the brand name Tagrisso, it was included in the National Reimbursement Drug List in 2018. In September 2019, the NMPA further approved osimertinib for first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR mutations. In December 2020, the first-line NSCLC indication for Tagrisso was added to the National Reimbursement Drug List, while its second-line NSCLC indication was successfully renewed, making it the only third-generation EGFR-TKI with a first-line NSCLC indication covered by national medical insurance.

We look forward to the early formal approval of osimertinib in China for adjuvant therapy in adult patients with EGFR-mutated NSCLC following surgery. We believe that with price reductions under the national medical insurance program, osimertinib will benefit more patients.

The Domestic Third-Generation EGFR-TKI Market Is Dominated by Three Major Players, with Two Additional Products Having Submitted Marketing Applications

Currently, three EGFR-TKIs have been approved in China: osimertinib, aumolertinib, and alflutinib, among which two are domestically produced and one is imported. In addition to furmonertinib, both osimertinib and aumolertinib have been successfully included in the National Reimbursement Drug List (NRDL). It is reported that the latest price of osimertinib is CNY 5,580 per box (80 mg × 30 tablets), with one box per month and a 70% reimbursement rate, resulting in a monthly out-of-pocket treatment cost of CNY 1,674. Meanwhile, the latest price of aumolertinib is CNY 3,520 per box (55 mg × 20 tablets), with three boxes required per month and a 70% reimbursement rate, leading to a monthly out-of-pocket treatment cost of CNY 3,168, which is higher than that of osimertinib.

In addition, two third-generation EGFR-TKIs are currently in the marketing application stage: ivosertinib from Acea Biosciences and befotertinib from Betta Pharmaceuticals. The marketing application for ivosertinib was accepted by the CDE in June 2018 and is expected to be approved this year. Furthermore, several other third-generation EGFR-TKIs are in clinical trials, including BPI-7711 from BeiGene, aumolertinib from Simcere Pharmaceutical, and RX518 from Runxin Biopharmaceutical.

The market for third-generation EGFR-TKIs alone demonstrates the continuously strengthening R&D capabilities of China’s pharmaceutical industry, which is also gradually expanding into overseas markets. In May 2020, Acea Biotech exclusively licensed to Sorrento Therapeutics the rights to all indications of avitinib in all territories outside China. In July 2020, Hansoh Pharma exclusively granted EQRx the rights to develop and commercialize almonertinib in territories excluding mainland China, Hong Kong, Macao, and Taiwan.

In addition, among the multiple EGFR-TKIs approved in China, apart from almonertinib and furmonertinib, there is another domestically produced EGFR-TKI, namely icotinib (trade name: Conmana) developed by Betta Pharmaceuticals. It is the only domestically developed first-generation EGFR-TKI approved in China, which received approval in May 2016 and achieved sales of RMB 1.87 billion in 2020.