AstraZeneca Announces EU CHMP Positive Opinions for Selumetinib and Tagrisso

Compiled by Keke

On April 26, AstraZeneca announced that selumetinib, a drug co-developed with MSD, has been recommended for conditional marketing authorization in the European Union (EU) for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in pediatric patients aged three years and older with neurofibromatosis type 1 (NF1).

On the same day, AstraZeneca also announced that Tagrisso (osimertinib) has been recommended for marketing authorization in the European Union for the adjuvant treatment of adult patients with early-stage (Stage IB, II, and IIIA) epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC) who have undergone complete tumor resection and remain candidates for therapy. If approved, Tagrisso will be indicated for patients whose tumors harbor EGFR exon 19 deletions or exon 21 (L858R) mutations.

Selumetinib

AstraZeneca and MSD announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion on the results of the Phase II clinical trial SPRINT Stratum 1, sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI). Safety and efficacy data from the SPRINT trial (with longer follow-up) will be provided to the CHMP as conditions for the recommended approval.

The Phase 1/2 clinical trial SPRINT Stratum 1 aimed to evaluate the objective response rate (ORR) and the impact, as assessed through patient-reported and functional outcomes, of selumetinib monotherapy in pediatric patients with NF1-related inoperable plexiform neurofibromas (PNs). The trial demonstrated an ORR of 66% (33 out of 50 patients achieved confirmed partial response) in children with NF1-associated PNs treated with oral selumetinib monotherapy administered twice daily. ORR is defined as the percentage of patients achieving a complete or partial response with confirmed tumor volume reduction of at least 20%.

Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-regulated kinase (ERK) pathway. Both MEK and ERK are key components of the RAS-regulated RAF-MEK-ERK pathway, which is frequently activated in various types of cancer.

Selumetinib was approved in the United States in April 2020 for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). In addition, clinical trials of selumetinib in adult patients with NF1-associated PN, as well as an age-appropriate alternative formulation for pediatric patients, are scheduled to commence this year.

Tagrisso

AstraZeneca announced that the CHMP issued a positive opinion on the results of the Phase III ADAURA clinical trial. In this trial, Tagrisso demonstrated statistically significant and clinically meaningful improvements in disease-free survival (DFS) both in the primary analysis population of patients with Stage II and IIIA EGFR-mutated non-small cell lung cancer (NSCLC) and in the overall study population of patients with Stage IB–IIIA disease.

The ADAURA trial is a randomized, double-blind, global, placebo-controlled Phase 3 clinical study evaluating adjuvant therapy in 682 patients with stage IB, II, and IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). Patients who had completed tumor resection and adjuvant chemotherapy received either Tagrisso 80 mg oral tablets or placebo for three years, or until disease recurrence. The trial enrolled patients at more than 200 centers across over 20 countries in the United States, Europe, South America, Asia, and the Middle East. The primary endpoint was disease-free survival (DFS) in patients with stage II and IIIA disease, while the key secondary endpoint was DFS in patients with stage IB, II, and IIIA disease. Data release was initially expected in 2022. In April 2020, an independent data monitoring committee recommended unblinding the trial two years early based on confirmation of overwhelming efficacy. Investigators and patients continued treatment while maintaining blinding. The trial will continue to assess overall survival.

Tagrisso (osimertinib) is a third-generation irreversible EGFR-TKI with clinical activity against central nervous system metastases. In multiple countries, including the United States and China, Tagrisso is approved for the treatment of early-stage lung cancer, as first-line therapy for patients with locally advanced or metastatic EGFR-mutated NSCLC, and for the treatment of locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

Currently, the Phase III trials of Tagrisso, including the locally advanced unresectable cohort (LAURA), the neoadjuvant resectable cohort (Neoadura), and the combination chemotherapy cohort (FLAURA2), are still ongoing. AstraZeneca is also addressing tumor resistance mechanisms through the Phase II trials SAVANNAH and ORCHARD, which evaluate the combination of Tagrisso with savolitinib (an oral, potent, and highly selective MET-TKI) as well as other potential novel agents.

Reference Sources:

1.Selumetinib recommended for approval in the EU by CHMP as the first medicine for paediatric patients with neurofibromatosis type 1 and plexiform neurofibromas

2.Tagrisso recommended for approval in the EU by CHMP for the adjuvant treatment of patients with early-stage EGFR-mutated lung cancer