AMGEN recently announced that the European Commission (EC) has conditionally approved the targeted anti-cancer drug Lumykras (sotorasib): a first-in-class KRASG12C inhibitor for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) who have previously undergone disease progression after at least one systemic therapy. Ongoing approval for this indication will depend on the validation and description of clinical benefits in confirmatory clinical trials.
It is worth mentioning that Lumykras is the first targeted therapy in the European Union for KRAS G12C mutations, which is one of the most common biomarkers in NSCLC. It is estimated that about 13-15% of Patients with European NSCLC carry the KRAS G12C mutation.
Sotorasib, the first KRAS G12C inhibitor to enter clinical development, received FDA approval (trade name Lumakras) in May 2021 for the treatment of adult patients who have previously received at least one systemic therapy and have been confirmed by FDA-approved tests with KRAS G12C mutations, locally advanced stages, or metastatic NSCLC. In clinical trials, sotorasib treatment has shown rapid, deep, and long-lasting anticancer activity with positive benefit-risk profiles.
To date, sotorasib has been ratified by 35 countries worldwide. In China, sotorasib was included as a "breakthrough therapeutic drug" by the NmPA Drug Evaluation Center (CDE) in February 2021. This determination is directed at patients with locally advanced or metastatic NSCLC who have previously received at least one systemic treatment and who have received at least one previous systemic treatment.
It is worth mentioning that Lumakras is the first KRAS targeted therapy approved after nearly 40 years of research, and the first and only targeted therapy approved for the treatment of locally advanced or metastatic NSCLC patients carrying KRAS G12C mutations. NSCLC is the most common type of lung cancer, accounting for about 84% of the 2.2 million newly diagnosed lung cancer cases worldwide each year. KRAS mutations, the most common driver mutations in NSCLC, are now a "drug-ready" target. KRAS mutations account for about 25% of NSCLC mutations; among them, KRAS G12C is the most common type of KRAS mutation in NSCLC. About 13% of patients with non-squamous NSCLC carry the KRAS G12C mutation.
The EU approval is based on a positive outcome of the late NSCLC patient cohort in the Phase 2 CodeBreaK 100 study. The study is the largest clinical trial to date in a population of patients carrying the KRAS G12C mutation. Data from a cohort of 124 PATIENTs with POSITIVE NSCLC mutations in KRAS G12C who progressed after receiving immunotherapy and/or chemotherapy showed that Lumakras was well-treated and tolerable.
In this cohort, patients treated with 960 mg of Lumakras orally once daily had an objective response rate (ORR) of 37.1% (95% CI: 28.6 to 46.2), a median duration of remission (DoR) of 11.1 months, a disease control rate (DCR) of 80.6%, and a median overall survival (mOS) of 12.5 months. The most common adverse reactions were diarrhea (34%), nausea (25%), and fatigue (21%). The most common severe (grade ≥3) adverse reactions were elevated alanine aminotransferase levels (ALT; 5%), elevated aspartate aminotransferase levels (AST; 4%), and diarrhea (4%).
Sotorasib (AMG510) chemical structural formula (Image: selleck.cn)
KRAS is one of the first oncogenes to be discovered, and its mutation is present in about 1/4 of human tumors, making it one of the most definitive targets in oncology drug discovery. Unfortunately, despite the promising prospects, KRAS has been nearly unassailable for a long time, because the protein is an unsigned, nearly spherical structure with no obvious binding sites, and it is difficult to synthesize a compound that can target binding and inhibit the activity of the phase. This also makes KRAS synonymous with "unpopular" targets in the field of oncology drug research and development.
sotorasib (AMG 510) is one of the first small molecule inhibitors that successfully targeted KRAS and entered clinical development in humans to target the KRAS protein that inhibits the G12C mutation. Sotorasib specifically and irreversibly inhibits its proproliferative activity by locking the G12C mutant KRAS protein into a non-activated GDP-binding state.
By developing sotorasib, Amgen has taken on one of the toughest challenges in cancer research over the past 40 years. Sotorasib was the first KRASG12C inhibitor to enter the clinic. At present, Amgen is advancing the largest and most extensive global KRASG12C inhibitor development project at an unparalleled pace, exploring more than 10 drug combinations and clinical trial sites spanning five continents. To date, Lumakras/Lumykras has treated more than 3,000 patients worldwide through clinical development projects and commercial use.
原文出处：EUROPEAN COMMISSION APPROVES LUMYKRAS® (SOTORASIB) FOR PATIENTS WITH KRAS G12C-MUTATED ADVANCED NON-SMALL CELL LUNG CANCER
【Source: China.com Medical Channel】