Amgen's Lumakras (Sotorasib) Approved in Japan as First-in-Class KRAS G12C Inhibitor for Advanced NSCLC

News on January 20, 2022 /BioValleyBIOON/ -- Amgen recently announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has approved the targeted anticancer drug Lumakras (sotorasib, AMG 510). This drug is a first-in-class KRAS G12C inhibitor, used to treat patients with non-small cell lung cancer (NSCLC) who have progressed after prior systemic anticancer therapy, are positive for the KRAS G12C mutation, and have unresectable, advanced and/or recurrent disease.

Sotorasib is the world's only KRAS G12C inhibitor to receive regulatory approval.In the United States, Lumakras (U.S. trade name) received accelerated approval in May 2021 for the treatment of: patients who have received at least one systemic therapy and...FDAApproved testing methods confirm the presence of KRAS G12C mutations in adult patients with locally advanced or metastatic NSCLC. In the EU, Lumykras (European trade name) received conditional approval in January 2022 for the treatment of adult patients with advanced NSCLC carrying KRAS G12C mutations whose disease has progressed after receiving at least one prior systemic therapy.

Notably, Lumakras/Lumykras is the first KRAS-targeted therapy approved after nearly 40 years of research, and is the first and only targeted therapy approved for treating patients with locally advanced or metastatic NSCLC carrying the KRAS G12C mutation. Globally, there are new cases each year.Diagnosis2.2 million lung cancer cases, with NSCLC accounting for approximately 84%. KRAS mutations account for about 25% of NSCLC mutations; among these, KRAS G12C is one of the most common driver mutations in NSCLC and has now become a "druggable" target.

Lumakras/Lumykras's active pharmaceutical ingredient is sotorasib, which is the first KRAS G12C inhibitor to enter clinical development. At the end of January 2021,Sotorasib Granted Breakthrough Therapy Designation by China's National Medical Products Administration (NMPA) Center for Drug Evaluation (CDE)This is Amgen's first application for "Breakthrough Therapy" designation in China, and also the first "Breakthrough Therapy" designation application since its strategic cooperation with BeiGene.

Amgen's Executive Vice President of Research and Development, David M. Reese, stated: "As the first and only approved KRASG12C inhibitor, today's approval marks a shift in the treatment paradigm for NSCLC patients in Japan. In just over three years from the first patient dosing in the pivotal CodeBreak 100 trial, Lumakras has now been approved in nearly 40 countries, demonstrating our commitment to accelerating transformative medicines for cancer patients with unmet medical needs."

This approval is based on the positive results from the Phase II CodeBreaK 100 study cohort of patients with advanced NSCLC. This study is the largest to date in the patient population harboring KRAS G12C.Clinical TrialData from a cohort of 124 patients with KRAS G12C mutation-positive NSCLC whose disease progressed after receiving immunotherapy and/or chemotherapy showed that Lumakras has good efficacy and tolerability.

In this cohort, 123 evaluable patients (including 10 patients from Japan, data cut-off date: September 1, 2020) were treated with 960mg of Lumakras orally once daily.Objective Response Rate (ORR,TumorThe proportion of patients with a volume reduction ≥30% was 37%.(95% CI: 28.8-46.6), 81% (95% CI: 73-87) of patients achieved disease control (the proportion of patients achieving complete response, partial response, and stable disease for more than 3 months). The median duration of response (DoR) was 11.1 months, the median progression-free survival (PFS) was 6.8 months (95% CI: 5.1-8.2), and the median overall survival (OS) was 12.5 months (95% CI: 10.0-not estimable [NE]). The most common adverse reactions (≥20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. In 9% of patients, adverse reactions led to permanent discontinuation of the treatment.Adverse Reactions。

The previously released exploratory analysis also showed, across a range ofBiomarkerEncouraging results of Lumakras were observed in the subgroupsTumorResponses, including patients with negative or low levels of PD-L1 expression and patients with STK11 mutations. This co-mutation is associated with poor prognosis in NSCLC patients receiving checkpoint inhibitors and chemotherapy.

Currently, Amgen is conducting a global Phase 3 randomized, active-controlled study (CodeBreaK 200), comparing Lumakras with docetaxel chemotherapy in patients with KRAS G12C-mutant NSCLC.

Sotorasib (AMG510) Chemical Structure (Image Source: selleck.cn)

KRAS G12C is the most common KRAS mutation in NSCLC. In the United States, approximately 13% of NSCLC adenocarcinoma patients have the KRAS G12C mutation, with about 25,000 new patients diagnosed each year.DiagnosisFor NSCLC with KRAS G12C mutation. For patients with KRAS G12C-mutated NSCLC who have failed first-line treatment, treatment options are very limited, and there is a significant unmet medical need. In second-line KRAS G12C-mutated NSCLC patients, the efficacy of current therapies is unsatisfactory, with response rates ranging from 9-18% and a median progression-free survival (PFS) of only about 4 months.

KRAS is one of the first oncogenes discovered, with mutations present in approximately 1/4 of human tumors, making it one of the most well-defined targets in the field of oncology drug development. Unfortunately, despite its promising prospects, KRAS has long been nearly impossible to conquer. This is because the protein has a featureless, nearly spherical structure with no obvious binding sites, making it difficult to synthesize a compound that can specifically target and inhibit its activity. This has also made KRAS a...TumorA synonym for "undruggable" targets in the field of drug development.

Sotorasib (AMG 510) is one of the first small-molecule inhibitors to successfully target KRAS and enter human clinical development, specifically inhibiting KRAS proteins with the G12C mutation. Sotorasib specifically and irreversibly inhibits the pro-proliferative activity of the G12C mutant KRAS protein by locking it in an inactive GDP-bound state.

By developing sotorasib, Amgen has taken on one of the toughest challenges in cancer research over the past 40 years.Sotorasib is the first KRASG12C inhibitor to enter clinical trials and is currently undergoing the broadest clinical program, CodeBreaK, exploring 10 drug combinations across four continents globally. In just over two years, the CodeBreaK program has also established the most comprehensive clinical dataset for 13 types.TumorMore than 800 patients of this type were studied. (Bioon.com)

Source of the original text:LUMAKRAS® (SOTORASIB) RECEIVES APPROVAL IN JAPAN FOR PATIENTS WITH KRAS G12C-MUTATED ADVANCED NON-SMALL CELL LUNG CANCER