LUMAKRAS (sotorasib) is an oral, first-in-class therapy indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) following at least one previous systemic therapy.
Developed by American biopharmaceutical firm Amgen, LUMAKRAS is available as immediate-release, yellow, oblong-shaped, film-coated tablets in 120mg dosage strength.
In August 2019, the US Food and Drug Administration (FDA) granted Fast Track designation to sotorasib for the treatment of patients with previously treated metastatic NSCLC with a KRAS G12C mutation.
The QIAGEN therascreen KRAS RGQ polymerase chain reaction (PCR) kit and the Guardant360 CDx test obtained FDA approval as a companion diagnostic for detecting NSCLC patients eligible for treatment with LUMAKRAS.
In December 2020, Amgen submitted a new drug application (NDA) to the FDA and a marketing authorisation application (MAA) to the European Medicines Agency (EMA) seeking approval for sotorasib to treat NSCLC patients with the KRAS G12C mutation.
In January 2021, Amgen submitted MAAs for sotorasib in Australia, Brazil, Canada and the UK to participate in the FDA’s Project Orbis initiative. In April 2021, the company submitted NDAs in Japan (J-NDA) and Switzerland.
The FDA reviewed the NDA under its Real-Time Oncology Review (RTOR) pilot programme and, in February 2021, granted priority review designation for sotorasib.
In May 2021, LUMAKRAS received accelerated approval from the FDA for the treatment of locally advanced or metastatic NSCLC with the KRAS G12C mutation.
The drug also holds breakthrough therapy designation in the US and China, and has secured orphan drug designation from the FDA for KRAS G12C-positive NSCLC and colorectal cancer.
In June 2021, Amgen chose US-based oncology pharmacy company Onco360 as a speciality pharmacy provider for LUMAKRAS.
NSCLC is the most common form of lung cancer, accounting for up to 85% of all lung cancer cases.
KRAS is a member of the rat sarcoma (RAS) family and is the most frequently mutated oncogene. It is vital for the regulation of signalling pathways responsible for cell growth and division.
KRAS G12C is a single-point mutant-oncogenic form of RAS GTPase and is observed in around 13% of NSCLC patients in the US, resulting in continuous cancer cell proliferation, development and survival.
Some of the most common symptoms of NSCLC include the worsening of chronic cough, cough producing blood, wheezing, unexplained weight loss, chest pain or painful breathing, decreased appetite, and lung infections such as bronchitis and pneumonia.
Advanced stage symptoms include bone pain, headaches or seizures due to brain metastases, and lumps in lymph nodes.
Sotorasib is a highly selective inhibitor of KRAS G12C that potentially suppresses the rapid proliferation of cancer cells.
Sotorasib forms an irreversible, covalent bond with the cysteine residue of KRAS G12C, holding the protein in its inactive form that blocks the oncogenic signalling. This results in apoptosis only in KRAS G12C tumour cell.
The FDA’s accelerated approval of LUMAKRAS was based on the results obtained from the single-arm, open-label, multi-centre clinical trial CodeBreaK 100. The study enrolled a subset of patients with locally advanced or metastatic NSCLC with KRAS G12C mutations.
It is the largest clinical trial conducted exclusively on the KRAS G12C-mutated NSCLC patients. A total of 126 patients were included in the study, of which 124 were confirmed with KRAS G12C-mutated NSCLC.
The primary endpoint of the study was the overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to version 1.1 of the Response Evaluation Criteria in Solid Tumours (RECIST) specification.
All patients received at least one prior line of systemic therapy for metastatic NSCLC. In the study, patients received 960mg of sotorasib once daily until disease progression or unacceptable toxicity.
Sotorasib achieved 36% ORR with a median response duration of ten months. The disease control rate that includes patients achieving complete and partial responses or stable disease for more than three months was 81%.
The most common side effects of LUMAKRAS-treated patients in the clinical trial include diarrhoea, musculoskeletal pain, nausea, fatigue, liver damage and cough.
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