The U.S. Food and Drug Administration has approved the first therapy for adult patients with non-small cell lung cancer whose tumours have a KRAS–G12C genetic mutation.
About 80-85% of lung cancers are non-small cell lung cancer (NSCLC). In recent years, there has been great progress in the treatment of NSCLC, which has been met with a substantial reduction in mortality. This has largely been due to the development of targeted therapies and checkpoint inhibitors. However, the prognosis for patients with advanced NSCLC receiving second or subsequent lines of therapy is poor. In fact, only 6-20% of such patients have a response, with a median progression-free survival of 2-4 months.
In 25-30% of non-squamous-cell NSCLCs, there is an activating mutation in the KRAS oncogene. This makes it the most prevalent genomic driver event in NSCLC. In these patients, standard treatment options only provide a modest clinical benefit. Among all KRAS mutations, the KRAS p.G12C single-nucleotide variation is the most frequent. This variant favours the active form of KRAS and results in the hyperactivation of downstream oncogenic pathways and uncontrolled cell growth. For decades, researchers have considered KRAS ‘undruggable’ as its active form does not include a suitable pocket for drugs to bind. This view persisted until several breakthrough structural and mechanistic studies established a foundation for the development of covalent and selective KRAS-G12C inhibitors.
Sotorasib – a therapy for lung cancer
In a recent paper in NEJM, researchers presented the results from the phase II portion of the CodeBreak 100 trial. In this trial, 126 patients with KRAS p.G12C–mutated advanced NSCLC were treated with the Amgen-developed drug sotorasib (Lumakras). Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS-G12C. It covalently binds to a pocket within the inactive form, trapping the protein in an inactive state. All patients in the study had been treated previously with either immunotherapy (PD1-inhibitors) or platinum-based combination chemotherapy.
The team found that 37.1% of patients saw their tumours shrink by at least 20%. In addition, 80.6% of patients showed signs of slowing of tumour growth (or disease control). The median progression-free survival was 6.8 months, and the median overall survival was 12.5 months.
Overall, these findings show that sotorasib can result in durable clinical benefits in patients with previously treated KRAS-G12C-mutated NSCLC. As a result of these promising findings, the FDA approved sotorasib on May 28th as a targeted therapy for these patients. This is the first approved targeted therapy for tumours with any KRAS mutation.
The researchers are now conducting a phase III clinical trial comparing the effectiveness of sotorasib with the chemotherapy drug docetaxel in 345 patients who have NSCLC and this specific KRAS mutation.
Image credit: By Eraxion – canva