Nearly 43% of patients with non-small cell lung cancer (NSCLC) that had a specific KRAS mutation responded to the experimental drug adagrasib, which also showed activity against metastases, according to results of a study published in the New England Journal of Medicine.
Mutations in the potent oncogene known as KRAS occur in about one in four patients with NSCLC, and approximately 13% of NSCLC patients’ tumours are driven by a specific KRAS mutation called G12C. KRAS mutations have long been considered nearly impossible to attack with targeted drugs after many years of research attempts. However, in 2021 a targeted drug, sotorasib, became the first drug approved by the Food and Drug Administration for NSCLC patients with the G12C mutation, based on a clinical trial showing a 36% response rate in those patients after having initially received treatment with chemotherapy and a PD-1 immune checkpoint inhibitor.
Reporting the results of a new phase 2 trial, investigators led by Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber, showed that treatment with a different KRASG12C mutant inhibitor, adagrasib, yielded a 42.9% objective response rate and a median overall survival rate of 12.6 months in a cohort of 112 patients who had previously received both chemotherapy and immunotherapy with a PD-1 immune checkpoint blocker. Notably, adagrasib treatment also achieved a 33.3% response rate in 33 patients who had stable metastatic lesions in the brain and central nervous system that had spread from the lung tumours.
“These data highlight that inhibiting KRASG12C can lead to clinically meaningful benefits to NSCLC patients with this form of lung cancer,” said Dr Jänne. “Brain metastases are challenging to treat and having a pharmacologic agent that shows activity in this setting is an advancement and movement in the right direction.”
Patients with KRASG12C have had few options after initial chemotherapy and immunotherapy stopped working. In the new clinical trial of adagrasib, taking the oral drug twice daily resulted in a median progression-free survival (the time patients lived before the cancer began to worsen again) was 6.5 months and the median response duration was 8.5 months.
Because the KRASG12C tumor cells typically continue to proliferate, researchers believe sustained inhibition with drugs may be necessary. Thus, adagrasib was optimised for favourable properties including a long half-life of 23 hours and the ability to penetrate the central nervous system. Clinical activity with adagrasib has been shown in patients with other KRASG12C tumors, including colorectal, pancreatic, biliary tract, and other cancers.
Source: Dana-Farber Cancer Institute
