According to the results of a study conducted by researchers at the Dana-Farber Cancer Institute.
Mutations in the powerful oncogene known as KRAS occur in about one in four patients with NSCLC, and about 13% of tumors in patients with NSCLC are caused by a specific KRAS mutation called G12C. KRAS mutations have long been considered almost 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 whose tumors harbored the G12C mutation, based on a clinical trial showing a response rate of 36% in these patients after initially receiving treatment. with chemotherapy and a PD-1 immune checkpoint inhibitor.
Presentation of results from a new phase 2 trial presented at the 2022 annual meeting of the American Society of Clinical Oncology (ASCO) and published simultaneously in the New England Journal of Medicine, researchers led by Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber, have shown that treatment with a different KRASG12C the mutant inhibitor, adagrasib, gave an objective response rate of 42.9% 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 lung tumors.
“These data demonstrate that inhibition of KRASG12C may lead to clinically meaningful benefits for NSCLC patients with this form of lung cancer,” Jänne said. “Brain metastases are difficult to treat and to have a pharmacological agent that shows activity in this setting is progress and a move in the right direction.
Patients with KRASG12C had few options after the initial chemotherapy and immunotherapy stopped working. In the new adagrasib clinical trial, the median progression-free survival (how long patients live before the cancer starts to get worse again) was 6.5 months and the median duration of response was 8, 5 months. The oral medication was taken twice daily.
Because the KRASG12C tumor cells usually continue to proliferate, researchers believe that sustained inhibition with drugs may be necessary. Therefore, adagrasib has been optimized for favorable properties including a long half-life (23 hours) and ability to enter the central nervous system. Clinical activity of adagrasib has been demonstrated in patients with other KRASG12C tumors, including colorectal, pancreatic, bile duct and other cancers.
This clinical trial was sponsored by Mirati Therapeutics, Inc.
KRYSTAL-1: Activity and Safety of Adadagrasib (MRTX849) in Patients With Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC) With KRASG12C mutation (Abstract 9002) will be presented by Alexander I. Spira, MD, PhD, Virginia Cancer Specialists Research Institute, at the Lung Cancer — Non-Small Cell Metastatic Oral Abstract Session on Friday, June 3, 2022.