Pictured on the left is a scan showing a lung tumor (circled in yellow) that has spread to the muscle. The image on the right shows the same person after two months of sotorasib therapy. No tumor is visible in the yellow circle on the right. Photo by Siddhartha Devarakonda

The new drug sotorasib reduces tumor size and shows promise in improving survival among people with lung tumors caused by a specific DNA mutation, according to results of a global phase 2 clinical trial. The drug is designed to shut down the effects of the mutation, which is found in about 13% of people with lung adenocarcinoma, a common type of non-small-cell lung cancer. Non-small-cell lung cancer makes up over 80% of all lung cancers. And more than 200,000 new cases of non-small-cell lung cancer are diagnosed annually in the United States.

The Food and Drug Administration approved sotorasib in 2021 as a targeted therapy for patients with non-small-cell lung cancer whose tumors express a specific mutation—called G12C—in the KRAS gene and who have undergone at least one previous therapy for their cancer. Sotorasib, also known by the brand name Lumakras, is made by Amgen, which funded the trial.

“This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies,” says the study’s co-senior author Ramaswamy Govindan, MD, medical oncologist at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. We’re also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival.”

The study, published June 4, 2021, in The New England Journal of Medicine, involved 126 patients with non-small-cell lung cancer that had a specific mutation in the KRAS gene. A single DNA error swaps out an important protein building block, placing a cysteine where a glycine should be. Tumors with the mutation manufacture a version of the KRAS protein that is almost constantly active, driving tumor growth. Sotorasib, taken daily by mouth, blocks tumor growth by trapping the KRAS protein in its inactive form.

Most people in the trial previously had been treated with standard chemotherapy along with an immunotherapy drug that targets a protein called PD-1. To evaluate this new therapy, all participants in the study were treated with sotorasib; phase 2 trials evaluating safety and effectiveness often do not include a placebo group. The drug caused at least some tumor shrinkage in 102 out of 126 patients (82%).About 37% of the patients’ tumors reduced in size at least 30%.

In contrast, response rates to standard therapy in these patients range from 6% to 20%. Forty-two patients’ tumors (34%) showed a partial response to the therapy, meaning the tumor shrank substantially and its growth was controlled for a period of time; and four patients (3%) showed a complete response that left no evidence of disease. For tumors that shrank, the tumor size was reduced by about 60%, on average.

The effects of sotorasib lasted an average of 11 months, and the drug also showed progression-free survival—meaning the tumor did not continue growing during this time—of almost seven months. In contrast, people with this lung cancer who receive standard therapy have an average progression-free survival of two to four months. The average overall survival for all patients in the trial was 12 months.

“We are hopeful that this approach will be a new option for patients with lung cancer driven by this specific type of KRAS gene alteration,” says Govindan. “KRAS gene alterations have long been considered not amenable for targeted therapies. A number of combination regimens are being tested here at Siteman Cancer Center and at other leading cancer centers around the world.”

Govindan and his team have led pioneering studies to define genomic alterations in lung cancer, including making key contributions to The Cancer Genome Atlas, a national effort supported by the National Institutes of Health. The researchers currently are conducting a phase 3 clinical trial comparing the effectiveness of sotorasib with a chemotherapy drug called docetaxel in 345 patients who have non-small-cell lung cancer and this specific KRAS mutation.

Originally published by Washington University School of Medicine at medicine.wustl.edu/news