The new drug sotorasib reduces tumor size and shows promise for improving survival in patients with lung tumors caused by a specific DNA mutation, according to the results of a global phase 2 clinical trial. The drug is designed to stop the effects of the mutation, which is found in about 13% of patients with lung adenocarcinoma, a common type of non-small cell lung cancer.
The Food and Drug Administration approved sotorasib on May 28 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 had at least one prior therapy for their cancer.
Non-small cell lung cancer accounts for more than 80% of all lung cancers. More than 200,000 new cases of non-small cell lung cancer are diagnosed each year in the United States.
The study, led by researchers from Washington University School of Medicine in St. Louis, NYU Langone Health’s Perlmutter Cancer Center in New York, MD Anderson Cancer Center in Houston, and Memorial Sloan Kettering Cancer Center in New York, will be released on June 4. presented. at the annual meeting of the American Society of Clinical Oncology and published the same day in The New England Journal of Medicine.
Sotorasib, also known by the brand name Lumakras, is made by Amgen, which funded the trial.
“This is a group of patients whose tumors were difficult to treat and for whom we had no targeted therapies,” said co-senior author and medical oncologist Ramaswamy Govindan, MD, the Anheuser Busch Endowed Chair in Medical Oncology at Washington University. “The new drug addresses an unmet need of these patients and targets the most common mutation we can pursue. We also continue to study this drug in combination with other experimental drugs to see if we can further improve responses and survival.” .”
The study included 126 patients with non-small cell lung cancer with a specific mutation in the KRAS gene. A single DNA mistake swaps out an important protein building block and places a cysteine where a glycine should be. Tumors with the mutation produce a version of the KRAS protein that is almost constantly active and stimulates tumor growth. Sotorasib, taken by mouth daily, blocks tumor growth by trapping the KRAS protein in its inactive form.
Most patients in the trial had previously been treated with standard chemotherapy along with an immunotherapy drug that targets a protein called PD-1. To evaluate this new therapy, all patients enrolled in the study were treated with sotorasib; Phase 2 studies evaluating safety and effectiveness often do not include a placebo group.
The drug caused in 102 of 126 patients (82%). About 37% of the patients’ tumors decreased in size by at least 30%. In contrast, response rates to standard therapy in these patients range from 6% to 20%.
The tumors of 42 patients (34%) showed a partial response to therapy, meaning the tumor shrank significantly and its growth was controlled over a period of time; and four patients (3%) showed a complete response leaving no evidence of disease. For tumors that shrank, tumor size was reduced by about 60% on average.
The effects of sotorasib lasted an average of 11 months, and the drug also showed a progression-free survival — meaning the tumor didn’t continue to grow during this time — of nearly seven months. In contrast, patients with this lung cancer who receive standard therapy have an average progression-free survival of two to four months. The mean overall survival for all patients in the study was 12 months.
“We are hopeful that this approach will be a new option for patients with lung cancer caused by this specific type of KRAS gene change,” said Govindan, who treats patients at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. School of Medicine. “KRAS gene changes have long been considered unsuitable for targeted therapies. A number of combination regimens are being tested here at the Siteman Cancer Center and in other leading cancer centers around the world. This highlights the work Washington University has excelled in several decades in the past – – studying the genomic changes in tumors with the aim of identifying treatment targets. This early cancer genome research is now coming full circle to help our patients.”
Govindan and his team have led pioneering studies to define genomic changes in lung cancer, including making major contributions to The Cancer Genome Atlas, a national effort supported by the National Institutes of Health (NIH).
“The excitement surrounding this study result is that sotorasib is now the first targeted therapy for lung cancer patients with KRAS mutations,” said co-corresponding author Vamsidhar Velcheti, MD, of NYU Langone Health. “KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited treatment options.”
Approximately 7% of patients discontinued treatment with sotorasib due to serious adverse events, but none of the adverse events were life-threatening and no patient died as a result of the treatment. The drug caused side effects severe enough to require a reduced dose of the drug in about 22% of patients. Nearly 70% of patients experienced side effects related to the drug; the most common were diarrhea, fatigue, nausea and elevated liver enzyme levels, the latter an indicator of liver damage.
“Sotorasib showed clinically significant benefit with no new safety concerns in patients with this particular form of KRAS-mutated lung cancer,” Govindan said. “Going forward, our team will seek to inform the development of combination therapies with sotorasib and other emerging drugs, and determine which one best matches the mix of mutations in each patient’s cancer cells.”
The researchers are currently conducting a Phase 3 clinical trial comparing the effectiveness of sotorasib with a chemotherapy drug called docetaxel in 345 patients with non-small cell lung cancer and this particular KRAS mutation.
This work was supported by Amgen, which makes sotorasib. This work was also supported in part by the National Institutes of Health (NIH) Cancer Center Core at Memorial Sloan Kettering Cancer Center, grant number P30 CA008748.
Velcheti, of New York University, is a paid consultant for Amgen.
Skoulidis F, Li BT, Dy GK, Prijs TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. Sotorasib for lung cancers with KRAS p.G12C mutations (CodeBreak 100). The New England Journal of Medicine. June 4, 2021.
Washington University School of Medicine’s 1,500 faculty physicians also serve as the medical staff of the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, education, and patient care and is consistently ranked among the best medical schools in the nation, according to US News & World Report. Through its ties to Barnes Jewish and St. Louis Children’s Hospitals, the School of Medicine is affiliated with BJC HealthCare.