Recently approved sotobarib targeted therapy prolongs survival in KRAS G12C mutated lung cancer

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CA lung seen in CXR. Credit: James Heilman, MD / Wikipedia

The results of the phase II cohort of the CodeBreaK 100 study showed that treatment with the KRAS G12C sotorasib inhibitor achieved an objective response rate of 37.1% and an average overall survival of 12.5 months in patients previously treated with non-cellular lung cancer with KRAS G12C mutation (NSCLC), according to researchers at the MD Anderson Cancer Center at the University of Texas. The findings were presented today at the 2021 annual meeting of the American Society of Clinical Oncology (ASCO) and published in the New England Journal of Medicine.

The results of the trials indicated that targeted therapy was safe and tolerable in a population of previously treated patients. The reported findings make sotorasib the first KRAS G12C inhibitor to demonstrate the overall benefit of survival in a recorded phase II clinical trial.

Sotorasib was approved by the Food and Drug Administration on May 28, 2021, based on previously reported results from the CodeBreaK 100 trial. It is the first direct KRAS inhibitor to obtain regulatory approval. .

KRAS has been an elusive therapeutic target for more than 30 years and was considered “indrugable.” This trial provides compelling evidence that mutant KRAS can be successfully and selectively targeted, leading to significant prolongation of uncompromised survival. quality of life, ”said lead author Ferdinandos Skoulidis, MD, Ph.D., assistant professor of Thoracic / Head & Neck Medical Oncology. “These results, along with the regulatory approval of sotorasib, represent an important milestone for patients with KRAS G12C-mutated lung cancer, who now have an approved specific therapy option.”

KRAS is the most common oncogenic engine in NSCLC, which is mutated in 25-30% of patients. Sotorasib (AMG 510) is an irreversible and selective small molecule inhibitor targeting a specific type of mutant KRAS protein called KRAS G12C, which is found in approximately 13% of all lung adenocarcinomas.

The study reveals rapid and lasting clinical benefits with tolerable side effects

The single-arm multicenter trial enrolled 126 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC who had progressed after receiving immune checkpoint inhibitors and / or platinum-based chemotherapy. Sotorasib is an oral medicine once a day. The main final criterion was the objective response, assessed by an independent central review.

The study found an objective response in 46 patients (37.1%), including four complete responses (3.2%) and 42 partial responses (33.9%). One hundred patients (80.6%) had control of the disease, with tumors shrinking or remaining stable. He was 12.5 months, mean duration of response was 11.1 months, and progression-free survival was 6.8 months.

Toxicities were manageable and mostly low-grade, with only nine patients (7.1%) discontinuing therapy due to treatment-related adverse events. Of the 88 patients (69.8%) who had treatment-related adverse events, 25 (19.8%) were grade 3 events and one (0.8%) was grade 4.

Study participants had a mean age of 63.5 years and were evenly distributed (50%) between men and women. Most patients (81.7%) were white, followed by Asians (15.1%), blacks (1.6%), and other races (1.6%). Patients had received up to three previous lines of therapy and 96.8% had metastatic disease. 81% of patients had previously received platinum-based chemotherapy and immune control point inhibitors.

“In eight out of 10 patients, the tumor shrank or remained stable, and these patients frequently saw improvements in their symptoms,” Skoulidis said. “They are able to lead an active and long life, because that it is not associated with any significant toxicity that adversely affects the patient ‘s quality of life. “

Sotorasib is effective in challenging the subgroup and more research is ongoing

The study also analyzed responses between molecular subgroups and found especially encouraging results among patients with STK11 co-mutations, with no simultaneous mutations in KEAP1. The objective response rate of 50% and median progression-free survival of 11 months in this group is notable because STK11-mutated tumors tend to respond poorly to standard care therapies, including immunotherapy and chemotherapy.

The researchers in the study also found a response to sotorasib in other molecular subgroups. The drug showed broad and consistent activity in patients with a wide range of age-related baseline characteristics, previous lines of therapy, and other demographic data.

“These results of the study change practice, but our work is not finished,” Skoulidis said. “Numerous efforts are being made to understand the determinants of the response to sotorasib and to characterize the full spectrum of possible mechanisms of resistance. These results represent a fundamental step in our progress against KRAS mutant tumors and will likely be a step in the right direction. to an even more effective effectiveness. combined regimes. the future looks promising. ”


Sotorasib provides lasting clinical benefits for patients with non-small cell lung cancer and KRAS mutations


More information:
Ferdinandos Skoulidis et al, Sotorasib for KRAS p.G12C mutated lung cancers, New England Journal of Medicine (2021). DOI: 10.1056 / NEJMoa2103695

Citation: Recently approved sotobarib targeted therapy prolongs survival in KRAS G12C mutated lung cancer (2021, June 4) retrieved June 4, 2021 from https://medicalxpress.com/news/2021-06-newly-therapy -sotorasib-prolongs-survival. html

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