Targeting a Specific Genetic Mutation May Change Therapeutic Landscape For Non-Small Cell Lung Cancer

Findings from the recent CodeBreak 100 trial demonstrated that sotorasib, an inhibitor of KRAS G12C, was effective in treating patients with non-small cell lung cancer (NSCLC) and the KRAS G12C mutation. The KRAS G12C mutation is the most common genetic mutation in these patients and is considered as a treatment.

“These treatments have been quite effective in this population, which is very difficult to treat, and there are no good medical options for these patients,” said Dr. Vamsidhar Velcheti, director of thoracic medical oncology at NYU Langone’s Perlmutter Cancer Center in New York City. . interview with CURE ®. “This is a good clinical validation of the effect of innovating this KRAS protein with drugs that target this mutant protein.”

The phase 2 CodeBreak 100 test included 126 patients with locally advanced or metastatic NSCLC with a KRAS G12C mutation; they were treated with 960 milligrams of oral sotorasib once a day. Patients showed a median progression-free survival (time from treatment to disease worsening or progressing) of 6.8 months, and 80% of patients achieved disease control with sotorasib. The drug had a response rate of 37.1%, or the proportion of patients who had a partial or complete response to treatment.

The mutated RAS gene can induce growth of cancer cells and lead to rapid spread of these cells. Although the effects of the mutated RAS gene were discovered nearly 50 years ago, the path to developing new drugs to target KRAS has not been easy “due to the complexity of the biology of this mutation and how drugs work on this mutation,” Velcheti said. Several clinical trials have evaluated different types of drugs and approaches to target this gene mutation.

Although not yet a successful treatment, it has progressed over the past few years thanks to advances in medical medicine.

“We were able to develop newer drugs that interact with certain specific subtypes of mutant KRAS protein and help disrupt the KRAS signals in the cancer cell,” Velcheti said. “These newer drugs developed to specific types of mutations in KRAS can disrupt the signaling function of this mutant protein and thereby (lead) to death of the cancer cell, preventing it from growing and spreading.”

Velcheti added that the safety profile of sotorasib is much better than the current standard treatments for patients with NSCLC, such as chemotherapy and immunotherapy. These standard treatments have many side effects that can lead to reduced blood counting, among other complications. Taking sotorasib may lead to hepatic function, but severe side effects have been observed in less than 5% of patients.

Adagrasib is another KRAS G12C inhibitor studied for the treatment of patients with NSCLC. Currently sotorasib is the KRAS G12C inhibitor, which is the closest to receiving approval from a Food and Drug Administration (FDA), with a date on the Prescription Drug User Act of August 16, 2021. The FDA decides before this that date whether the drug. must be approved to treat patients with NSCLC with the KRAS G12C mutation after receiving at least one prior system therapy.

Although KRAS G12C inhibitors appear to be a major advancement in treating patients with a KRAS mutation, “the percentage of patients responding to the drug is still relatively low compared (with) the other types of gene mutations where we have seen patients respond very well to treatment, “said Velcheti. “We are still trying to understand why that is the case. And there are many clinical trials on new pioneering combinations with other potential drugs to improve the percentage of patients who would benefit from these drugs. A lot of active research is going on, a lot of clinical trials evaluating these. I would strongly encourage patients to consider these clinical trials in order to possibly improve the success of sotorasib. “

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