Targeting a Specific Genetic Mutation May Change Treatment Landscape for Non-Small Cell Lung Cancer

Findings from the recent CodeBreak 100 trial demonstrated that sotorasib, a KRAS G12C inhibitor, 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 has been gaining attention as a treatment target.

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

The phase 2 CodeBreak 100 trial included 126 patients with locally advanced or metastatic NSCLC with a KRAS G12C mutation; they were treated with 960 milligrams of oral sotorasib once per 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 road to developing new drugs to target KRAS hasn’t been easy “because of the complexity of the biology of this mutation and how drugs work on this mutation,” Velcheti said. Several clinical trials have assessed different types of drugs and approaches to target this gene mutation.

Although there is not yet a successful treatment option, progress has been made over the past several years thanks to advances in medicinal chemistry.

“We’ve been 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 that have been 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 counts, among other complications. Taking sotorasib may lead to liver function abnormalities, but severe side effects were observed in less than 5% of patients.

Adagrasib is another KRAS G12C inhibitor being studied for the treatment of patients with NSCLC. Currently, sotorasib is the KRAS G12C inhibitor that is the closest to receiving Food and Drug Administration (FDA) approval, with a Prescription Drug User Fee Act date of Aug. 16, 2021. The FDA is expected to decide by this date whether the drug should be approved to treat patients with NSCLC with the KRAS G12C mutation after receiving at least one previous systemic therapy.

Although KRAS G12C inhibitors seem to be a major advancement in treating patients with KRAS mutation, “the percentage of patients responding to the drug is still relatively low compared (with) the other types of gene mutations where we’ve seen patients respond really well to treatment,” Velcheti said. “We’re still trying to understand why that’s the case. And there are a lot of clinical trials looking at novel innovative combinations with other potential drugs to improve the percentage of patients who would benefit from these drugs. There’s a lot of active research going on, a lot of clinical trials evaluating these. I would strongly encourage patients to consider those clinical trials to potentially improve on the success of sotorasib.”

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