Novel Drug Proven Effective Against Mutated Lung Cancer

Tumor size in lung cancer patients who have a specific genetic error in the KRAS gene is reduced, as per the CODEBREAK 100 phase 2 clinical trial at the NYU Langone Health / NYU Grossman School of Medicine, that was presented at the American Society of Clinical Oncology (ASCO) annual meeting and published in the New England Journal of Medicine.

The study team analyzed the efficacy and safety of the drug sotorasib on daily administration in 126 patients with non-small-cell lung cancer (NSCLC) that harbors a specific mutation – p.G12C (glycine replaced by cysteine at position 12 in the protein's structure) in the DNA code for KRAS.

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Lung cancer is a malignant tumor in the lung tissues. Smoking is the main cause of lung cancer with symptoms like recurrent respiratory diseases.

‘Tumor size in lung cancer patients who have a specific genetic error in the KRAS gene is reduced by a novel KRASG12C inhibitor drug – Sotorasib. It specifically targets a building block (cysteine residue) in the gene that is present only in its inactive form that is, when mutated, thereby demonstrating significant benefit without any new safety concerns in patients.’

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The RAS gene family is among the most frequently mutated in human cancers, with one member of the group, KRAS, the most commonly occurring mutant in solid tumors and has remained "undruggable" for decades.

The KRAS gene encodes a protein switch that regulates growth but becomes "stuck in the "on" mode" when mutated, signaling cells to continually multiply in tumors. Among 200,000 patients who are diagnosed with lung cancer annually in the United States, this mutation is present in only about 13%.

The Drug – Sotorasib

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The drug sotorasib is a KRASG12C inhibitor, developed by Amgen Inc., and was recently approved by the U.S. Food and Drug Administration for the treatment of adult patients with KRAS G12C-mutated NSCLC.

It was found that 37.1% of patients in the study saw their tumors shrink by at least 30%, termed an "objective response", and 82% of those treated experienced some slowing of tumor growth or "disease control". The average response duration of the drug was 11.1 months, for a median progression-free survival of 6.8 months.

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The study also showed that 70% of patients had treatment-related adverse events, only about 20% had more severe events that required reduction of the dose of sotorasib. About 7% of patients had to stop treatment because of severe side effects. The most frequent of these were diarrhea, nausea, fatigue, and an increase in liver enzyme levels. There were no life-threatening side effects and no treatment-related deaths in the study.

Breakthrough Treatment for Mutated KRAS Cancer

Immunotherapy (PD1-inhibitors) or platinum-based combination chemotherapy was previously administered in all patients in the study. The currently available treatments have two and four months of median progression-free survival. Since those treatments were no longer effective to stop the regrowth of the cancers, the present study was conducted.

"The excitement surrounding this trial result is that sotorasib, just approved for clinical use, becomes the first targeted therapy for lung cancer patients with KRAS mutations. KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited therapeutic options," says co-corresponding study author Vamsidhar Velcheti, MD, associate professor of Medicine at NYU Grossman of Medicine, and director of thoracic medical oncology at Perlmutter Cancer Center.

The drug targets a specific building block (cysteine residue) present only in the inactive form of KRAS that is, when the mutated. Thus the drug Sotorasib had significant benefit without any new safety concerns in patients with a specific form of KRAS mutant lung cancer.

The team also anticipates develop and test the efficacy of combination therapies using this drug. Also ongoing phase 3 CodeBreak 200 trial (NCT04303780), would compare the effect of sotorasib against chemotherapy, docetaxel.

Source-Medindia