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New drug effective against lung cancers caused by common genetic error

 

A new drug reduced tumor size in patients who have lung cancer patients with a specific, disease-causing change in the gene KRAS, a study found.

The results of the CODEBREAK 100 phase 2 clinical trial were presented June 4, 2021, at the American Society of Clinical Oncology (ASCO) annual meeting and published simultaneously in the New England Journal of Medicine. The efficacy and safety of the drug sotorasib, developed by Amgen Inc., was tested in patients with non-small-cell lung cancer (NSCLC) harboring a specific change, or mutation, in the DNA code for KRAS.

The KRAS mutant protein targeted in the study was p.G12C, in which a glycine building block has been mistakenly replaced a cysteine at position 12 in the protein’s structure. This change is present in about 13 percent of the more than 200,000 patients diagnosed with lung cancer each year in the United States. KRAS encodes a protein switch that regulates growth but becomes “stuck in the “on” mode” when mutated, signaling cells to continually multiply in tumors.

Sponsored by Amgen – and led by researchers from Perlmutter Cancer Center at NYU Langone Health, Washington University School of Medicine, MD Anderson Cancer Center, and Memorial Sloan Kettering – the global trial included 126 patients that received daily, oral sotorasib. This KRASG12C inhibitor was recently approved by the U.S. Food and Drug Administration for the treatment of adult patients with KRAS G12C-mutated NSCLC.

The researchers found that 37.1 percent of patients in the study saw their tumors shrink by at least 30 percent, termed an “objective response.” About 82 percent of those treated experienced some slowing of tumor growth or “disease control.”

All patients in the study had been treated previously with either immunotherapy (PD1-inhibitors) or platinum-based combination chemotherapy, but those treatments were no longer effective for them, and their cancers had begun to regrow. With no targeted options, such patients typically do poorly, with response rates to standard treatments between 6 and 20 percent, according to previous studies.

“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,” 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. “KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited therapeutic options.”

The average duration of responses to sotorasib in the current trial was 11.1 months, with a median period during which disease did not worsen (progression-free survival) of 6.8 months, say the study authors. With currently available treatments, median progression-free survival for these patients is between two and four months.

“Sotorasib showed clinically significant benefit without any new safety concerns in patients with this specific form of KRAS mutant lung cancer,” says co-corresponding author Ramaswamy Govindan MD, the Anheuser Busch Chair in Medicine at Washington University School of Medicine. “Moving forward, our team will seek to inform the development of combination therapies featuring sotorasib and other emerging drugs, and to determine which best fit the mix of mutations in each patient’s cancer cells.”

First of Its Kind

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. KRAS has considered “undruggable” for decades because its active form does not include a suitable pocket to which drugs can attach.

Sotorasib is a novel covalent inhibitor that, thanks to recent advances in medical chemistry, can target a specific building block (cysteine residue) only present in the inactive form of KRAS. When the mutated KRAS switch toggles into its inactive state, sotorasib can attach to a structural feature called the switch II pocket and react with the mutant cysteine at position 12, freezing KRAS in the inactive state.

The phase 2 trial CodeBreak 100 study also focused on safety, finding that, while nearly 70 percent of patients had treatment-related adverse events, only about 20 percent had more severe events that required reduction of the dose of sotorasib. About 7 percent 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.

All patients in the single-arm CodeBreak 100 trial were treated with sotorasib, and none with placebo, as is standard in early studies of this type. The ongoing phase 3 CodeBreak 200 trial (NCT04303780), which is comparing the effect of sotorasib against a chemotherapy, docetaxel, will seek to confirm the current results in 345 patients with NSCLC harboring the KRAS p.G12C mutation.

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Along with Velcheti and Govindan, the study authors included first authors Ferdinandos Skoulidis of the University of Texas MD Anderson Cancer Center in Houston, and Bob Li of Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine in New York. Other study authors were Grace Dy of Roswell Park Cancer Institute in Buffalo; Timothy Price of Queen Elizabeth Hospital and University of Adelaide, Australia; Gerald Falchook of Sarah Cannon Research Institute at HealthONE, Denver; J├╝rgen Wolf of the Center for Integrated Oncology at the University Hospital Cologne in Germany; Antoine Italiano of the Early Phase Trials and Sarcoma Units, Bergonie Cancer Institute, Bordeaux, France; Martin Schuler of West German Cancer Center at the University Duisburg-Essen, Germany; Hossein Borghaei of Fox Chase Cancer Center in Philadelphia; Fabrice Barlesi and Benjamin Besse of M. Gustave Roussy Institute in Villejuif, France; Terufumi Kato of Kanagawa Cancer Center, Yokohama, Japan; Alessandra Curioni-Fontecedro of University Hospital Zurich, Switzerland; Adrian Sacher of Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Alexander Spira of Virginia Cancer Specialists, Fairfax, VA; Suresh Ramalingam of Winship Cancer Institute of Emory University; and Toshiaki Takahashi of the Division of Thoracic Oncology, Shizuoka Cancer Center, Japan. Study authors from Amgen Inc. of Thousand Oaks, California, were Abraham Anderson, Agnes Ang, Qui Tran, Omar Mather, Haby Henary, Gataree Ngarmchamnanrith, and Gregory Friberg.

The study was funded by Amgen Inc. and is listed at ClinicalTrials.gov (NCT03600883). Dr. Velcheti is a paid consultant of Amgen, with the relationship managed according to the policies of New York University.

 

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