Sotorasib delays progression of advanced KRAS-mutant non-small cell lung cancer
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Sotorasib significantly extended PFS compared with standard-of-care docetaxel as second-line therapy for patients with KRASG12C-mutated non-small cell lung cancer, data from the randomized phase 3 CodeBreak 200 trial showed.
Results of the study — presented at ESMO Congress — suggest sotorasib (Lumakras, Amgen) could become the new second-line standard of care for this subset of patients, the investigators noted.
Background
Previous studies established docetaxel as the standard of care for patients with NSCLC who experienced disease progression despite prior treatment with platinum-based chemotherapy or immunotherapy, according to Melissa L. Johnson, MD, director of the lung cancer research program at Sarah Cannon Research Institute at Tennessee Oncology.
Sotorasib — a first-in-class, oral, irreversible KRAS inhibitor — previously received conditional FDA approval for use in adults with KRASG12C-mutated locally advanced or metastatic NSCLC who received at least one prior systematic therapy, making it the first approved targeted therapy for tumors with any KRAS mutation.
The FDA based its conditional approval on results of the phase 1/phase 2 CodeBreak 100 trial, a single-arm study in which sotorasib conferred a 41% overall response rate, median PFS of 6.3 months and median OS of 12.5 months among patients with advanced KRASG12C-mutated NSCLC, Johnson added.
“We conducted the first randomized phase 3 trial of the KRASG12C inhibitor sotorasib compared with docetaxel for previously treated patients with NSCLC who harbor KRAS mutations,” she said during the presentation.
Methodology
The multicenter CodeBreak 200 trial randomly assigned 345 patients in 1:1 ratio to either oral sotorasib dosed at 960 mg per day (n = 171; median age, 64 years; range, 32-88; 36.3% female; 12.3% Asian) or IV docetaxel dosed at 75 mg/m2 every 3 weeks (n = 174; median age, 64 years; range 35-87; 45.4% female;12.6% Asian). The study included patients with locally advanced and unresectable or metastatic KRASG12C-mutated NSCLC who received at least one prior line of therapy, including platinum-based chemotherapy and an immune checkpoint inhibitor.
Greater than 95% of all patients in both treatment groups currently or formerly smoked.
Researcher did not include patients with active brain metastases in the study.
The trial’s protocol was amended in February 2021 to reduce total enrollment and allow for crossover from docetaxel to treatment with sotorasib.
PFS as determined by blinded independent central review served as the trial’s primary endpoint. Secondary endpoints included treatment efficacy, safety, tolerability and patient-reported outcomes.
Aug. 2 served as the data cutoff date for the analysis, with median follow-up of 17.7 months.
Key findings
The trial met its primary endpoint, with sotorasib demonstrating a significant increase in PFS compared with docetaxel (median, 5.6 months vs. 4.5 months; HR = 0.66; 95% CI, 0.51-0.86).
Investigators noted an estimated 12-month PFS rate of 24.8% in the sotorasib group compared with 10.1% in the docetaxel group.
Sotorasib conferred a significantly higher ORR (28.1% vs. 13.2%), higher disease control rate (82.5% vs. 60.3%) and longer median duration of response (8.6 months vs. 6.8 months) compared with docetaxel.
In terms of tumor response, 80.4% of patients who received sotorasib experienced tumor shrinkage compared with 62.8% in the docetaxel group.
Investigators noted no significant difference in median OS between the sotorasib (10.6 months; 95% CI, 8.9-14.) and docetaxel (11.3 months; 95% CI, 9-14.9) groups.
Safety results showed 70.4% of patients in the sotorasib group had treatment-related adverse events compared with 86.1% in the docetaxel group. Grade 3 or higher (33.1% vs. 40.4%) and serious (10.7% vs. 22.5%) treatment-related adverse events occurred more frequently in the docetaxel group. Three patients died of treatment-related adverse events during the study, including one in the sotorasib group and two in the docetaxel group.
Clinical implications
“The frequency of KRASG12C-mutated NSCLC is about 13% of all non-small cell lung cancer,” Johnson told Healio. “Thus, this trial stands to impact a significant ‘slice’ of the non-small cell lung cancer pie.”
Because CodeBreak 200 met its primary endpoint, with a 34% reduction in risk for disease progression or death, Johnson said the results should solidify sotorasib’s full approval by the FDA.
“I think the results will allow sotorasib to become the standard of care for patients with KRASG12C-mutated non-small cell lung cancer,” she told Healio.
Similar data sets have led to the approval of several other targeted therapies, Johnson added.
Perspective
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Natasha B. Leighl, MD
Results from the CodeBreak 200 trial signal a tremendous advance for patients with advanced NSCLC. It is a positive, confirmatory trial, and I believe sotorasib is the new standard of care for patients who have previously received chemotherapy and immunotherapy for KRASG12C-mutated lung cancer.
There will be some variability in the speed of adopting sotorasib as the standard for this setting due to price negotiations but, hopefully, this will proceed rapidly.
The crossover design of the study shows a significant increase in PFS but not OS, which will lead me to always question the overall impact this drug has on long-term survival benefit.
The positive results from the CodeBreak 200 trial will help move more of our patients beyond chemotherapy. Whereas today sotorasib is the new standard of care, by next year it could be considered standard as first-line therapy in combination with other agents, or there could be another drug in the pipeline that provides sotorasib with some competition.
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Johnson ML, et al. Abstract LBA10. Presented at: European Society for Medical Oncology Congress. Sept. 9-13, 2022; Paris.
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