Approximately 13% of patients with lung adenocarcinoma harbor the KRAS p.G12C mutation, which is associated with poor clinical outcomes. During the American Society of Clinical Oncology (ASCO) 2021 virtual annual meeting, Ferdinandos Skoulidis, MD, PhD, MRCP, Assistant Professor, Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, provided updated results from the phase 2 component of the CodeBreaK 100 clinical trial, which evaluated sotorasib (Lumakras), a small-molecule inhibitor of the KRAS p.G12C mutation, in previously treated patients with non–small-lung cancer (NSCLC) whose tumors express this aberration. These results were simultaneously published in the New England Journal of Medicine (2021 June 4. Epub ahead of print).
“Sotorasib represents a breakthrough in targeted therapy for NSCLC patients with a KRAS p.G12C mutation. After nearly 4 decades of research, we now have an effective and well tolerated oral therapy against mutant KRAS—the most common driver oncogene in lung cancer,” Dr Skoulidis said.
The CodeBreaK 100 Study
The phase 2 part of the CodeBreaK 100 trial included 126 patients (median age, 63.5 years; 50% women; 81.7% white; 92.9% former or current smokers) with locally advanced or metastatic KRAS p.G12C–mutated NSCLC whose disease progressed on previous standard therapies. The majority of patients (81%) had previously received both platinum-based chemotherapy and PD-1 or PD-L1 inhibitors. Patients received sotorasib 960 mg/day until disease progression, death, or unacceptable toxicity. Radiographic scans were conducted every 6 weeks up to week 48 and every 12 weeks thereafter.
The primary end point of the study was overall response rate (ORR) according to RECIST v1.1 by independent central review. Key secondary end points included duration of response, disease control rate, time to recurrence, progression-free survival (PFS), overall survival (OS), and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.
At a median follow-up of 15.3 months, the ORR among 124 evaluable patients was 37.1% (95% confidence interval [CI], 28.6-46.2), which included a complete response rate of 3.2% and a partial response rate of 33.9%. Median duration of response was 11.1 months (95% CI, 6.9-not evaluable). Median PFS was 6.8 months (95% CI, 5.1-8.2) and median OS was 12.5 months (95% CI, 10-not evaluable).
Subgroup Analysis
Sotorasib exhibited consistent and robust efficacy across patient subgroups defined by baseline clinical characteristics, including those aged ≥65 years (ORR, 44.1%), heavily pretreated patients (ORR per previous lines of therapy: two, 32.6%; three, 39.3%), and those who progressed on checkpoint inhibitors within the previous 3 months (ORR, 34.4%). Notably, the highest response rate was seen in patients who previously received PD-1/PD-L1 inhibitors but not platinum-based chemotherapy (ORR, 69.2%).
In an exploratory biomarker analysis, sotorasib demonstrated efficacy in molecular subgroups defined by co-occurring genomic alterations including STK11 and KEAP1, that are associated with poor outcomes with standard of care. Interestingly, patients with STK11-mutant but KEAP1 wild-type tumors appeared to derive increased benefit from sotorasib whereas KEAP1 mutations were associated with lower ORR. Due to the small number of patients, further study is needed to determine which subgroups derive differential benefit from sotorasib.
Safety Profile
Sotorasib was well-tolerated, with 69.8% of patients experiencing treatment-related adverse events (AEs), most of which were grade 1 to grade 2 and manageable. No treatment-related deaths occurred as of data cutoff on March 15, 2021.
The most common treatment-related AEs of any grade included diarrhea (31.7%), nausea (19%), elevated alanine aminotransferase and aspartate transaminase (15.1% each), and fatigue (11.1%).
Grade ≥3 treatment-related AEs occurred in 19.8% of patients, the most common being elevated alanine aminotransferase (6.3%) and aspartate transaminase (5.6%), and diarrhea (4%). Treatment-related AEs led to dose modifications and treatment discontinuation in 22.2% and 7.1% of patients, respectively.
FDA Approval
On May 28, 2021, sotorasib received accelerated approval by the FDA for the treatment of adults with locally advanced or metastatic NSCLC with a KRAS p.G12C mutation, as determined by an FDA-approved test, following at least one previous line of systemic therapy.
