
Amgen announced results from the global Phase 3 CodeBreaK 200 trial, which showed once-daily oral Lumakras /Lumykras (sotorasib) led to significantly superior progression-free survival (PFS; primary endpoint) and a significantly higher objective response rate (ORR) in patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), compared with intravenous chemotherapy, docetaxel. Notably, patient-reported outcomes were improved with Lumakras versus docetaxel.
"The totality of evidence from this study supports Lumakras as an important targeted treatment option for patients with non-small cell lung cancer who harbor the KRAS G12C mutation, and reinforces the critical need for comprehensive biomarker testing for all patients with advanced disease," said David M. Reese, MD, Amgen executive vice president of research and development.
Lumakras significantly improved PFS as determined by blinded independent central review compared to docetaxel in heavily pretreated patients (median PFS of 5.6 versus 4.5 months respectively; HR, 0.66 [95% CI: 0.51, 0.86]; P = 0.002). PFS favored Lumakras across all clinically relevant subgroups, including those with a history of brain metastases at baseline. The proportion of patients with PFS at one year was 25% for Lumakras versus 10% for docetaxel. Lumakras demonstrated a significantly higher ORR than docetaxel with double the response rates in the Lumakras arm (28% versus 13%, respectively; P < 0.001) and showed consistent benefit across other efficacy secondary endpoints, specifically improved disease control rate (DCR; 83% versus 60%, respectively); faster time to response (TTR; 1.4 versus 2.8 months, respectively); and longer duration of response (DOR; 8.6 versus 6.8 months, respectively). Overall survival (OS; a key secondary endpoint) was not significantly different between treatment arms (10.6 versus 11.3 months, respectively; HR, 1.01 [95% CI: 0.77, 1.33]; P = 0.53).
The study was not powered to detect a statistical difference in OS, and more than one-third of patients on docetaxel went on to receive a KRASG12C inhibitor, either in protocol cross-over (26.4%) or as subsequent therapy (7.5%). A clinically meaningful improvement in patient reported outcomes was also observed with Lumakras versus docetaxel. Change over time (improvement from baseline to week 12) in global health status, physical functioning and dyspnea favored Lumakras. Time to deterioration (delaying symptoms from getting worse) in global health status, physical functioning and cancer-related symptoms (dyspnea and cough) were delayed with Lumakras compared to docetaxel.
There were fewer treatment-related adverse events (TRAEs) for Lumakras versus docetaxel. Grade ≥ 3 TRAEs (33% Lumakras; 40% docetaxel) and serious TRAEs (11% Lumakras; 23% docetaxel) were lower with Lumakras compared to docetaxel. The most common TRAEs reported by at least 15% of patients in either treatment group were diarrhea (34% Lumakras; 19% docetaxel), fatigue (7% Lumakras; 25% docetaxel), alopecia (1% Lumakras; 21% docetaxel), nausea (14% Lumakras; 20% docetaxel) and anemia (3% Lumakras; 18% docetaxel).
"This is the first Phase 3 randomized clinical trial for a KRASG12C inhibitor to show benefit in heavily pretreated patients who have limited treatment options," said Melissa L. Johnson, MD, director of Lung Cancer Research at Sarah Cannon Research Institute at Tennessee Oncology and presenting author. "It is encouraging that progression-free survival benefits were consistent across all clinically relevant subgroups, including those with a history of brain metastases, and that sotorasib response rates were more than double compared to docetaxel response rates. This data represents a major advance for the treatment of patients with KRAS G12C-mutated non-small cell lung cancer."
Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined. Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 8% for those with metastatic disease.
KRAS G12C is the most common KRAS mutation in NSCLC. About 13% of patients with NSCLC harbor the KRAS G12C mutation. Unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately four months following second-line treatment of KRAS G12C-mutated NSCLC.
The CodeBreaK clinical development program for Amgen's drug sotorasib is designed to study patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.
CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline. The Phase 2 trial in colorectal cancer (CRC) enrolled 62 patients and results have been published.1
CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated, locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.