The combination of osimertinib and savolitinib has shown clinically meaningful improvements in patients with de novo MET-aberrant, EGFR-mutant advanced non-small cell lung cancer (NSCLC) compared to osimertinib alone. These findings were presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.
FLOWERS Trial Results
The phase II CTONG2008 (FLOWERS) trial demonstrated a 90.5% objective response rate (ORR) for the combination therapy versus 60.9% for osimertinib monotherapy. The study, a prospective, open-label, two-arm, randomized, multicenter clinical trial conducted in China, enrolled 44 patients with histologically confirmed, locally advanced or metastatic NSCLC. Patients were treatment-naive for advanced disease, had a documented EGFR-sensitizing mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and MET-aberrant/positive disease. MET aberrancy was defined as either MET immunohistochemistry (IHC) 3+ staining in at least 75% of cells or amplification by fluorescence in situ hybridization (MET gene copy number ≥ 5 or MET/CEP7 ≥ 2) or next-generation sequencing (MET copy number ≥ 5).
"The FLOWERS/CTONG2008 trial is the first phase II prospective, randomized study to report the efficacy and safety data of osimertinib with or without savolitinib as first-line treatment in de novo MET-aberrant, EGFR-mutant advanced NSCLC patients," said lead study author Jin-Ji Yang, MD, of Guangdong Lung Cancer Institute at the Guangdong Provincial People’s Hospital.
Patients were randomly assigned 1:1 to receive either 80 mg of osimertinib once daily or the same dose of osimertinib plus 300 mg of savolitinib twice daily. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. The primary endpoint was objective response rate, with secondary endpoints including disease control rate, duration of response, progression-free survival, overall survival, safety, and tolerability.
Improved Response and Survival
At the data cutoff date of May 28, 2024, with a median follow-up of 8.2 months, the objective response rate was 90.5% for the combination (n = 21) compared with 60.9% for osimertinib monotherapy (n = 23). Patients treated with the combination demonstrated deeper and more durable responses, with a median best reduction in tumor size of –47.7% vs –42.2% in the monotherapy arm. The median duration of response was 18.6 months vs 8.4 months in the combination and monotherapy arms, respectively.
Preliminary progression-free survival data demonstrated a trend favoring the combination therapy, with a median progression-free survival of 19.6 months vs 9.3 months in the monotherapy arm (hazard ratio [HR] = 0.80, 95% confidence interval = 0.19–1.81). Overall survival data are not yet mature.
Adverse Events
Grade 3 or higher treatment-related adverse events occurred more frequently in the combination arm (57.1% vs 8.7%). The most common treatment-related adverse events in the combination arm included rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.8%).
SAVANNAH Trial Results
Updated data from the phase 2 SAVANNAH trial (NCT03778229) showed that treatment with osimertinib in combination with savolitinib generated a high, durable overall response rate (ORR) in patients with EGFR-mutant, MET-overexpressed and/or -amplified non–small cell lung cancer (NSCLC) who experienced disease progression on osimertinib. In the subgroup of patients with high levels of MET expression, the ORR was 49% (95% CI, 39%-59%) for all patients (n = 108) and 52% (95% CI, 41%-63%) among those without prior chemotherapy (n = 87).
Future Directions
Future studies are likely to focus on longer-term follow-up to assess overall survival benefits and potential expansion to other subgroups of patients with NSCLC. Additionally, researchers may explore optimal dosing strategies to further improve the safety profile while maintaining efficacy.
"Osimertinib with savolitinib demonstrated a manageable safety profile. With these results, the combination has the potential to provide a novel first-line treatment option for patients who do not respond well to EGFR tyrosine kinase inhibitor therapy," Dr. Yang concluded.
