The combination of the EGFR tyrosine kinase inhibitor osimertinib and the MET inhibitor savolitinib has demonstrated clinically meaningful improvements compared with osimertinib alone as a first-line treatment of patients with de novo MET-aberrant, EGFR-mutant advanced non–small cell lung cancer (NSCLC). These findings were presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer in San Diego.1 Results of the phase II CTONG2008 (FLOWERS) trial showed a 90.5% objective response rate for the combination therapy vs 60.9% for osimertinib monotherapy.
Osimertinib with savolitinib has the potential to provide a novel first-line treatment option for patients who do not respond well to EGFR tyrosine kinase inhibitor therapy.— Jin-Ji Yang, MD
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“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 (Guangdong Academy of Medical Sciences) at the Southern Medical University in Guangzhou, China, during the oral presentation. “Patients on osimertinib plus savolitinib [were] showing deeper and more durable responses over the study.”
Study Details
As Dr. Yang reported, the coexistence of amplified or overexpressed MET and EGFR mutations has been shown to reduce sensitivity to EGFR tyrosine kinase inhibitors, likely contributing to primary resistance to first-line EGFR tyrosine kinase inhibitor monotherapy.
The CTONG2008 (FLOWERS) trial, a prospective, open-label, two-arm, randomized, multicenter clinical trial conducted in China, aimed to address this challenge by combining osimertinib with savolitinib. The phase II study enrolled 44 patients with histologically confirmed, locally advanced or metastatic NSCLC. Patients were required to be treatment-naive for advanced disease, have 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 majority of patients had tumors classified as MET-aberrant by IHC alone (86% in the monotherapy arm, 76% in the combination arm).
Participants 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.
Improvement in Overall Response Rate
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). In the combination arm, 19 patients (90.5%) achieved a partial response, whereas in the monotherapy arm, 14 patients (60.9%) achieved a partial response. The disease control rate was 95.2% and 87.0% in the osimertinib/savolitinib and osimertinib monotherapy arms, respectively. The osimertinib monotherapy arm did include two patients with uncommon EGFR mutations (EGFR S768I + G719S, EGFR G719A + E709G) whose response classification was not specified; all patients in the combination arm had an EGFR exon 19 deletion or L858R mutation.
Patients treated with the combination demonstrated deeper and more durable responses throughout the study follow-up, said Dr. Yang, 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, and the data are not yet mature.
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.
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%). Grade ≥ 3 treatment-related adverse events that occurred only in the combination arm included alanine transaminase increase (19%), thrombocytopenia (14.3%), peripheral edema (9.5%), leukopenia (9.5%), neutropenia (9.5%), aspartate transaminase increase (9.5%), and diarrhea (4.8%).
What Next?
According to Dr. Yang, 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,” he concluded.
EXPERT POINT OF VIEW
Paul K. Paik, MD
Abstract discussant Paul K. Paik, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, New York, underscored the promise of the CTONG2008 (FLOWERS) data while also urging caution in their interpretation.
Dr. Paik noted that the study was not a general first-line trial for all patients with EGFR-mutant lung cancer. Instead, it focused on a specific subset of patients with MET aberrations, which have been associated with a poorer prognosis. The trial’s design, which included both an exploratory experimental arm and, in essence, an exploratory control arm, was crucial for understanding its significance. As such, Dr. Paik argued, the results should not be directly compared with those of other first-line EGFR tyrosine kinase inhibitor trials, especially those not specifically targeting MET-aberrant populations.
Cautionary Comments on Biomarkers and Safety
A significant portion of Dr. Paik’s discussion centered on the biomarkers used in the study, particularly MET overexpression and MET amplification. He noted that although these biomarkers were somewhat predictive, their correlation was not perfect, complicating the interpretation of the trial’s outcomes. MET amplification, a common acquired resistance mechanism, has shown modest efficacy when targeted in various trials, he explained. However, data on MET overexpression, particularly in EGFR-positive lung cancer, remained limited, with only a small subset of patients demonstrating these aberrations.
The trial’s definitions of MET aberrations—specifically MET protein overexpression and MET amplification—were consistent with those used in previous studies. However, Dr. Paik pointed out, the variability in the correlation between MET overexpression and MET amplification and the continuous nature of these variables raised questions about the overall performance of these biomarkers.
“Furthermore, as the treatment landscape continues to evolve, it will become increasingly challenging to determine where this combination therapy should fit, particularly as more agents receive approval,” he commented.
Dr. Paik also discussed the safety profile of the combination therapy, noting the increased incidence of peripheral edema and cytopenias. Although these adverse events were reported to be manageable, he suggested they represent a trade-off that needed careful consideration when determining the clinical utility of this combination therapy.
Finally, Dr. Paik emphasized that further studies, particularly those with internal controls for biomarker performance, would be necessary to fully understand the potential of combining osimertinib with savolitinib in this specific patient population.
DISCLOSURE: Dr. Yang reported no conflicts of interest. Dr. Paik reported financial relationships with EMD Serono, Bicara, Novartis, and Summit.
REFERENCE
1. Yang JJ, Li A, Feng WN, et al: Osimertinib with or without savolitinib as 1L in de novo MET aberrant, EGFRm advanced NSCLC (CTONG 2008): A phase II trial. 2024 World Conference on Lung Cancer. Abstract PL04.10. Presented September 9, 2024.
