Approximately 75 percent of patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced disease. The median overall survival and 5-year survival rates are historically poor. In the U.S., 5-year survival rate of NSCLC is approximately 26 percent, while that of advanced NSCLC is much lower, approximately 7 percent.
A subset of advanced NSCLC patients (15-55%) have epidermal growth factor receptor (EGFR)-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC is the preferred first-line treatment in EGFR-mutated (EGFRm) advanced NSCLC. However, acquired resistance due to the overexpression and/or amplification of the tyrosine kinase receptor MET has limited the efficacy of EGFR TKIs. Platinum-based chemotherapy remains the standard of care with limited efficacy. Consequently, researchers are investigating new approaches to target MET activity to circumvent this obstacle.
Recently, positive preliminary results for this patient population were announced via the findings of the SAVANNAH study (NCT03778229). It is an ongoing global, randomized, single-arm, Phase II trial studying the efficacy of savolitinib added to osimertinib in patients with EGFRm NSCLC with MET overexpression and/or amplification who progressed following treatment with osimertinib. Savolitinib is a third-generation highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors.
To date, the trial has enrolled 294 patients in more than 80 centers globally. Of those patients, MET overexpression and/or amplification levels of patients were determined by two tests: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). At data cutoff, 196 patients were treated and 193 were available for efficacy evaluation. In the analysis, 193 patients had at least IHC50+ and/or FISH5+ and were treated with savolitinib 300 or 600 mg once-daily (QD) or 300 mg twice daily in combination with oral osimertinib 80 mg QD. The primary endpoint is objective response rate (ORR). Key secondary endpoints include progression-free survival (PFS), duration of response (DoR), disease-control rate (DCR), and safety.
Across the entire study, the preliminary results show an ORR of 32 percent with a median DOR of 8.3 months (95% CI: 6.9-9.7). The median PFS was 5.3 months (95% CI: 4.2-5.8) and the DCR was 61 percent (95% CI: 53-68%). Among patients IHC90+ and/or FISH10+ (n=108), osimertinib plus savolitinib demonstrated an ORR of 49 percent (95% CI: 39-59%) with a median DOR of 9.3 months (95% CI: 7.6-10.6). The median PFS was 7.1 months (95% CI; 5.3-8.0) and the DCR was 74 percent (95% CI, 65-82%).
A reduced clinical benefit was noted among patients without ICH90+ and/or FISH10+ status (n=77). In patients whose tumors did not show high levels of MET, the ORR was 9 percent (95% CI: 4-18%) with a median DOR of 6.9 months (95% CI: 4.1-16.9%). The median PFS was only 2.8 months (95% CI: 2.6-4.3) and the DCR was 43 percent (95% CI: 32-55%). The highest ORR was observed in patients with high levels of MET who were not treated with prior chemotherapy (52% [95% CI: 41-63%]).
In the safety analysis set (n=196), 62 percent were women and the median age was 63 years (range, 34-86). Less than half (45%) of patients in this analysis experienced Grade 3 or higher adverse events (AEs), 20 percent of patients experiencing Grade 3 or higher AEs related to study treatment. Serious AEs were reported in 29 percent of patients, 7 percent of which were related to the study treatment. AEs attributable to savolitinib and leading to discontinuation occurred in 13 percent of patients.
For additional insights on patients with EGFRm NSCLC with high levels of MET overexpression and/or amplification, Oncology Times chatted with study author, Filippo de Marinis, MD, who is Director of the Thoracic Oncology Division and Vice Director of the Lung Cancer Program at the European Institute of Oncology, IRCCs, Milan.
Oncology Times: What are some of the current treatment challenges when it comes to patients with EGFR-mutated NSCLC?
de Marinis: "Frontline treatment with EGFR-targeted therapy can provide high response rates and durable survival benefit in patients with EGFRm NSCLC. However, resistance to EGFR TKIs occurs in most cases during treatment with different patterns of progression. While the EGFR T790M point mutation is the most frequent acquired resistance mechanism in patients treated with first- or second-generation EGFR TKIs, MET overexpression/amplification represents the most common resistance mechanism identified in tumors after progression on osimertinib. The identification of the resistance mechanism through tumor rebiopsy at progression represents one of the major challenges to optimize a biomarker-driven approach to treat osimertinib resistance."
Oncology Times: MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells. What does the prevalence of MET depend on?
de Marinis: "All patients screened in the SAVANNAH trial underwent tumor rebiopsy for the identification of MET-driven resistance. Among them, 62 percent had MET overexpression/amplification defined as IHC50+ and/or FISH5+, and 34 percent had high MET (defined as IHC90+ and/or FISH10+). This implies that the prevalence of MET depends on testing and cutoff level definitions."
Oncology Times: There are many different types of tissue- and blood-based assays available for biomarker testing. What was the rationale for utilizing IHC and FISH for this study?
de Marinis: "IHC detects the protein on the surface of cancer cells, while FISH can detect a specific DNA sequence from cell DNA. Of note, the presence of a specific DNA sequence, does not necessarily determine the presence of the corresponding protein. MET protein is a receptor tyrosine kinase, and its role in tumor growth and progression depends on its aberrant activation. In EGFR mutant NSCLC, this has been found related to MET amplification and not to MET mutation. Hence, the rationale for using IHC and FISH to screen for MET amplification and MET protein overexpression on tissue samples."
Oncology Times: What are the potential clinical implications of the findings of this study and the next steps?
de Marinis: "The combination of osimertinib plus savolitinib demonstrated an ORR of 49 percent (CI: 39-59%) in patients with EGFR-mutant NSCLC with high levels of MET overexpression and/or amplification after progression on osimertinib. ORR was 32 percent (95% CI: 26-39) in all patients (MET IHC50+ and/or FISH5+).
"Nowadays, the standard of care for patients after progression on osimertinib is platinum-based chemotherapy. Several compounds are under investigation in the post-osimertinib setting, some of them are biomarker unselected. The results of SAVANNAH suggest the opportunity to consider a biomarker-based approach by adding savolitinib to osimertinib at the time of disease progression in molecularly selected population as an effective treatment approach. The randomized Phase III SAFFRON trial will better investigate this treatment option."
Dibash Kumar Das is a contributing writer.