AstraZeneca and HUTCHMED have announced promising results from the SAVANNAH Phase II trial evaluating the combination of Tagrisso (osimertinib) plus savolitinib in patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) who developed resistance to Tagrisso treatment.
The preliminary data, presented at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer in Vienna, Austria, showed that the combination achieved an objective response rate (ORR) of 49% (95% confidence interval [CI], 39-59%) in patients with high levels of MET overexpression and/or amplification, defined as IHC90+ and/or FISH10+.
Key Findings from SAVANNAH
The study revealed that patients with high levels of MET who had not received prior chemotherapy demonstrated the highest response rate at 52% (95% CI, 41-63%). In contrast, patients whose tumors did not show high levels of MET had a significantly lower ORR of just 9% (95% CI, 4-18%).
Additional efficacy data for patients with high MET levels included:
- Median duration of response: 9.3 months (95% CI, 7.6-10.6)
- Median progression-free survival: 7.1 months (95% CI, 5.3-8.0)
- Disease control rate: 74% (95% CI, 65-82%)
The safety profile of the Tagrisso plus savolitinib combination was consistent with the known profiles of each treatment alone, with no new safety signals identified. Less than half (45%) of patients experienced Grade 3 or higher adverse events, with the most frequently reported being pulmonary embolism, dyspnea, decreased neutrophil count, and pneumonia. Adverse events attributable to savolitinib leading to discontinuation occurred in 13% of patients.
MET as a Key Resistance Mechanism
The findings highlight the significance of MET as a resistance mechanism in EGFR-targeted therapy. Among patients screened for enrollment in SAVANNAH, all of whom experienced disease progression on Tagrisso, 62% had tumors with MET overexpression and/or amplification, and more than one-third (34%) met the defined high MET level cut-off.
"Acquired resistance to targeted therapy and disease progression are difficult realities for most patients with EGFR-mutated non-small cell lung cancer," said Professor Myung-Ju Ahn, Principal Investigator in the SAVANNAH trial from Samsung Medical Center, Sungkyunkwan University School of Medicine in South Korea. "These preliminary SAVANNAH results potentially support a novel approach for identifying patients with MET overexpression and/or amplification who are most likely to benefit from a MET-directed therapy, like savolitinib."
Implications for Treatment Paradigm
The current standard of care for patients with EGFR-mutated lung cancer who progress on targeted treatment is chemotherapy. The SAVANNAH results suggest that adding savolitinib to Tagrisso at the time of disease progression could provide biomarker-selected patients with a potentially less toxic, more effective treatment option.
Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer at AstraZeneca, noted: "We look forward to better understanding the potential of the Tagrisso plus savolitinib regimen in this trial and in the SAFFRON Phase III trial."
Weiguo Su, Chief Executive Officer and Chief Scientific Officer at HUTCHMED, added: "The preliminary results of the SAVANNAH study also affirm the role of molecular testing prior to initiating subsequent treatment for non-small cell lung cancer patients who experience disease progression on an EGFR-targeted therapy."
Study Design and Patient Selection
In the SAVANNAH analysis, patients' MET overexpression and/or amplification levels were determined by two tests:
- Immunohistochemistry (IHC), which detects if cancer cells have a particular protein or marker on their surface
- Fluorescence in situ hybridization (FISH), which detects a specific DNA sequence from cancer cells
All patients in this analysis (n=193) had at least IHC50+ and/or FISH5+, and were treated with savolitinib 300mg once daily added to Tagrisso 80mg once daily following disease progression on Tagrisso alone.
Moving Forward: The SAFFRON Phase III Trial
Based on these promising results, the global SAFFRON Phase III trial has been initiated to further assess the Tagrisso plus savolitinib combination versus platinum-based doublet chemotherapy in patients with EGFRm, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC following Tagrisso. Patients are being prospectively selected using the high MET level cut-off identified in SAVANNAH.
About NSCLC and MET Aberrations
Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths. NSCLC accounts for 80-85% of all lung cancer cases, with the majority of patients (approximately 75%) diagnosed with advanced disease.
Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia, have EGFRm NSCLC. While EGFR-targeted therapy can provide a durable survival benefit to these patients, most eventually develop resistance to their treatment.
MET is a tyrosine kinase receptor that plays an essential role in normal cell development. MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is the primary mechanism of acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.
About Savolitinib and Tagrisso
Savolitinib, marketed in China under the brand name Orpathys, is an oral, potent, and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations, gene amplification, or protein overexpression.
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system metastases. It has been used to treat approximately 575,000 patients across indications worldwide.
