Preliminary results from the SAVANNAH Phase II trial showed that osimertinib (Tagrisso®; AstrtaZeneca*), a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), plus savolitinib (Orpathys®; HUTCHMED, AstraZeneca), demonstrated an objective response rate (ORR) of 49% (95% confidence interval [CI], 39-59%) in patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) with high levels of mesenchymal-epithelial transition (MET) overexpression and/or amplification, defined as IHC90+ and/or FISH10+, whose disease progressed on treatment with osimertinib.

The highest objective response rate (ORR) was observed in patients with high levels of MET who were not treated with prior chemotherapy (52% [95% CI, 41-63%]). In patients whose tumors did not show high levels of MET, the ORR was 9% (95% CI, 4-18%). These results are being shared at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC), taking place on August 6-9, 2022 in Vienna, Austria.

Savolitinib, is an oral, potent, and highly selective receptor tyrosine kinase mesenchymal epithelial transition factor (MET) inhibitor being jointly developed and commercialized by AstraZeneca and HUTCHMED.

Durable survival benefit
While EGFR-targeted therapy can provide a durable survival benefit to patients with EGFRm NSCLC, most will eventually develop resistance to their treatment, with MET being the most common resistance biomarker. [1] Among patients screened for enrolment in SAVANNAH, all of whom experienced disease progression on osimertinib, 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 NSCLC. 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,” said Myung-Ju Ahn, MD, Ph.D, Professor of Hemato-Oncology at the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and Principal Investigator in the SAVANNAH Phase II trial.

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“They also suggest that with the right biomarker testing strategy, MET may be a more prevalent target among resistant patients than previously understood, supporting further investigation of the osimertinib plus savolitinib regimen,” Ahn added.

Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. Photo courtesy: © 2016 – 2022 AstraZeneca. Used with permission.

Less toxic and more effective
“The current standard of care for patients with EGFR-mutated lung cancer who progress on targeted treatment is chemotherapy,” noted Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca.

“The results from SAVANNAH suggest savolitinib added to osimertinib at the time of disease progression could possibly provide these biomarker-selected patients with a potentially less toxic, more effective treatment option. We look forward to better understanding the potential of the osimertinib plus savolitinib regimen in this trial and in the SAFFRON Phase III trial,” Massacesi added.

Encouraging news
“It is encouraging to see the savolitinib and osimertinib combination regimen progress into a global Phase III study, SAFFRON, with a well-supported patient selection strategy that could benefit more patients than previously recognized,” said Weiguo Su, Chief Executive Officer and Chief Scientific Officer, HUTCHMED.

“The preliminary results of the SAVANNAH study also affirm the role of molecular testing prior to initiating subsequent treatment for NSCLC patients who experience disease progression on an EGFR-targeted therapy. We are aligned in pursuing a selective, patient-centric approach in development efforts for savolitinib in this setting,” Su concluded.

In this 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, and 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 osimertinib 80mg once daily following disease progression on osimertinib alone.

Trial design
SAVANNAH is an ongoing global, randomized, single-arm Phase II trial studying the efficacy of savolitinib added to osimertinib in patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression and/or amplification who progressed following treatment with osimertinib. Patients 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 trial has enrolled 294 patients to date in more than 80 centers globally, including centers in the U.S., Canada, Europe, South America and Asia. The primary endpoint is ORR. Key secondary endpoints include PFS, DoR and safety.

Summary of efficacy resultsi:

EndpointAll patients (IHC50+ and/or FISH5+; n=193)Patients with high levels of METii
(IHC90+ and/or FISH10+)
Patients with lower levels of METii(n=77)
No prior chemo (n=87)
ORR, % (95% CI)32 (26, 39)49 (39, 59)52 (41, 63)9 (4, 18)
Median DoRiii, months (95% CI)8.3 (6.9, 9.7)9.3 (7.6, 10.6)9.6 (7.6, 14.9)6.9 (4.1, 16.9)
Median PFSiv,
months (95% CI)
5.3 (4.2, 5.8)7.1 (5.3, 8.0)7.2 (4.7, 9.2)2.8 (2.6, 4.3)
DCRv, % (95% CI)61 (53, 68)74 (65, 82)75 (64, 83)43 (32, 55)
  1. Analysis data cut-off: 27 August 2021
  2. Eight patients excluded from subgroup analyses due to invalid or missing test results
  3. DoR, duration of response
  4. PFS, progression-free survival
  5. DCR, disease control rate

The safety profile of osimertinib plus savolitinib was consistent with the known profiles of the combination and each treatment alone. No new safety signals were identified. Less than half (45%) of patients in this analysis experienced Grade 3 or higher adverse events (AEs), with those most frequently reported including pulmonary embolism, dyspnea, decreased neutrophil count and pneumonia. AEs attributable to savolitinib and leading to discontinuation occurred in 13% of patients.

The global SAFFRON Phase III trial will further assess the osimertinib plus savolitinib combination versus platinum-based doublet chemotherapy in patients with EGFRm, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC following osimertinib. Patients are being prospectively selected using the high MET level cut-off identified in SAVANNAH.

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. [2] Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC. [3] The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease and approximately 10-15% of NSCLC patients in the U.S. and Europe and 30-40% of patients in Asia have EGFRm NSCLC. [4][5][6][7]

MET is a tyrosine kinase receptor that has an essential role in normal cell development.8 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. [8][9] The prevalence of MET depends on the sample type, detection method and assay cut-off used. [10]

Note: * AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

Note: ** Savolitinib (Orpathys®; HUTCHMED, AstraZeneca) has been granted conditional approval in China to treat patients with non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. This approval follows a priority review designation by the Center for Drug Evaluation of China’s National Medical Products Administration (NMPA) and marks the first global regulatory approval for the oral, potent, and highly selective MET tyrosine kinase inhibitor (TKI).

Clinical trials
A Phase II Study of HMPL-504 in Lung Sarcomatoid Carcinoma and Other Non-small Cell Lung Cancer – NCT02897479
Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (SAVANNAH) – NCT03778229
Osimertinib With or Without Savolitinib as 1L in de Novo MET+, EGFR+ NSCLC (FLOWERS) – NCT05163249
Savolitinib Plus Osimertinib Versus Platinum-based Doublet Chemotherapy in Participants With Non-Small Cell Lung Cancer Who Have Progressed on Osimertinib Treatment (SAFFRON) – NCT05261399
A Study Comparing Savolitinib Plus Osimertinib vs Savolitinib Plus Placebo in Patients With EGFRm+ and MET Amplified Advanced NSCLC (CoC) – NCT04606771
Study on Savolitinib Combined With Osimertinib in Treatment of Advanced NSCLC With MET Amplification (SACHI) – NCT05015608
Clinical Study on Savolitinib + Osimertinib in Treatment of EGFRm+/MET+ Locally Advanced or Metastatic NSCLC (SANOVO) – NCT05009836
Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD) – NCT03944772
AZD9291 in Combination With Ascending Doses of Novel Therapeutics – NCT02143466

Highlights of Prescribing information
Osimertinib (Tagrisso®; AstrtaZeneca) [Prescribing Information]

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[7] Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Histological Samples in 11. Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013:6;2800-12.8.
[8] Uchikawa E, et al. Structural basis of the activation of c-MET receptor. Nat Commun. 2021;12(4074).9.
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[10] Coleman N, Hong L, Zhang J, Heymach J, Hong D, Le X. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2021 Dec;6(6):100319. doi: 10.1016/j.esmoop.2021.100319. Epub 2021 Nov 24. PMID: 34837746; PMCID: PMC8637467.

Featured image by Robina Weermeijer on Unsplash. Used with permission.

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