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Savolitinib shows some activity for papillary renal cell carcinoma
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Savolitinib monotherapy demonstrated antitumor activity and appeared tolerable among patients with advanced papillary renal cell carcinoma, according to phase 2 study results.
“These results confirm that savolitinib ... holds promise as a personalized treatment for patients with metastatic MET-driven papillary renal cell carcinoma,” Toni K. Choueiri, MD, director of Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and colleagues wrote.
Prognosis for patients with advanced papillary renal cell carcinoma is poor, and therapeutic options remain limited.
Phase 1 study results showed savolitinib (AZD6094/HMPL-504; AstraZeneca, Hutchison MediPharma) — a selective MET inhibitor — yielded partial responses among patients with advanced or metastatic papillary renal cell carcinoma.
Choueiri and colleagues evaluated the safety and efficacy of savolitinib and sought to correlate activity with MET pathway alterations.
Researchers enrolled 111 patients with locally advanced disease who received 600 mg savolitinib once daily. Ninety-eight percent of patients had metastatic disease, 45% previously underwent systemic therapy, 73% underwent nephrectomy and 20% underwent radiotherapy. Twenty-eight patients received prior therapy with the kinase inhibitor sunitinib (Sutent, Pfizer).
Savolitinib antitumor activity by MET status served as the primary endpoint. Secondary endpoints included PFS and change in target lesions/tumor size from baseline.
A total of 109 patients received at least one dose of savolitinib. Among these, 44 had MET-driven disease, 46 had MET-independent disease and 19 had unknown MET status.
Researchers reported an overall response rate of 7% among those treated. Eight patients with MET-driven disease experienced a partial response compared with none with MET-independent disease (P = .002).
Median PFS was 6.2 months (95% CI, 4.1-7) among patients with MET-driven disease and 1.4 months (95% CI, 1.4-2.7) among patients with MET-independent disease (P < .001).
Half of patients (n = 22) with MET-driven disease achieved stable disease compared with 24% of patients (n = 11) with independent disease.
A majority (88%) of patients experienced at least one treatment-related adverse event. Frequent adverse events associated with treatment included nausea, fatigue, vomiting and peripheral edema.
Abnormal liver function tests occurred among 20% of patients. Commonly observed hepatic adverse events included increased aspartate aminotransferase (11%; grade 3, 4%) and increased alanine aminotransferase (10%, grade 3, 5%).
“These data ... [justify] the recently launched phase 3 trial comparing savolitinib with sunitinib in a population of patients with MET-driven papillary renal cell carcinoma,” the researchers wrote.
Despite a modest ORR, the ability to identify MET pathway alterations underscores the importance of molecular analysis, Brian M. Shuch, MD, assistant professor of urology and of radiology and biomedical imaging, and director of the genitourinary cancer genetics and prevention program at Yale School of Medicine, and colleagues wrote in a related editorial.
“The savolitinib trial is an important step in determining what the standard of care should be in this population,” Shuch and colleagues wrote. “Moving forward, we await the results of larger trials that involve MET inhibitors, including comparisons to traditional antivascular endothelial growth factor receptor-targeted therapy (sunitinib).”
A new frontline therapy for papillary renal cell carcinoma — an unmet need — might be defined in the next few years, they added.
“The widespread availability of molecular profiling to guide therapy and the availability of well-tolerated MET-directed agents that are undergoing clinical development promise an available effective agent in the near future,” they wrote. – by Melinda Stevens
Disclosures: AstraZeneca funded this study. Choueiri reports advisory/consultant roles with Alligent, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Eisai, Exelixis, Foundation Medicine, Genentech, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer and Prometheus; and honoraria from National Comprehensive Cancer Network and UpToDate. Please see the full study for a list of all other authors’ relevant financial disclosures. Shuch reports an advisory/consultant role with Pfizer. One editorial author reports advisory/consultant roles with Cerulean Pharma, Clovis Oncology, Eisai, EMD Genentech, Exelixis, Merck, Novartis, Pfizer and Serono.
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