Investigators Explore Savolitinib Plus Durvalumab in MET-Driven Advanced Papillary RCC

A global phase 3 clinical trial has been initiated to evaluate savolitinib (Orpathys) in combination with durvalumab (Imfinzi) to treat patients with MET-driven advanced papillary renal cell carcinoma (RCC), according to a joint press release from the drug developers HUTCHMED Limited and AstraZeneca PLC.¹

The first patient in the study was dosed with the experimental combination on October 28, 2021.

Savolitinib is an oral, potent, and highly selective small molecule inhibitor of the receptor tyrosine kinase MET. In preclinical studies, savolitinib achieved anti-tumor activity and treatment was not impacted by co-dosing with commonly used agents like rifampicin, itraconazole, and midazolam.^1-3

In the open-label, randomized, 3-arm, multicenter phase 3 study (SAMETA; NCT05043090) the efficacy and safety of savolitinib plus durvalumab, a PD-L1 inhibitor, will be investigated in approximately 200 patients with MET-driven unresectable and locally advanced or metastatic papillary RCC, who have not received any prior systemic anti-cancer therapy in the metastatic setting.⁴

Patients will be randomized 2:1:1 to be evaluated receiving a selection of interventions. In 1 arm, patients will be treated with oral savolitinib 600 mg once daily in combination with durvalumab 1500 mg via intravenous (IV) infusion every 4 weeks. In another arm, patients will receive oral sunitinib (Sutent) 50 mg once daily for 4 consecutive weeks followed by a sunitinib-free interval of 2 weeks every 6 weeks. In the final treatment arm, patients will be treated with durvalumab monotherapy at 1500 mg IV every 4 weeks.

All therapies administered in the study will continue until objective radiological progressive disease per RECIST v1.1, until unacceptable toxicity occurs, or until a patient voluntarily withdraws.

The primary end point being investigated in SAMETA is progression-free survival (PFS). The analysis of the primary end point will include all randomized patients. The secondary end points of the study include overall survival, objective response rate, duration of response, disease control rate, PFS2, patient-reported outcomes, and pharmacokinetics.

Patients are eligible to enroll in the study given they have histologically confirmed unresectable and locally advanced or metastatic disease that is centrally confirmed as MET-driven. Patients must have no prior treatment with systemic anti-cancer therapy in the metastatic setting, a Karnofsky core of > 70, at least 1 lesion, adequate organ and bone marrow function, and a life expectancy of ≥ 12 weeks at day 1 of the study.

The study includes individuals who have a history of serious liver disease with or without normal liver function tests. In addition, patients with spinal cord compression or brain metastases may be excluded, along with patients with active or prior cardiac disease, active infection, active or prior autoimmune or inflammatory disorder, or those who received a live unattenuated vaccine within 30 days.

SAMET’s lead investigator is Toni Choueri, MD, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg chair and professor of Medicine, Harvard Medical School.

_References:

_{1. HUTCHMED and AstraZeneca initiate SAMETA global phase III trial of savolitinib in combination with pd-l1 inhibitor IMFINZI® in patients with met-driven advanced papillary renal cell carcinoma. News release. HUCHMED and AstraZeneca. November 1, 2021. Accessed November 2, 2021. https://bit.ly/2ZKCiQS}

_{2. Jones RD, Grondine M, Borodovsky A, et al. A pharmacokinetic–pharmacodynamic model for the MET tyrosine kinase inhibitor, savolitinib, to explore target inhibition requirements for anti-tumour activity. Brr J Pharmacol. 2021;178(3):600-613. doi:10.1111/bph.15301}

_{3. Ren S, Vishwanathan K, Cantarini M, et al. Clinical evaluation of the potential drug–drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam. 2021. Published online ahead of print. doi: 10.1111/bcp.14994.}

_{4. Savolitinib plus durvalumab versus sunitinib and durvalumab monotherapy in met-driven, unresectable and locally advanced or metastatic PRCC (SAMETA). Clinicaltrials.gov. Accessed Novemeber 2, 2021.}