Savolitinib Might Improve Outcomes in Some Patients With Papillary Renal Cell Carcinoma

By Will BOggs MD

June 08, 2020

NEW YORK (Reuters Health) - Savolitinib appears to improve outcomes in patients with MET-driven papillary renal-cell carcinoma (PRCC) compared with sunitinib, the standard of care, according to results from the SAVOIR randomized clinical trial.

This is "proof of concept that a papillary RCC can have a subset that is MET-dependent," Dr. Toni K. Choueiri of Dana-Farber Cancer Institute and Harvard Medical School, in Boston, told Reuters Health by email. "We needed a targeted approach really badly in RCC, so we hope this is a start and a new trial will be more definitive."

In a phase-2 study of savolitinib in 109 patients with PRCC, eight of 44 (18%) patients who were determined to have MET-driven disease showed partial responses, compared with no responses among patients with MET-independent PRCC.

In the current phase-3 study, Dr. Choueiri and colleagues assessed the efficacy and safety of savolitinib versus sunitinib (the current standard-of-care treatment) in patients with MET-driven, unresectable and locally advanced or metastatic PRCC.

The study was halted prematurely after enrolling 60 patients because a concurrent retrospective molecular epidemiology study on the outcomes of patients with MET-driven PRCC on sunitinib suggested that MET-driven status did not appear to be a negative predictive factor for treatment outcomes. The researchers concluded that their trial would be unlikely to detect a difference in efficacy between the treatment groups and terminated recruitment.

Among those enrolled, 17 of 33 patients (52%) in the savolitinib group experienced progression events, compared with 20 of 27 patients (74%) in the sunitinib group, a difference that was not statistically significant.

Median progression-free survival (PFS) was 7.0 months in the savolitinib group versus 5.6 months in the sunitinib group, the researchers report in JAMA Oncology.

Nine patients (27%) in the savolitinib group and 13 patients (48%) and the sunitinib group died, a difference that fell short of statistical significance.

The overall response rate (ORR) was also nominally higher in the savolitinib group (9/33, 27%) than in the sunitinib group (2/27, 7%). All responses in both groups were partial.

None of the responding patients in the savolitinib group had disease progression as of the data cutoff, compared with one of the two responding patients in the sunitinib group.

Adverse events of any cause occurred with similar frequency in the two groups, and adverse events led to discontinuation in six patients in the savolitinib group versus five in the sunitinib group.

Disease progression was the most common reason for treatment discontinuation in both groups.

"I think overall it is impossible to make assertions because the study is underpowered and had to stop at 60 patients and did not enroll the full 180 patients," Dr. Choueiri said. "Nevertheless, we are encouraged by ORR differences, hazard ratio (HR) for PFS and HR for overall survival for a savolitinib, which is a tyrosine kinase inhibitor (TKI) specific against MET."

"We hope that now the field knows that a MET-targeted approach can work in a subset of papillary RCC where there is no standard," he said. "We hope to have a next trial with savolitinib, and that trial is appealing to the community and the patients and stays relevant with all the changes that are happening in the RCC field."

Dr. Mehmet Asim Bilen of Winship Cancer Institute of Emory University, in Atlanta, who recently reviewed PRCC and MET inhibitors, told Reuters Health by email, "Due to the early stop of this clinical trial and small sample size, we cannot make a definitive conclusion. However, the data suggest encouraging efficacy and safety profile of savolitinib over sunitinib in patients with MET-driven papillary RCC. Additionally, future studies of savolitinib are reasonable with other combinations such as immunotherapy."

"Most importantly, this is one of the first molecularly selected phase-3 clinical trials that were conducted in this rare subtype," he said. "Because of this reason, this study opened up an important door in the field and demonstrates that a similar trial can be conducted in the future."

"Overall, MET is an appealing drug target in genomically selected papillary RCC, and developing effective MET targeted therapies is needed in this patient population since they have worse outcomes," said Dr. Bilen, who was not involved in the research. "Therapeutic interventions targeted to the MET pathway in papillary RCC should resume alone or in combinations with other agents in order to improve patient outcomes."

AstraZeneca provided funding for the study, employed several authors and had financial ties to others, including Dr. Choueiri.

SOURCE: JAMA Oncology, online May 29, 2020.