Combo Falters in Papillary Renal Cancer, but Some Promise in MET-Driven Subset

Treatment with an investigational MET inhibitor plus a PD-L1 inhibitor induced responses in fewer than a third of patients with metastatic papillary renal cancer, but the combination showed promise for one subgroup, findings from the phase II CALYPSO trial showed.

In the single-arm study, 12 of 41 patients (29%, 95% CI 16-46) had a confirmed response following treatment with savolitinib and durvalumab (Imfinzi), a rate that fell short of the primary endpoint, a confirmed response rate (cRR) over 50%, reported Thomas Powles, MD, of the Barts Cancer Institute and Queen Mary University of London, and colleagues.

However, they observed that nine of the 17 patients with MET-driven tumors (53%, 95% CI 28-77) had a confirmed response, an efficacy signal that was maintained when it came to duration of response and survival outcomes, the group detailed in the Journal of Clinical Oncology.

Median progression-free survival was 4.9 months in the full study population and 12 months in the group with MET-driven tumors, while median overall survival was 14.1 and 27.4 months, respectively.

“Overall, these data have resulted in SAMETA, a large randomized phase III trial that is formally testing the combination in MET-driven individuals,” the group wrote. (The study will use sunitinib (Sutent) or durvalumab alone as comparator arms.)

“This may herald a new era of personalized combination therapy in PRC [papillary renal cancer] where MET-driven tumors are prominent,” said Powles and co-authors.

In an editorial accompanying the study, Mehmet Asim Bilen, MD, of the Winship Cancer Institute of Emory University in Atlanta, and colleagues noted that although the cohort of patients with MET-driven tumors was small in CALYPSO, it is the first MET biomarker analysis within a trial testing the combination of a MET targeted therapy with checkpoint inhibition.

The question now, they suggested, is what agents will be the “ideal partners” within this combination strategy, and detailed several potential options. Considering the disease has had few treatment options in the recent past, “determining the ideal approach among many promising ones is a most welcome quandary.”

Asim Bilen and co-authors said that attention to the tolerability of combinations will be “paramount,” and observed that while MET-specific agents like savolitinib can help patients avoid the typical toxicities caused by antiangiogenic agents, they can expose them to others, including nausea, fatigue, and peripheral edema.

Also, the utility of a biomarker-dependent drug like savolitinib in the clinic will depend on how fast next-generation sequencing can be completed, the editorialists observed, adding that “a broader targeting agent such as cabozantinib [Cabometyx] could prove more desirable in a situation where mutational status is not readily available.”

The single-arm CALYPSO trial evaluated durvalumab (1,500 mg every 4 weeks) and savolitinib (600 mg once daily) in 41 patients with advanced papillary renal cancer.

Patients in the study had a median age of 62 years, and 83% were men. Most had a Heng intermediate-risk score (63%), a third had received prior therapy for advanced disease, and two-thirds had tumors that were PD-L1-positive. MET status was unavailable for 10 patients.

The cRR was higher in patients who had not received prior therapy (37% vs 14% in those with prior therapy). In the subset of patients with PD-L1-positive tumors, 33% responded.

Among responders, the median duration of response was 9.4 months in the full study population and 11.5 months in the MET-driven subset.

Regarding safety, treatment-related adverse events (TRAEs) occurred in 83% of patients, with nausea, edema, fatigue, and vomiting being most common. Grade ≥3 TRAEs occurred in 41%. Toxicity in the MET-driven patients were similar to those in the full study population.

Serious adverse events (AEs) occurred in 39% of patients, including two grade 5 events (infection and a treatment-related cerebral infarction). The most common serious AEs were infection, dyspnea, and tachycardia. Serious AEs in MET-driven patients were less frequent but similar to those in the treated population, Powles’ group noted.