Simlukafusp Alfa Combo Shows Promising Early Efficacy in Unresectable RCC

The addition of simlukafusp alfa (FAP-IL2v) to atezolizumab (Tecentriq) with or without bevacizumab (Avastin) conferred early efficacy among patients with unresectable, metastatic renal cell carcinoma (RCC), according to findings from a phase 1b trial (NCT03063762) published in the Journal for ImmunoTherapy of Cancer.¹

Specifically, among patients treated with or without bevacizumab, the objective response rate (ORR) was 47% vs 25%, with 8% vs 0% experiencing a complete response (CR) and 39% vs 25% experiencing a partial response (PR). Additionally, the disease control rate (DCR) was 89% vs 61%, with a median duration of response (DOR) of not estimable (NE; 95% CI, 12.6 months-NE) and NE (95% CI, 15.3 months-NE), respectively. The median progression-free survival (PFS) was 18.3 months (95% CI, 11.0-22.1) vs 6.3 months (95% CI, 1.9-18.2) in each of the respective arms.

Dose-limiting toxicities (DLTs) were observed in 1 patient treated in arm A, a doublet arm containing weekly or twice weekly atezolizumab, and none were observed in arm B, which included weekly or biweekly bevacizumab. The DLT in arm A was a treatment-related vasogenic cerebral edema event, which resolved with dose interruption of simlukafusp alfa. Additionally, the maximum tolerated dose (MTD) for the investigational agent was not reached, with a recommended dose for extension of 10 mg.

“Triplet therapy had better clinical activity than doublet therapy in key parameters, although formal statistical testing was not performed. The most active treatment option among these combinations appeared to be the triplet regimen [every 3 weeks],” lead study author Jose Luis Perez-Gracia, MD, coordinator of the Oncology Clinical Trials Area and medical coordinator of the Central Clinical Trials Unit at Clinica Universidad de Navarra, wrote in the publication with study coinvestigators. “The safety profile was consistent with the known safety profiles of the individual drugs. No unexpected overlapping toxicities were identified.”

Investigators of the phase 1b trial enrolled patients 18 years and older with confirmed unresectable advanced or metastatic clear cell or sarcomatoid RCC. In the dose-escalation portion, patients were permitted to have received up to 1 prior therapy. However, patients in the dose-expansion portion of the trial could not have received prior therapy, including in the adjuvant setting.

In the dose-extension portion of the trial, patients were randomly assigned to 1 of 4 arms: arm A or B assessing doublet or triplet therapy with induction and maintenance treatment; or arm C or D, in which patients were treated with the recommended simlukafusp alfa dose found in the dose-escalation stage once every 3 weeks for all study drugs.

Across all cohorts (n = 66), the median age was 57.5 years (range, 35-78) and 78.8% of patients were male. Moreover, 77.3% of patients were White, 71.2% were not Hispanic or Latino, and 71.2% had an ECOG performance status of 0. Most patients were in the intermediate Integrated Motzer Score Risk Group (54.5%) and received no prior therapies (90.9%); the median duration of treatment was 11.01 months (range, 0.0-38.9).

The primary end point of the study was determining the MTD or recommended dose in the dose-escalation portion of the trial and antitumor activity in the dose-extension portion of the trial, specifically ORR. Secondary end points included safety and tolerability, pharmacodynamics, pharmacokinetics, and additional antitumor activity measures.

Adverse effects (AEs) of any grade related to simlukafusp alfa were reported in all patients treated on the study, the most common of which were pyrexia (83%), chills (68%), and nausea (52%). Moreover, serious AEs occurred in 58% of all patients, including 47% due to study treatment. The rates of AEs were generally similar across all study arms; however, the rates of pyrexia, pruritus, and diarrhea were higher with the triplet regimen.

Reference

Perez-Gracia JL, Mellado B, Hansen AR, et al. Simlukafusp alfa (FAP-­ IL2v) plus atezolizumab with or without bevacizumab in unresectable, metastatic renal cell carcinoma: a randomized, open-label phase Ib study. J Immunother Cancer. 2026;14:e012466. doi:10.1136/jitc-2025-012466