The novel immunocytokine simlukafusp alfa (FAP-IL2v) combined with atezolizumab (Tecentriq), with or without bevacizumab (Avastin), demonstrated a manageable safety profile and encouraging antitumor activity in patients with unresectable, metastatic renal cell carcinoma (RCC), according to results from a phase 1b study (NCT03063762) published in the Journal for ImmunoTherapy of Cancer.
Among patients receiving the doublet (n = 28) the objective response rate (ORR) was 25.0% (90% CI, 14.2%-40.2%), the disease control rate (DCR) was 60.7% (90% CI, 45.2%-74.3%), and the median duration of response (DOR) was not estimable (NE; 95% CI, 15.3 months to NE). The median progression-free survival (PFS) with the doublet was 6.3 months (95% CI, 1.9-18.2).
The triplet regimen (n = 38) yielded an ORR of 47.4% (90% CI, 34.7%-60.4%), a DCR of 89.5% (90% CI, 78.5%-95.2%), and a median DOR of NE (95% CI, 12.6 months to NE). The median PFS with the triplet was 18.3 months (95% CI, 11.0-22.1).
Although the triplet therapy demonstrated greater clinical activity across key parameters, the investigators noted that formal statistical comparisons between arms were not performed.
“The combination of [simlukafusp alfa] plus atezolizumab with or without bevacizumab did not improve response rates, as compared with current standard therapy for metastatic RCC,” José Luis Pérez-Gracia, MD, PhD, a consultant oncologist at Clinica Universidad de Navarra, Pamplona, Spain, and his coauthors wrote in the publication.
Simlukafusp Alfa Plus Atezolizumab With/Without Bevacizumab
- The novel immunocytokine simlukafusp alfa plus atezolizumab, with or without bevacizumab, demonstrated a manageable safety profile and antitumor activity in patients with unresectable, metastatic RCC.
- However, the doublet and triplet regimens did not improve response rates compared with standard therapies.
- Pharmacodynamic results confirmed the ability of IL-2–based therapies to induce an inflammatory infiltrate, supporting continued research of IL-2–based therapies and other novel immunocytokines in mRCC.
How was the phase 1b study designed?
The randomized, multicenter, open-label phase Ib study enrolled adult patients with confirmed unresectable advanced/metastatic RCC with a component of clear cell and/or sarcomatoid histology.1,2 Patients were also required to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, an evaluable Memorial Sloan-Kettering Cancer Center risk score, and a life expectancy of at least 12 weeks.
The phase Ib study comprised 2 parts: a dose-escalation phase using a 3+3 design and a dose-extension phase. During dose escalation, patients with unresectable metastatic RCC who had received up to 1 prior systemic therapy were enrolled. All patients received simlukafusp alfa plus atezolizumab during cycle 1 before random assignment to either the doublet arm (arm A: simlukafusp alfa plus atezolizumab every 2 weeks) or the triplet arm (arm B: simlukafusp alfa plus atezolizumab and bevacizumab every 2 weeks). During dose extension, treatment-naive patients were randomly assigned receive the doublet or triplet as a twice-weekly dose (arms A and B) or 3 times a week (arms C and D).
The recommended dose of simlukafusp was 10 mg; this dose was selected for the extension phase based on the previously established monotherapy dose, potential additive toxicity from combination therapy, and evidence that 10 mg generated profound lymphocyte expansion and activation. The maximum tolerated dose (MTD) was not reached.
The study’s primary end points were the incidence of dose-limiting toxicities, determining the MTD of simlukafusp alfa, determining the recommended dose of simlukafusp alfa, and ORR. Secondary end points included pharmacokinetic measures, DCR, complete response rate, DOR, PFS, and overall survival.
What were the pharmacokinetic and safety data that were shared in the publication?
In terms of safety, all 66 patients experienced at least 1 adverse effect (AE) considered related to simlukafusp alfa, the most common of which were pyrexia (83%), chills (68%), and nausea (52%). Serious AEs occurred in 58% of patients overall, 47% of which were considered related to any study drug.
Expected IL-2 class–specific AEs were observed, including liver function test abnormalities (70%), infusion-related reactions (38%), and hypotension (15%). Notably, no cases of capillary leak syndrome were reported. Only 3 cases of serious treatment-related hypotension, all of which were grade 3, were documented.
Two treatment-related deaths were recorded: 1 from grade 5 acute kidney injury (arm A, attributed to simlukafusp alfa and atezolizumab) and another from pancytopenia that occurred 236 days after the last dose of study treatment. A third death, from grade 5 hemothorax in arm D, was considered possibly related to antiplatelet treatment. Rates of AEs leading to simlukafusp alfa dose interruption or modification were 61% during dose escalation and 53% during dose extension.
Pharmacodynamic analyses supported the mechanism of action of IL-2. In peripheral blood, simlukafusp alfa induced pronounced and sustained expansion of natural killer (NK) cells, CD8-positive T cells, and CD4-positive T cells. Peripheral regulatory T cell (Treg) levels remained unchanged, consistent with simlukafusp alfa‘s engineered selectivity away from Treg activation. Expansion of immune cell populations in early cycles was accompanied by elevated levels of soluble CD25, a marker of sustained systemic immune activation.
In paired tumor biopsies from 18 patients in arms A and B, a significant increase in T effector signature score was observed on-treatment vs baseline (P = .002). Marked increases in tumor-infiltrating lymphocyte density, including CD3-positive and CD8-positive T cells, proliferating CD8-positive T cells, and perforin-positive cytotoxic T and NK cells, were documented following both regimens. Responders demonstrated more pronounced on-treatment changes in tumor tissue compared with nonresponders, particularly for CD3-positive T cells and NK cells.
“Our results do not support further development of [simlukafusp alfa] in this setting. However, our pharmacodynamic results confirm the ability of IL-2–based therapies to induce an inflammatory infiltrate, supporting continued research of IL-2–based therapies and other novel immunocytokines in metastatic RCC,” Pérez-Gracia and his coauthors wrote in their conclusion.
References
- 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(4):e012466. doi:10.1136/jitc-2025-012466
- Study to evaluate safety, pharmacokinetics and therapeutic activity of RO6874281 as a combination therapy in participants with unresectable advanced and/or metastatic renal cell carcinoma (RCC). ClinicalTrials.gov. Updated February 17, 2023. Accessed May 5, 2026. https://clinicaltrials.gov/study/NCT03063762
