Simlukafusp alfa (FAP-IL2v) plus atezolizumab with or without bevacizumab in unresectable, metastatic renal cell carcinoma: a randomized, open-label phase Ib study.

[BACKGROUND] Simlukafusp alfa (FAP-IL2v) was engineered to preferentially activate CD8+ T and natural killer (NK) cells in tumor microenvironments overexpressing fibroblast activation protein (FAP). Checkpoint inhibitors combined with antiangiogenic agents are standard therapy for metastatic renal cell carcinoma (mRCC), which overexpresses FAP. Here, we explored the efficacy, safety, and pharmacodynamic effects of FAP-IL2v in combination with atezolizumab with or without bevacizumab in patients with mRCC.

[METHODS] Patients with treatment-naïve or pretreated clear cell and/or sarcomatoid mRCC were eligible. Dose escalation explored FAP-IL2v every 2 weeks (Q2W) with atezolizumab Q2W (doublet, arm A), and with atezolizumab and bevacizumab Q2W (triplet, arm B) in patients treated with up to one prior systemic therapy. Dose extension explored in untreated patients the recommended FAP-IL2v dose administered Q2W (doublet, arm A; and triplet, arm B) or 3-weekly (doublet, arm C; and triplet, arm D). Primary objectives were the recommended FAP-IL2v dose and antitumor activity. Secondary objectives included safety, pharmacodynamics, and exploratory biomarkers in peripheral blood and paired biopsies.

[RESULTS] By the data cut-off date (31 August, 2021), 66 patients were enrolled. The median duration of treatment was 11.0 months. Objective response rates (ORRs) were 25% for the doublet and 47% for the triplet, and median progression-free survival was 6.3 and 18.3 months, respectively. Safety profiles were consistent with the individual drugs, including expected interleukin-2 (IL-2) class-specific adverse events (AEs). Two deaths were recorded caused by AEs related to study treatment (acute kidney injury, n=1; pancytopenia, n=1). Expansion and activation of NK and T cells, but not regulatory T cells, was observed in peripheral blood, leading to increased tumor infiltration and inflammation in paired biopsies. The addition of bevacizumab led to a reduced angiogenesis signature score and reduced vessel density.

[CONCLUSION] The combination of FAP-IL2v plus atezolizumab with or without bevacizumab was consistent with the known safety profile of the individual drugs. The maximum tolerated dose was not reached, with a recommended FAP-IL2v dose of 10 mg. ORR was higher among patients receiving the triplet therapy compared with the doublet. Pharmacodynamic results were consistent with the mechanism of action of IL-2, supporting further research in this field.