ASCO 2021: Randomized Phase Ib Study To Evaluate Safety, Pharmacokinetics and Therapeutic Activity of Simlukafusp α in Combination With Atezolizumab ± Bevacizumab in Patients With Unresectable Advanced/ Metastatic Renal Cell Carcinoma (Rcc) (NCT03063762)

( There have been transformational changes in systemic treatment for patients with advanced renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches.

While CheckMate 214 first brought combination therapy with dual checkpoint inhibition to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors and tyrosine-kinase inhibitors in the first-line setting. However, the use of combination therapy in the first-line setting has further emphasized the need to identify novel therapeutic targets. One such agent is simlukafusp α (FAP-IL2v), a novel IL-2v immunocytokine engineered to preferentially activate effector CD8 T and NK cells, but not regulatory T cells (Tregs), due to abolished binding to Interleukin-2 receptor α (IL-2Rα) and retained affinity to IL-2Rβγ. Simlukafusp α has high-affinity binding to fibroblast activation protein which leads to its accumulation in malignant lesions as fibroblast activation protein is expressed on cancer-associated fibroblasts.


In the Kidney and Bladder Poster session at the 2021 American Society of Clinical Oncology 2021 Annual Meeting held on Friday, June 4th, 2021, Dr. Jose Perez-Gracia presented results of a phase Ib randomized study of simlukafusp α and atezolizumab with or without bevacizumab (NCT03063762).

To do so, the authors enrolled 69 patients with unresectable advanced/ metastatic clear-cell and/or sarcomatoid RCC. In the initial Dose-Escalation (DE) phase, there were two arms: patients in Arm A received simlukafusp α 5-25 mg weekly for 4 weeks, and every 2 weeks thereafter in combination with atezolizumab 840mg every 2 weeks, and those in Arm B had the further addition of bevacizumab 10 mg/kg every 2 weeks.

The subsequent Extension Part including patients who were not previously treated and again involved two arms: patients in Arm C (n=3) received simlukafusp α + atezolizumab every 3 weeks while those in Arm D (n=25) received simlukafusp α + atezolizumab + bevacizumab (“triplet”) every three weeks. The primary study objectives were to find the recommended dose of simlukafusp α and to examine the objective response rate (ORR) by RECIST v1.1.


Among the 69 enrolled patients, the median age of patients was 57 years (range: 35-78) and 79% were men. Based on the initial dose-escalation phase, the recommended dose of simlukafusp α was 10 mg for extension. Across each arm, the median treatment duration (in days) was 106 (range: 1-1031) for patients in Arm A, 324 (29-1094) for those in Arm B, 659 (71-768) for those in Arm C, and 437 (1-822) in Arm D.

Among 25 patients who were evaluable for therapeutic activity in Arm A, the ORR was 24% (6 PR; 90% CI 12.95, 40.12). In Arm B, there were 15 evaluable patients with an ORR of 46.7% (1 CR, 6PR; 90% CI 27.67, 66.68). Among the 3 evaluable patients in Arm C, ORR was 33.3% (1PR; 90% CI 7.83, 74.65). And finally, in Arm D, among the 23 evaluable patients there ORR was 47.8% (2 CR, 9 PR; 90% CI 35.74, 68.15). Twelve patients are continuing on study treatment as of the data cut-off.

Median progression-free survival was longest in Arm D, suggesting a benefit to the triplet approach (18.3 months, 95% CI 12.9-22.1).


The authors further considered mechanistic studies, finding that simlukafusp α led to preferential expansion and activation of NK and CD8 T cells in peripheral blood, without expansion of Tregs, and to augmented tumor infiltration and tumor inflammation. Additionally, they noted that responses were observed not only among those with PD-L1 positive or inflamed tumors but also in patients with PD-L1 negative tumors (n=13) and poorly infiltrated tumors classified as immune deserts (n=2).

The authors assessed treatment-related grade 3 (71.2%) and 4 (9.1%) adverse events, of which the most common were pyrexia (10.6 %) and infusion-related reactions (9.1%). Elevations in at least one of liver transaminases/GGT/ alkaline phosphatase/bilirubin were common, affecting 65.2% of patients. Further, treatment-related adverse events led to dose modification or interruption in 37.9 % of patients, and treatment discontinuation in 3%. Additionally, there was one treatment-related death (1.5%).

The authors further found evidence of a consistent pharmacodynamic profile with preferential expansion and activation of effector NK and T cells, but not Treg, in peripheral blood. In tumor tissue, there was evidence of increased on-treatment densities if TIL subsets and a strong presence of PD-L1+ immune cells.


The authors concluded that the combination of simlukafusp α with atezolizumab and bevacizumab was feasible and tolerable, however, clinical activity of the triplet was comparable to historic data from IMmotion151 of atezolizumab and bevacizumab.

Presented by: Jose L. Perez-Gracia, Medical Coordinator of the Central Unit for Clinical Trials, Specialist in Medical Oncology, Head of the Urological Tumors Area of the University of Navarra Clinic, in Pamplona, Spain

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021.
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