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.