Clinical activity and safety of simlukafusp alfa, an engineered interleukin-2 variant targeted to fibroblast activation protein-α, combined with atezolizumab in patients with recurrent or metastatic cervical cancer.
Authors: Italiano Antoine , Verlingue Loic , Prenen Hans , Guerra Eva M. , Tosi Diego , Perets Ruth , Lugowska Iwona , Moiseenko Vladimir , Gumus Mahmut , Arslan Cagatay , Lindsay Colin R. , Richard Muriel , Dejardin David , Boetsch Christophe , Kraxner Anton , Evers Stefan , Vardar Taner , Keshelava Nino , Teichgräber Volker , Dziadziuszko Rafal 
Published: June 2021

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Background: Simlukafusp alfa (SIM; FAP-IL2v) comprises an interleukin-2 variant (IL-2v) moiety and an antibody against fibroblast activation protein-α (FAP). The binding of SIM to FAP, expressed on cancer-associated fibroblasts, accounts for retention and accumulation in malignant lesions. The engineered IL-2v moiety has an abolished binding to IL-2Rα while the affinity to IL-2Rβγ is retained, resulting in activation of immune effector CD8 T and NK cells, but not of regulatory T cells, and therefore may augment activity of PD-(L)1 inhibitors. Methods: The clinical activity and safety of the SIM and atezolizumab (ATZ) combination in patients with recurrent or metastatic (R/M) cervical squamous cell carcinoma (SCC) were evaluated in a phase 2 basket study (NCT03386721). Patients (pts) were treated with SIM 10 mg IV and ATZ 1200 mg IV once every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1 assessed by investigators. Secondary endpoints were: disease control rate (DCR), duration of response (DoR), progression free survival (PFS). Results: 47 Pts with ECOG ≥1 and median age of 53 years (range: 25-69) were enrolled. All pts were checkpoint inhibitor naïve and 40 (85%) had ≥ 1 previous lines of therapy in the metastatic setting. The median number of cycles was 6 (range: 1-29). The ORR was 27% (90% CI: 18, 39) and DCR was 71% (90% CI: 58, 80) in 44 response-evaluable patients: 2 (5%) had complete response, 10 (23%) partial response, and 19 (43%) stable disease. Responses were observed across PD-L1 subgroups (SP142 assay, IC/TC cut-off ≥ 1%) with 8/22 and 4/18 responders in PD-L1+ and PD-L1- patients, respectively. Responses were durable, the median DoR was 13.3 months (95% CI: 7.6, 14.7). PFS probability at 6 months was 0.4 (95% CI: 0.27, 0.59). The most common adverse events (AE) (reported in > 30% patients), irrespective of relatedness to treatment and severity, were pyrexia (74.5%), anemia (48.9%), asthenia (48.9%), AST increased (44.7%), nausea (42.6%), ALT increased (42.6%), vomiting (36.2%) and diarrhea (31.9%). Grade 3 and 4 AEs related to SIM were observed in 63.8 % and 29.8 % of pts, respectively, while serious AEs (SAE) related to SIM were reported in 40.4%. The most common SAEs (reported in > 5% pts) irrespective of relatedness to treatment were infusion related reaction (14.9%), pyrexia (6.4%) and hydronephrosis (6.4%). One Grade 5 event occurred, which was unrelated to treatment. Conclusions: SIM in combination with ATZ demonstrated an acceptable safety profile in pts with R/M cervical SCC. The anti-tumor activity compares favorably to the approved PD-1 inhibitors in this setting and supports further exploration of IL-2v and checkpoint inhibition in this patient population of high unmet medical need. Clinical trial information: NCT03386721.