Phase 2 study of the antitumour activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in patients with recurrent and/or metastatic cervical squamous cell carcinoma

Abstract

Background: Simlukafusp alfa (FAP-IL2v) is an immune cytokine engineered to selectively promote immune responses in the tumour microenvironment. We evaluated the antitumour activity and safety of FAP-IL2v plus atezolizumab in recurrent and/or metastatic cervical squamous cell carcinoma (SCC) in a phase 2 basket study (NCT03386721).

Methods: Patients with confirmed metastatic, persistent or recurrent cervical SCC who had progressed on ≥1 anti-cancer therapy and had measurable disease were enrolled. FAP-IL2v 10 mg was administered once every 3 weeks (Q3W) or once weekly (QW) for 4 weeks then once every 2 weeks (Q2W) with the corresponding Q3W or Q2W atezolizumab regimens. The primary endpoint was objective response rate by investigator assessment.

Findings: Forty-eight patients were enrolled (Q3W: n = 47; QW/Q2W: n = 1). Among 45 response evaluable patients, objective responses occurred in 12 patients (27%; CI 16.0-41.0), including 3 complete and 9 partial responses. Responses occurred in 6/19 PD-L1 positive patients (32%; 95% CI 15.4-54.0) and 5/24 PD-L1 negative patients (21%; 95% CI 9.2-35.6). Median duration of response was 13.3 months (95% CI 7.6-NE). Median progression-free survival was 3.7 months (95% CI 3.3-9.0). Adverse events (AEs) were consistent with the known safety profile of each drug. AEs leading to withdrawal of either agent occurred in 6 patients (13%). Pronounced expansion and activation of natural killer and CD8 T cells in peripheral blood and increased tumour infiltration and inflammation were observed.

Interpretation: FAP-IL2v plus atezolizumab is clinically active and has manageable safety in patients with recurrent and/or metastatic cervical SCC.

Funding: F. Hoffmann-La Roche Ltd.

Keywords: Cervical cancer; IL-2; Immunotherapy; PD-L1; Squamous cell carcinoma.

Fig. 1

CONSORT study diagram. ∗All patients who received at least one dose of study treatment. ^†All patients who received at least one dose of study treatment and had at least one baseline and one on-study tumour assessment, including those who discontinued treatment because of disease progression before the first on-study tumour assessment. Two patients discontinued treatment due to AEs before the first tumour assessment and one patient was ineligible due to missing on-study tumour assessment.

Fig. 2

Antitumour activity following treatment with FAP-IL2v plus atezolizumab. (a) Best percent change in sum of diameters of target lesion from baseline (column colour indicates confirmed best overall response), and (b) change in sum of target lesion over time in the response-evaluable population. Kaplan–Meier estimate of progression-free survival in (c) the overall antitumour-evaluable population, and (d) by PD-L1 status. Sum of diameter of target lesions post-baseline and PD-L1 status was unavailable for two patients (PD-L1 status could not be determined due to the absence of baseline/archival biopsy or analysis failure). PD-L1 status was determined using the Ventana SP263 assay with a cut-off of TAP ≥5% and was unavailable for two additional patients. Tick marks on the Kaplan–Meier plots show censoring of the data at the last time the patient was known to be alive. TAP, tumour area positive.

Fig. 3

Pharmacodynamics in tumour tissue and peripheral blood following treatment with FAP-IL2v plus atezolizumab (Q3W schedule). (a) Immune cell infiltration of the tumour microenvironment (CD3+ and CD8+ T cells, proliferating CD8+ T cells, perforin-positive cytotoxic T and NK cells) and PD-L1 expression in immune cells, as measured by IHC in paired tumour biopsies from baseline and on-treatment (C2D8). (b) Transcriptomic changes in paired tumour biopsies from baseline and on-treatment (C2D8). Only patients with paired BL and on-treatment (C2D8) samples are shown for A and B. (c) Peripheral immune effector cell expansion (NK, CD8+, CD4+ T cells) from baseline measured by flow cytometry. (d) Immune cell activation (sCD25) and peripheral T cell proliferation (Ki67+) from baseline measured in plasma by immunoassay and flow cytometry, respectively. (e) Immune effector cell infiltration at baseline in responders (CR/PR) vs non-responders (SD/PD) as measured in tumour biopsies by IHC. (f) Treg tumour infiltration at baseline and PD-L1 expression (tumour and immune cells) in responders (CR/PR) vs non-responders (SD/PD) as measured in tumour biopsies by IHC. Drug administration: pre-dose = CxD1; 1 week/7 days post-administration = CxD8; duration of 1 cycle = 21 days. Samples from the same patient are joined by grey lines. Point colour indicates best overall response. Gene signature scores summarise the expression levels of all genes that are in a given signature. BL, baseline; C, cycle; D, day; IC, immune cell; IHC, immunohistochemistry; NR, non-responder; R, responder; TC, tumour cell.