Phase Ib Study of the Immunocytokine Simlukafusp Alfa (FAP-IL2v) in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma

Abstract

Purpose: This phase Ib trial evaluated fibroblast activation protein-α-targeted IL2 variant (FAP-IL2v), a novel immunocytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC).

Patients and methods: Patients received FAP-IL2v either on a continuous weekly (QW) schedule or QW for 4 weeks and then every 2 weeks (Q2W). Cetuximab was dosed at QW or Q2W schedules. The primary objectives were to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, and clinical activity for the combination of FAP-IL2v with cetuximab. Exploratory objectives included pharmacodynamic analyses.

Results: A total of 58 patients were enrolled, 19 patients into the dose-escalation part, and 39 patients into the expansion part. The maximum tolerated dose of FAP-IL2v was defined as 10 mg (QW/Q2W) in combination with cetuximab (500 mg/m2, Q2W), which was further tested in the expansion part. The most common FAP-IL2v-related adverse events with a grade 3 or 4 severity were hypophosphatemia (19%), lymphopenia (16%), and infusion-related reaction (14%). The pharmacokinetics of FAP-IL2v in combination with cetuximab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded intratumoral NK and CD8 T cells. Four patients achieved a partial response, and the objective response rate was 7% (95% confidence interval, 3.2-14.7).

Conclusions: The safety profile of FAP-IL2v in combination with cetuximab was acceptable, and pharmacodynamic markers support the proposed mode of action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).].

Figure 1.

Antitumor activity results based on RECIST 1.1. Best change in target lesions from baseline by CPI status (experienced vs. naïve) in patients (A) with prior cetuximab treatment (n = 32) and (B) without prior cetuximab treatment (n = 20). C, Swimlane plot for response over time by primary tumor type (oropharyngeal vs. non-oropharyngeal tumor) and CPI experience (CPI-experienced vs. -naïve). The number of patients with a primary tumor in the oropharynx was 26, whereas 26 patients had a non-oropharyngeal primary tumor, and for five patients, the primary tumor was unknown. Baseline PD-L1 status determined using Ventana SP142 assay and immune cell/IC or tumor cell/TC staining (PD-L1 negativity defined as IC0 TC0). In the waterfall plots, * denotes patients whose initial response was not confirmed at the subsequent tumor assessment. BOR, best overall response; CPI, checkpoint inhibitor, exp., experienced; Ext, extension; L, local; M, metastatic; NA, not available; NE, not evaluable; N, negative; P, positive; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of the longest diameters.

Figure 2.

Pharmacodynamic changes assessed with focus on patients who received a FAP-IL2 dose of 10 mg QW/Q2W. A, Immune cell expansion (NK, CD8⁺ T cells, CD4⁺ T cells, and Treg cells) measured in peripheral blood collected at baseline and various post-baseline timepoints. B, Immune cell infiltration density of the tumor microenvironment (CD3⁺ and CD8⁺ T cells, proliferating CD8⁺ T cells, cytotoxic T and NK cells, and Treg cells), PD-L1 expression in immune and tumor cells, and EGFR expression in tumor cells, measured in tumor tissue from biopsies taken at baseline and on-treatment (C2D10). For these exploratory analyses, a greater than 30% reduction in the sum of the longest diameters of the target lesions was considered a response. ABS, absolute count; BL, baseline; C, cycle; D, day, NR, nonresponder; R, responder.