Abstract 4151: Effect of camidanlumab tesirine (Cami) as monotherapy and in combination with pembrolizumab (PEM) on the immune cell profile in patients with selected advanced solid tumors
Authors: Puzanov Igor , Chen Christopher T. , LoRusso Patricia , Papadopoulos Kyriakos P. , Kummar Shivaani , Hamilton Erika , LeBruchec Yvan , Havenith Karin , Pantano Serafino , Toukam Marie , Wuerthner Jens , Boni Joseph 
Published: June 2022

Abstract
Background: Cami, an investigational anti-CD25, pyrrolobenzodiazepine-based antibody drug conjugate, imparts cytotoxicity on CD25+ regulatory T cells (Tregs), leading to immunomodulatory effects (eg, modifying effector T cell [Teff]:Treg intratumoral balance).
Objective: Describe the pharmacokinetics (PK) and circulating immune cell profile of Cami monotherapy and in combination with PEM in patients with advanced solid tumors.
Methods: In the dose-escalation phase 1b trial of Cami (NCT03621982) in patients with advanced solid tumors after failure of recommended therapies, we investigated Cami monotherapy (n=44; doses: 20, 30, 45, 60, 80, 100, 125, and 150 µg/kg every 3 weeks [Q3W]) and Cami combination therapy (n=12; doses: 30, 45, and 60 µg/kg with PEM 200 mg Q3W). Serum conjugated antibody (cAb) and total antibody (tAb) were quantified by a validated chemoimmunoluminescence assay. Soluble CD25 was quantified by a qualified enzyme-linked immunoassay. Circulating immune cell absolute counts were assessed by flow cytometry for Tregs (FoxP3+CD25+CD127low) as a fraction of absolute CD4+ cells, Teff (CD8+), and Teff:Treg. Statistical analyses were performed using a linear mixed-effects model (maximum likelihood) for the biomarker effects model with cAb area under the curve (AUC) during cycle 1, therapy (monotherapy vs combination), and treatment cycle as fixed effects and log AUC slope with intercept by subject or visit day as random effects.
Results: PK analysis found Cmax and AUC of cAb and tAb increased during cycles 1 and 2 with Cami monotherapy and combination therapy across the range of doses. Variability of AUCinf for cAb in cycle 1 appeared modest to marked across discrete dose groups (CV=14.7-98.1%). The clearance of cAb ranged from 1.34 to 3.52 L/day in cycle 1 with no apparent differences between monotherapy and combination therapy. Biomarker modeling demonstrated that cAb AUC and cycle were associated with a significant Tregs depletion and a significant positive effect on Teff:Treg ratio but with no relevant effect on Teff. Within cycle, treatment-related modulation of Teff and Tregs was observed for all doses and conditions. Soluble CD25 appears to be significantly positively affected by cycle 2 treatment.
Conclusions: PK exposure of Cami was dose-related with varying degrees of interpatient variability. Circulating Tregs were significantly decreased and Teff:Treg was significantly increased by Cami exposure, demonstrating the intended immunomodulatory effect of Cami in circulation and suggesting that a combination approach with Cami could address an immune-resistance mechanism. Future analyses will consider discrete PEM effect, correlates to tumor biopsy expression and response, and combined Cami+PEM effect in tumor biopsies. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group.
Citation Format: Igor Puzanov, Christopher T. Chen, Patricia LoRusso, Kyriakos P. Papadopoulos, Shivaani Kummar, Erika Hamilton, Yvan LeBruchec, Karin Havenith, Serafino Pantano, Marie Toukam, Jens Wuerthner, Joseph Boni. Effect of camidanlumab tesirine (Cami) as monotherapy and in combination with pembrolizumab (PEM) on the immune cell profile in patients with selected advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4151.