First-in-human Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Antitumor Activity of PF-07209960 in Patients with Advanced or Metastatic Solid Tumors

Overview

Journal ESMO Open

Publisher Elsevier

Specialty Oncology

Date 2025 Feb 18

PMID 39965362

Authors

A Naing

M McKean

L S Rosen

D Sommerhalder

N M Shaik

I-M Wang

C Le Corre

K A Kern

N H Mishra

S K Pal

Affiliations

Soon will be listed here.

Abstract

Background: PF-07209960 is an antibody-cytokine fusion molecule that consists of a single potency-reduced interleukin-15 (IL-15) mutein and a bivalent high-affinity anti-programmed cell death protein 1 (PD-1) full-length IgG. This phase I study (NCT04628780) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and potential clinical benefits of PF-07209960 in patients with selected locally advanced or metastatic solid tumors for whom no standard therapy was available.

Materials And Methods: Escalating doses (1-30 mg) of PF-07209960 were administered subcutaneously once every 2 weeks in 28-day cycles. The primary endpoints included dose-limiting toxicities (DLTs), adverse events (AEs), and laboratory abnormalities. The secondary endpoints included PK, anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against PF-07209960, and tumor response assessed using RECIST version 1.1.

Results: Thirty-seven patients received treatment with PF-07209960 (1-, 3-, and 10-mg groups, n = 4 each; 15 mg, n = 3; 20 mg, n = 16; 30 mg, n = 6). The median age was 59.0 years (range 31-88 years). Six (22.2%) patients had DLTs. The most frequently reported treatment-related AEs (TRAEs) (≥50%) were general disorders and administration site condition [21 (56.8%)] and skin and subcutaneous tissue disorders [20 (54.1%)]. The most frequently reported grade ≥3 TRAE was anemia [5 (13.5%)]. Two patients with microsatellite-stable colorectal cancer had confirmed partial response, one each from the PF-07209960 20-mg and 30-mg cohorts, with a duration of response of 9.5 and 3 months, respectively. The rate of ADA was 93.9% (31/33), of which 63.6% (21/33) was treatment induced and 30.3% (10/33) was treatment boosted.

Conclusion: PF-07209960 was generally manageable, with potential antitumor activity in some patients.

References

Wrangle J, Velcheti V, Patel M, Garrett-Mayer E, Hill E, Ravenel J . ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018; 19(5):694-704. PMC: 6089612. DOI: 10.1016/S1470-2045(18)30148-7. View

Dubois S, Conlon K, Muller J, Hsu-Albert J, Beltran N, Bryant B . IL15 Infusion of Cancer Patients Expands the Subpopulation of Cytotoxic CD56 NK Cells and Increases NK-Cell Cytokine Release Capabilities. Cancer Immunol Res. 2017; 5(10):929-938. PMC: 8177006. DOI: 10.1158/2326-6066.CIR-17-0279. View

Fehniger T, Caligiuri M . Interleukin 15: biology and relevance to human disease. Blood. 2001; 97(1):14-32. DOI: 10.1182/blood.v97.1.14. View

Guo Y, Luan L, Rabacal W, Bohannon J, Fensterheim B, Hernandez A . IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. J Immunol. 2015; 195(5):2353-64. PMC: 4543906. DOI: 10.4049/jimmunol.1500300. View

Miller J, Morishima C, McNeel D, Patel M, Kohrt H, Thompson J . A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors. Clin Cancer Res. 2017; 24(7):1525-1535. PMC: 6741437. DOI: 10.1158/1078-0432.CCR-17-2451. View

Dubois S, Losi J, Sabzevari H, Yamada N, Feigenbaum L, Waldmann T . IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci U S A. 2000; 97(21):11445-50. PMC: 17219. DOI: 10.1073/pnas.200363097. View

Waldmann T . The interleukin-2 receptor. J Biol Chem. 1991; 266(5):2681-4. View

Cai M, Huang X, Huang X, Ju D, Zhu Y, Ye L . Research progress of interleukin-15 in cancer immunotherapy. Front Pharmacol. 2023; 14:1184703. PMC: 10213988. DOI: 10.3389/fphar.2023.1184703. View

Petrera A, von Toerne C, Behler J, Huth C, Thorand B, Hilgendorff A . Multiplatform Approach for Plasma Proteomics: Complementarity of Olink Proximity Extension Assay Technology to Mass Spectrometry-Based Protein Profiling. J Proteome Res. 2020; 20(1):751-762. DOI: 10.1021/acs.jproteome.0c00641. View

10.

Conlon K, Lugli E, Welles H, Rosenberg S, Tito Fojo A, Morris J . Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2014; 33(1):74-82. PMC: 4268254. DOI: 10.1200/JCO.2014.57.3329. View

11.

Xu Y, Campos Carrascosa L, Yeung Y, Chu M, Yang W, Djuretic I . An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity. Cancer Immunol Res. 2021; 9(10):1141-1157. DOI: 10.1158/2326-6066.CIR-21-0058. View

12.

Sharma M, Khong H, Faak F, Bentebibel S, Janssen L, Chesson B . Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nat Commun. 2020; 11(1):661. PMC: 6994577. DOI: 10.1038/s41467-020-14471-1. View

13.

Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri F, Porter A . Translation of innovative designs into phase I trials. J Clin Oncol. 2007; 25(31):4982-6. DOI: 10.1200/JCO.2007.12.1012. View

14.

Schiavoni G, Gabriele L, Mattei F . The tumor microenvironment: a pitch for multiple players. Front Oncol. 2013; 3:90. PMC: 3628362. DOI: 10.3389/fonc.2013.00090. View

15.

Waldmann T, Dubois S, Tagaya Y . Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity. 2001; 14(2):105-10. View

16.

Eyles J, Puaux A, Wang X, Toh B, Prakash C, Hong M . Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest. 2010; 120(6):2030-9. PMC: 2877955. DOI: 10.1172/JCI42002. View

17.

Waldmann T . The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006; 6(8):595-601. DOI: 10.1038/nri1901. View

18.

Shi W, Lv L, Liu N, Wang H, Wang Y, Zhu W . A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity. Mol Ther. 2022; 31(1):66-77. PMC: 9840182. DOI: 10.1016/j.ymthe.2022.08.016. View

19.

Shi W, Liu N, Liu Z, Yang Y, Zeng Q, Wang Y . Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity. Cell Rep Med. 2024; 5(5):101531. PMC: 11148641. DOI: 10.1016/j.xcrm.2024.101531. View

20.

Zhou Y, Husman T, Cen X, Tsao T, Brown J, Bajpai A . Interleukin 15 in Cell-Based Cancer Immunotherapy. Int J Mol Sci. 2022; 23(13). PMC: 9266896. DOI: 10.3390/ijms23137311. View