Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study

Abstract

Purpose: Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855.

Patients and methods: Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria.

Results: Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82-302 days) and three patients with mCRPC (25%; duration, 50-124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase.

Conclusions: LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.

Trial registration: ClinicalTrials.gov NCT02265536.

Conflict of interest statement

Conflict of Interest Disclosure Statement:

K.A. Autio reports grants from Eli Lilly and Company during the conduct of the study; and grants from Amgen, Astra Zeneca, Glaxo Smith Klein, Merck, and Pfizer outside the submitted work.

C.A. Klebanoff reports grants from Eli Lilly and Company during the conduct of the study; personal fees from Achilles Biotherapeutics, Aleta Biotherapeutics, Bellicum Pharmaceuticals, Obsidian Therapeutics, Klus Pharma, Roche-Genentech, and G1 Therapeutics; and grants from Kite/Gilead outside the submitted work.

D. Schaer was an employee of Eli Lilly and Company at the time of the study.

J. Kauh is a former employee of Eli Lilly and Company.

S.F. Slovin has nothing to declare.

M. Adamow has nothing to declare.

V.S. Blinder reports personal fees from Pfizer outside the submitted work.

M. Brahmachary is a former employee of Eli Lilly and Company and may have Eli Lilly and Company stock.

M. Carlsen is an employee of Eli Lilly and Company.

E. Comen reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, outside the scope of the submitted work.

D.C. Danila reports research support from US Department of Defense, American Society of Clinical Oncology, Prostate Cancer Foundation, Stand Up 2 Cancer, Janssen Research & Development, Astellas, Medivation, Agensys, Genentech, CreaTV; and is a consultant for Angle LLT, AxImmune, Janssen, Astellas, Pfizer, Medivation, Agensys, Bayer, and ScreenCell.

T.N. Doman is an employee and stockholder of Eli Lilly and Company.

J.C. Durack is an investor and scientific advisory board member of Adient Medical and an advisory board member receiving consultancy fees from Verix Health, both outside the scope of the submitted work.

J.J. Fox has nothing to declare.

J.S. Gluskin has nothing to declare.

D.M. Hoffman has nothing to declare.

S. Kang is an employee of Eli Lilly and Company.

P. Kang has nothing to declare.

J. Landa has nothing to declare.

P.F. McAndrew has nothing to declare.

S. Modi reports research support from Genentech, Daiichi Sankyo, Seattle Genetics, Novartis, and Synta pharmaceuticals; has received Honoria/advisory fees from Genentech, Daiichi Sankyo, Seattle Genetics, Macrogenics, Carrick, GSK, and Astra Zeneca; and is on the Speakers Bureau for Daiichi Sankyo, Astra Zeneca, and Genentech.

M.J. Morris reports personal fees from Blue Earth Diagnostics, and ORIC Pharmaceuticals; and institutional research support from Johnson & Johnson, Bayer, Sanofi, Progenics, Corcept, Genentech-Roche, and Janssen outside the submitted work.

R. Novosiadly is a shareholder of Eli Lilly and Company, and Bristol-Myers Squibb.

D.E. Rathkopf reports research funding from Janssen, Celgene, Ferring, Novartis, Taiho, Tracon, AstraZeneca, and Genentech-Roche; and is an uncompensated consultant for Janssen, Tracon, AstraZeneca, and Genentech-Roche.

R. Sanford has nothing to declare.

S.C. Chapman is an employee and stockholder of Eli Lilly and Company.

C.M. Tate is an employee and stockholder of Eli Lilly and Company.

D. Yu is an employee of Eli Lilly and Company.

P. Wong provided laboratory services for processing and testing of study clinical samples via a laboratory service agreement with Eli Lilly and Company during the conduct of the study; and has uncompensated relationships with Leap Therapeutics, and Sellas Life Sciences.

H.L. McArthur reports grants and personal fees from Bristol-Myers Squibb, Merck, AstraZeneca, and MedImmune; personal fees from Daiichi-Sankyo, Eli Lilly and Company, Pfizer, Genentech, Immunomedics, Puma Biotech, Amgen, Seattle Genetics, Genomic Health, and Spectrum Pharmaceuticals outside the submitted work.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Treatment duration and response for MBC (A) and mCRPC (B) patients in study (N = 34). Each horizontal bar represents a patient. Response is per RECIST 1.1 criteria. Best overall response was SD (MBC, n = 5; mCRPC, n = 3) and PD (MBC, n = 16; mCRPC, n = 4). One MBC patient and five mCRPC patients were not evaluable (NE). MBC tumors were estrogen receptor (ER) and/or progesterone receptor (PR) positive; one patient had triple negative breast cancer (TNBC). Abbreviations: BOR, best overall response; HER2, human epidermal growth factor receptor 2; N, total number of patients; n, number of patients in the specified category; PD, progressive disease; Q2W, every two weeks; QW, weekly; WK1245, weeks 1, 2, 3, 4, and 5; SD, stable disease.

Figure 1.

Treatment duration and response for MBC (A) and mCRPC (B) patients in study (N = 34). Each horizontal bar represents a patient. Response is per RECIST 1.1 criteria. Best overall response was SD (MBC, n = 5; mCRPC, n = 3) and PD (MBC, n = 16; mCRPC, n = 4). One MBC patient and five mCRPC patients were not evaluable (NE). MBC tumors were estrogen receptor (ER) and/or progesterone receptor (PR) positive; one patient had triple negative breast cancer (TNBC). Abbreviations: BOR, best overall response; HER2, human epidermal growth factor receptor 2; N, total number of patients; n, number of patients in the specified category; PD, progressive disease; Q2W, every two weeks; QW, weekly; WK1245, weeks 1, 2, 3, 4, and 5; SD, stable disease.

Figure 2.

LY3022855 pharmacokinetics and target engagement. Mean (+/− standard deviation) serum concentration (ug/mL) versus time profiles for LY3022855 following intravenous administration in MBC and mCRPC patients who received ≥1 dose of LY3022855 on Cycle 1 Day 1 (A), and Cycle 1 Day 29 (B). (C) Time plots of circulating levels of CSF-1. (D) Increasing frequency of dosing with LY3022855 leads to greater target engagement and further reduction of pro-inflammatory macrophages as indicated by a reduction in circulating CD14dim and CD16bright macrophages. Abbreviations: n, number of subjects in the specified category; Q2W, every two weeks; QW, weekly; WK1245, weeks 1, 2, 3, 4, and 5.

Figure 3.

Peripheral blood immune cell subset changes by response per RECIST. Percentage change from baseline to Cycle 1 Day 8 (A) and Cycle 1 Day 36 (B). Solid lines indicate the median percent change from baseline; shaded areas represent the median absolute deviation. Day 8: PD, n = 16; SD, n = 8; all markers had observations from all patients with the exception of CD14+HLA-DR where PD, n = 9, and SD, n = 8. Day 36: PD, n = 7; SD, n = 7; all markers had observations from all patients with the exception of CD14+HLA-DR where PD, n = 4, and SD, n = 6. (C). FACS analysis for LAG3+CD4 and LAG3+CD8 cell subsets at Cycle 1 Day 36 in peripheral blood from a patient who had a BOR of SD (Patient A) and PD (Patient H). Abbreviations: BOR, best overall response; PD, progressive disease; SD, stable disease.

Figure 4.

Differential gene expression of tumor biopsies pre- and post-LY3022855 treatment. (A) Volcano plots showing fold change in immune gene expression post-LY3022855 treatment. A significant increase in immune gene expression in tumor biopsies of patients with clinical benefit (Patients C and D) post-LY3022855 treatment was observed. Minimal changes in immune gene expression in tumor biopsies of patients with no clinical benefit (Patients I, G, E, F, and H) was observed. Patient B was excluded from this analysis because only one pretreatment sample was available. (B) Heatmap shows the distribution of the 92-gene signature differentially expressed across patient matched MBC tumor biopsies pre- and post-LY3022855 treatment. Patients with some clinical benefit tended to have relatively higher expression in the genes including and above PRKCD and relatively lower expression in the genes including and below F12. Abbreviations: LY, LY3022855, n, number of differentially expressed genes.

Figure 4.

Differential gene expression of tumor biopsies pre- and post-LY3022855 treatment. (A) Volcano plots showing fold change in immune gene expression post-LY3022855 treatment. A significant increase in immune gene expression in tumor biopsies of patients with clinical benefit (Patients C and D) post-LY3022855 treatment was observed. Minimal changes in immune gene expression in tumor biopsies of patients with no clinical benefit (Patients I, G, E, F, and H) was observed. Patient B was excluded from this analysis because only one pretreatment sample was available. (B) Heatmap shows the distribution of the 92-gene signature differentially expressed across patient matched MBC tumor biopsies pre- and post-LY3022855 treatment. Patients with some clinical benefit tended to have relatively higher expression in the genes including and above PRKCD and relatively lower expression in the genes including and below F12. Abbreviations: LY, LY3022855, n, number of differentially expressed genes.