A Phase I/II Study of LY3022855 with BRAF/MEK Inhibition in Patients with Melanoma

Overview

Journal Invest New Drugs

Publisher Springer

Specialty Oncology

Date 2023 May 29

PMID 37247116

Authors

Elizabeth I Buchbinder

Anita Giobbie-Hurder

Rizwan Haq

Patrick A Ott

Affiliations

Soon will be listed here.

Abstract

BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600 mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

Citing Articles

Insights into CSF-1/CSF-1R signaling: the role of macrophage in radiotherapy.

Shang Q, Zhang P, Lei X, Du L, Qu B Front Immunol. 2025; 16:1530890.

PMID: 40007537 PMC: 11851012. DOI: 10.3389/fimmu.2025.1530890.

References

Chapman P, Hauschild A, Robert C, Haanen J, Ascierto P, Larkin J . Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364(26):2507-16. PMC: 3549296. DOI: 10.1056/NEJMoa1103782. View

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D . Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2014; 372(1):30-9. DOI: 10.1056/NEJMoa1412690. View

Larkin J, Ascierto P, Dreno B, Atkinson V, Liszkay G, Maio M . Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014; 371(20):1867-76. DOI: 10.1056/NEJMoa1408868. View

Dummer R, Ascierto P, Gogas H, Arance A, Mandala M, Liszkay G . Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018; 19(10):1315-1327. DOI: 10.1016/S1470-2045(18)30497-2. View

Kacinski B . CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann Med. 1995; 27(1):79-85. DOI: 10.3109/07853899509031941. View

Sasmono R, Oceandy D, Pollard J, Tong W, Pavli P, Wainwright B . A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood. 2002; 101(3):1155-63. DOI: 10.1182/blood-2002-02-0569. View

Bourette R, Rohrschneider L . Early events in M-CSF receptor signaling. Growth Factors. 2000; 17(3):155-66. DOI: 10.3109/08977190009001065. View

Pixley F, Stanley E . CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 2004; 14(11):628-38. DOI: 10.1016/j.tcb.2004.09.016. View

Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E . Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008; 320(5877):807-11. DOI: 10.1126/science.1154370. View

10.

Nowicki A, Szenajch J, Ostrowska G, Wojtowicz A, Wojtowicz K, Kruszewski A . Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer. 1996; 65(1):112-9. DOI: 10.1002/(SICI)1097-0215(19960103)65:1<112::AID-IJC19>3.0.CO;2-I. View

11.

Lewis C, Pollard J . Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006; 66(2):605-12. DOI: 10.1158/0008-5472.CAN-05-4005. View

12.

Bingle L, Brown N, Lewis C . The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002; 196(3):254-65. DOI: 10.1002/path.1027. View

13.

Lin E, Nguyen A, Russell R, Pollard J . Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001; 193(6):727-40. PMC: 2193412. DOI: 10.1084/jem.193.6.727. View

14.

Mok S, Tsoi J, Koya R, Hu-Lieskovan S, West B, Bollag G . Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer. 2015; 15:356. PMC: 4432503. DOI: 10.1186/s12885-015-1377-8. View

15.

Hu-Lieskovan S, Mok S, Moreno B, Tsoi J, Robert L, Goedert L . Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med. 2015; 7(279):279ra41. PMC: 4765379. DOI: 10.1126/scitranslmed.aaa4691. View

16.

Dubreuil P, Torres H, Courcoul M, Birg F, Mannoni P . c-fms expression is a molecular marker of human acute myeloid leukemias. Blood. 1988; 72(3):1081-5. View

17.

Kacinski B, Scata K, Carter D, Yee L, Sapi E, King B . FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene. 1991; 6(6):941-52. View

18.

Tang R, Beuvon F, Ojeda M, Mosseri V, Pouillart P, Scholl S . M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF mediated recruitment of tumour infiltrating monocytes?. J Cell Biochem. 1992; 50(4):350-6. DOI: 10.1002/jcb.240500403. View

19.

Kacinski B . CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract. Mol Reprod Dev. 1997; 46(1):71-4. DOI: 10.1002/(SICI)1098-2795(199701)46:1<71::AID-MRD11>3.0.CO;2-6. View

20.

Mroczko B, Groblewska M, Wereszczynska-Siemiatkowska U, Okulczyk B, Kedra B, Laszewicz W . Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clin Chim Acta. 2007; 380(1-2):208-12. DOI: 10.1016/j.cca.2007.02.037. View