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25-04-2023 | Melanoma | Brief Report

A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition

Authors: Elizabeth I. Buchbinder, Anita Giobbie-Hurder, Patrick A. Ott

Published in: Investigational New Drugs | Issue 3/2023

Abstract

Background: Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy. Methods: We performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110. Results: Between September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26–71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached). Conclusion: MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516CrossRefPubMedPubMedCentral

Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ et al (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin oncology: official J Am Soc Clin Oncol 29(10):1239–1246CrossRef

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372(1):30–39CrossRefPubMed

Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M et al (2014) Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371(20):1867–1876CrossRefPubMed

Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G et al (2018) 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 19(10):1315–1327CrossRefPubMed

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504CrossRefPubMedPubMedCentral

Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E et al (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487(7408):505–509CrossRefPubMedPubMedCentral

Mok S, Tsoi J, Koya RC, Hu-Lieskovan S, West BL, Bollag G et al (2015) Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer 15:356CrossRefPubMedPubMedCentral

Kacinski BM (1995) CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann Med 27(1):79–85CrossRefPubMed

10.

Sasmono RT, Oceandy D, Pollard JW, Tong W, Pavli P, Wainwright BJ et al (2003) A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101(3):1155–1163CrossRefPubMed

11.

Bourette RP, Rohrschneider LR (2000) Early events in M-CSF receptor signaling. Growth Factors 17(3):155–166CrossRefPubMed

12.

Pixley FJ, Stanley ER (2004) CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol 14(11):628–638CrossRefPubMed

13.

Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E et al (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320(5877):807–811CrossRefPubMed

14.

Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61CrossRefPubMedPubMedCentral

15.

Wang T, Xiao M, Ge Y, Krepler C, Belser E, Lopez-Coral A et al (2015) BRAF Inhibition stimulates Melanoma-Associated Macrophages to drive Tumor Growth. Clin cancer research: official J Am Association Cancer Res 21(7):1652–1664CrossRef

16.

Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L et al (2015) Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med 7(279):279ra41CrossRefPubMedPubMedCentral

17.

Nowicki A, Szenajch J, Ostrowska G, Wojtowicz A, Wojtowicz K, Kruszewski AA et al (1996) 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 65(1):112–119CrossRefPubMed

18.

Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66(2):605–612CrossRefPubMed

19.

Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196(3):254–265CrossRefPubMed

20.

Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193(6):727–740CrossRefPubMedPubMedCentral

21.

Dubreuil P, Torrès H, Courcoul MA, Birg F, Mannoni P (1988) c-fms expression is a molecular marker of human acute myeloid leukemias. Blood 72(3):1081–1085CrossRefPubMed

22.

Kacinski BM, Scata KA, Carter D, Yee LD, Sapi E, King BL et al (1991) FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene 6(6):941–952PubMed

23.

Tang R, Beuvon F, Ojeda M, Mosseri V, Pouillart P, Scholl S (1992) 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 50(4):350–356CrossRefPubMed

24.

Kacinski BM (1997) CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract. Mol Reprod Dev 46(1):71–74CrossRefPubMed

25.

Mroczko B, Groblewska M, Wereszczyńska-Siemiatkowska U, Okulczyk B, Kedra B, Łaszewicz W et al (2007) Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clin Chim Acta 380(1–2):208–212CrossRefPubMed

26.

Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ et al (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26(16):2707–2716CrossRefPubMed

27.

Scholl SM, Pallud C, Beuvon F, Hacene K, Stanley ER, Rohrschneider L et al (1994) Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J Natl Cancer Inst 86(2):120–126CrossRefPubMed

28.

Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78CrossRefPubMed

Title: A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition
Authors: Elizabeth I. Buchbinder
Anita Giobbie-Hurder
Patrick A. Ott
Publication date: 25-04-2023
Publisher: Springer US
Keywords: Melanoma
Melanoma
Published in: Investigational New Drugs / Issue 3/2023
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-023-01364-5

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