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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 7/2019

01-07-2019 | Metastasis | Original Article

Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases

Authors: Yenny Angela, Sebastian Haferkamp, Carsten Weishaupt, Selma Ugurel, Jürgen C. Becker, Florian Oberndörfer, Vesna Alar, Imke Satzger, Ralf Gutzmer

Published in: Cancer Immunology, Immunotherapy | Issue 7/2019

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Abstract

Background

PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment.

Methods

We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy.

Results

29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged.

Conclusions

The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.
Literature
1.
Petrella TM, Robert C, Richtig E, Miller WH, Masucci GV, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J (2017) Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer 86:115–124CrossRefPubMed
2.
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330CrossRefPubMed
3.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356CrossRefPubMedPubMedCentral
4.
5.
Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R (2007) Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110:1860–1867 CrossRefPubMed
6.
de Groot AF, Appelman-Dijkstra NM, van der Burg SH, Kroep JR (2018) The anti-tumor effect of RANKL inhibition in malignant solid tumors—a systematic review. Cancer Treat Rev 62:18–28 CrossRefPubMed
7.
Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696CrossRefPubMed
8.
Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553CrossRefPubMedPubMedCentral
9.
Smyth MJ, Yagita H, McArthur GA (2016) Combination Anti-CTLA-4 and Anti-RANKL in metastatic melanoma. J Clin Oncol 34:e104–e106CrossRefPubMed
10.
Ahern E, Harjunpää H, Barkauskas D, Allen S, Takeda K, Yagita H, Wyld D, Dougall WC, Teng MWL, Smyth MJ (2017) Co-administration of RANKL and CTLA4 antibodies enhances lymphocyte-mediated antitumor immunity in mice. Clin Cancer Res 23:5789–5801CrossRefPubMed
11.
Ahern E, Harjunpää H, O’Donnell JS, Allen S, Dougall WC, Teng MWL, Smyth MJ (2018) RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer. Oncoimmunology 7:e1431088CrossRefPubMedPubMedCentral
12.
Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, Lazar AJ, Faries MB, Kirkwood JM, McArthur GA, Haydu LE, Eggermont A, Flaherty KT, Balch CM, Thompson JF, for members of the American Joint Committee on Cancer Melanoma Expert Panel and the International Melanoma Database and Discovery Platform (2017) Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67:472–492CrossRefPubMedPubMedCentral
13.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2008) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRef
14.
Pflugfelder A, Kochs C, Blum A, Capellaro M, Czeschik C, Dettenborn T, Dill D, Dippel E, Eigentler T, Feyer P, Follmann M, Frerich B, Ganten MK, Gärtner J, Gutzmer R, Hassel J, Hauschild A, Hohenberger P, Hübner J, Kaatz M, Kleeberg UR, Kölbl O, Kortmann RD, Krause-Bergmann A, Kurschat P, Leiter U, Link H, Loquai C, Löser C, Mackensen A, Meier F, Mohr P, Möhrle M, Nashan D, Reske S, Rose C, Sander C, Satzger I, Schiller M, Schlemmer HP, Strittmatter G, Sunderkötter C, Swoboda L, Trefzer U, Voltz R, Vordermark D, Weichenthal M, Werner A, Wesselmann S, Weyergraf AJ, Wick W, Garbe C, Schadendorf D, German Dermatological Society; DermatologicCooperative Oncology Group (2013) Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”. J Dtsch Dermatol Ges 6:1–116
15.
16.
Long GV, Schachter J, Ribas A, Arance AM, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Anderson J, Krepler C, Ibrahim N, Robert C (2018) 4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006. J Clin Oncol 36:9503CrossRef
17.
Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T, Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan SL, Obermayer-Pietsch B, Langdahl BL, Al Dabagh R, Davison KS, Kendler DL, Sándor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz DD, Sulimani R, Saunders DP, Brown JP, Compston J (2015) International task force on osteonecrosis of the Jaw. J Bone Miner Res 30:3–23CrossRefPubMed
18.
Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD (2018) Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 19:1480–1492CrossRefPubMed
19.
Liede A, Hernandez RK, Wade SW, Bo R, Nussbaum NC, Ahern E, Dougall WC, Smyth MJ (2018) An observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer. Oncoimmunology 7:e1480301CrossRefPubMedPubMedCentral
20.
Afzal MZ, Shirai K (2018) Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumab in malignant melanoma: a retrospective analysis at a tertiary care center. Melanoma Res 28:341–347PubMed
21.
Kupas V, Weishaupt C, Siepmann D, Kaserer ML, Eickelmann M, Metze D, Luger TA, Beissert S, Loser K (2011) RANK is expressed in metastatic melanoma and highly upregulated on melanoma-initiating cells. J Invest Dermatol 131:944–955CrossRefPubMed
22.
Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and tregs in the melanoma tumor microenvironment is driven by CD8 + T Cells. Sci Transl Med 5:200ra116CrossRefPubMedPubMedCentral
23.
Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, Ezoe S, Kanakura Y, Sato E, Fukumori Y, Karbach J, Jäger E, Sakaguchi S (2013) Anti-CCR25 mAb selectively depletes effector-type FoxP3 + CD4 + regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci USA 110:17945–17950CrossRefPubMedPubMedCentral
24.
25.
Ahern E, Smyth MJ, Dougall WC, Teng MWL (2018) Roles of the RANKL-RANK axis in antitumour immunity—implications for therapy. Nat Rev Clin Oncol 15:676–693CrossRefPubMed
26.
Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–179CrossRefPubMed
27.
Santini D, Perrone G, Roato I, Godio L, Pantano F, Grasso D, Russo A, Vincenzi B, Fratto ME, Sabbatini R et al (2011) Expression pattern of receptor activator of NFkB (RANK) in a series of primary solid tumors and related metastases. J Cell Physiol 226:780–784CrossRefPubMed
28.
Standal T, Seidel C, Hjertner Ø, Plesner T, Sanderson RD, Waage A, Borset M, Sundan A (2002) Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 100:3002–3007CrossRefPubMed
29.
Jacobs JF, Nierkens S, Figdor CG, de Vries IJ, Adema GJ (2012) Regulatory T cells in melanoma: the final hurdle to-wards effective immunotherapy? Lancet Oncol 13:e32–e42CrossRefPubMed
30.
Bakhru P, Zhu ML, Wang HH, Hong LK, Khan I, Mouchess M, Gulati AS, Starmer J, Hou Y, Sailer D, Lee S, Zhao F, Kirkwood JM, Moschos S, Fong L, Anderson MS, Su MA (2017) Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity. JCI Insight 2(18):93265CrossRefPubMed
Metadata
Title
Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases
Authors
Yenny Angela
Sebastian Haferkamp
Carsten Weishaupt
Selma Ugurel
Jürgen C. Becker
Florian Oberndörfer
Vesna Alar
Imke Satzger
Ralf Gutzmer
Publication date
01-07-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 7/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-019-02353-5

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