Cancer Immunology, Immunotherapy

, Volume 68, Issue 7, pp 1187–1194 | Cite as

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

  • Yenny AngelaEmail author
  • Sebastian Haferkamp
  • Carsten Weishaupt
  • Selma Ugurel
  • Jürgen C. Becker
  • Florian Oberndörfer
  • Vesna Alar
  • Imke Satzger
  • Ralf Gutzmer
Original Article



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.


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


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.


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.


Melanoma Immunotherapy RANK/RANKL Bone metastasis Adverse events 



Adverse events


American Joint Committee on Cancer


Complete response


Common Terminology Criteria for Adverse Events


Cytotoxic T-lymphocyte-associated protein 4


European Medicines Agency


Food and Drug Administration


Immune checkpoint blockade


Lactate dehydrogenase



N + I+D

Nivolumab plus ipilimumab plus denosumab


Not reached


Objective rate response


Progressive disease


Programmed cell death protein1 inhibitor/inhibitors

PD-1i + D

PD1 inhibitor plus denosumab


Partial response


Receptor activator of NF-kB


Receptor activator of NF-kB ligand


Response evaluation criteria in solid tumors


Stable disease


Summary of product characteristics


Skeletal-related events


Author contributions

Authors whose names appear on this paper have contributed sufficiently to the scientific work and, therefore, share collective responsibility and accountability for the results. YA and RG planned the project. All authors contributed to the data collection. YA and RG contributed to the interpretation of the results. YA took the lead in writing the manuscript. All authors provided critical feedback and helped to shape the manuscript.


No specific funding was received for this study.

Compliance with ethical standards

Ethics approval

This is a retrospective multicenter study initiated by the German Dermatologic Cooperative Oncology Group (DeCOG). Human participants (melanoma patients) were involved but only by the retrospective chart review. Ethics approval for the retrospective data collection and anonymous analysis without informed consent of the patients was obtained from the Ethics committee of Hannover Medical School (vote number 1612). This vote states that there are no ethical concerns with regard to the anonymous retrospective analysis of routine clinical care data from own patients and that there is no general need to notify the ethics committee on such studies. The patient who is shown in Fig. 2 provided written informed consent for the use of his CT scans within this publication.

Conflict of interest

Ralf Gutzmer served as speaker to Roche, Bristol-Myers Squibb (BMS), Novartis, Merck Serono, Merck Sharp & Dohme (MSD), Almirall-Hermal, Amgen, Merck Serono, Pierre Fabre, SUN Pharma and received research grants from Novartis, Pfizer, Johnson & Johnson. He served as consultant to Roche Pharma, BMS, Novartis, MSD, Almirall-Hermal, LEO-Pharma, Amgen, Pfizer, Pierre Fabre, Roche Posay, Merck Serono, Regeneron, SUN Pharma and Incyte. Selma Ugurel received research support from BMS, medac, and Merck Serono and serves as speaker/consultant to BMS, MSD, Merck Serono, and Roche, and received travel grants from BMS, Medac, and MSD. Jürgen C. Becker received speaker fees from Amgen, MerckSerono, and Pfizer, advisory board honoraria from Amgen, CureVac, eTheRNA, Lytix, MerckSerono, Novartis, Rigontec, and Takeda as well as research grants from Alcedis, Boehringer Ingelheim, BMS and Merck Serono. He also received travel fees from 4SC and Incyte. Carsten Weishaupt served as speaker to Amgen, BMS, Curevac, La Roche Posay, Leo Pharma, MSD, Novartis, Roche, Takeda, TEVA. All other authors declared that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Dermatology and Allergy, Skin Cancer Center HannoverMedizinische Hochschule HannoverHannoverGermany
  2. 2.Department of DermatologyUniversity of RegensburgRegensburgGermany
  3. 3.Department of DermatologyUniversity of MünsterMünsterGermany
  4. 4.Department of DermatologyUniversity of Duisburg-EssenEssenGermany
  5. 5.Translational Skin Cancer Research (TSCR), German Cancer Consortium (DKTK)Essen/DüsseldorfGermany

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