Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM.

Methods

Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS).

Results

The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44–47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed.

Conclusion

Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Carvajal RD, Sacco JJ, Jager MJ, et al. Advances in the clinical management of uveal melanoma. Nat Rev Clin Oncol. 2023;20:99–115.

    Article  PubMed  Google Scholar 

  2. Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res. 2019;29:561–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Khoja L, Atenafu EG, Suciu S, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 2019;30:1370–80.

    Article  CAS  PubMed  Google Scholar 

  4. Lane AM, Kim IK, Gragoudas ES. Survival rates in patients after treatment for metastasis from uveal melanoma. JAMA Ophthalmol. 2018;136:981–6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385:1196–206.

    Article  CAS  PubMed  Google Scholar 

  6. Koch EA, Petzold A, Wessely A, et al. Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis. Cancers Basel. 2021;13:3359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mignard C, Huvier AD, Gillibert A, et al. Efficacy of immunotherapy in patients with metastatic mucosal or uveal melanoma. J Oncol. 2018;2018:1908065.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Najjar YG, Navrazhina K, Ding F, et al. Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study. J Immunother Cancer. 2020;8:e000331.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122:3344–53.

    Article  CAS  PubMed  Google Scholar 

  10. Pelster MS, Gruschkus SK, Bassett R, et al. Nivolumab and ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study. J Clin Oncol. 2021;39:599–607.

    Article  CAS  PubMed  Google Scholar 

  11. Piulats JM, Espinosa E, De La Merino CL, et al. Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: an open-label, multicenter, phase II trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021;39:586–98.

    Article  CAS  PubMed  Google Scholar 

  12. Pham JP, On L, Ardolino L, et al. Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res. 2023;33:316–25.

    Article  CAS  PubMed  Google Scholar 

  13. Moy CS, Albert DM, Diener-West M, et al. Cause-specific mortality coding: methods in the Collaborative Ocular Melanoma Study COMS report no. 14. Control Clin Trials. 2001;22:248–62.

    Article  CAS  PubMed  Google Scholar 

  14. National Comprehensive Cancer Network (NCCN 2022). NCCN clinical practice guidelines in oncology for melanoma: uveal. Version 2.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488.

  15. Prescribing information for the HEPZATO KIT Hepatic Delivery System. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201848s000lbl.pdf.

  16. Bethlehem MS, Katsarelias D, Bagge RO. Meta-analysis of isolated hepatic perfusion and percutaneous hepatic perfusion as a treatment for uveal melanoma liver metastases. Cancers Basel. 2021;13:4726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bagge RO, Nelson A, Shafazand A, et al. Isolated hepatic perfusion with melphalan for patients with isolated uveal melanoma liver metastases: a multicenter, randomized, open-label, phase III trial (the SCANDIUM trial). J Clin Oncol. 2023;41:3042–50.

    Article  CAS  Google Scholar 

  18. Modi S, Gibson T, Vigneswaran G, et al. Chemosaturation with percutaneous hepatic perfusion of melphalan for metastatic uveal melanoma. Melanoma Res. 2022;32:103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Meijer TS, Burgmans MC, de Leede EM, et al. Percutaneous hepatic perfusion with melphalan in patients with unresectable ocular melanoma metastases confined to the liver: a prospective phase II study. Ann Surg Oncol. 2021;28:1130–41.

    Article  PubMed  Google Scholar 

  20. Burgmans MC, de Leede EM, Martini CH, Kapiteijn E, Vahrmeijer AL, van Erkel AR. Percutaneous isolated hepatic perfusion for the treatment of unresectable liver malignancies. Cardiovasc Intervent Radiol. 2016;39:801–14.

    Article  PubMed  Google Scholar 

  21. Artzner C, Mossakowski O, Hefferman G, et al. Chemosaturation with percutaneous hepatic perfusion of melphalan for liver-dominant metastatic uveal melanoma: a single center experience. Cancer Imaging. 2019;19:31.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dewald CLA, Warnke MM, Brüning R, et al. Percutaneous hepatic perfusion (PHP) with melphalan in liver-dominant metastatic uveal melanoma: the German experience. Cancers Basel. 2022;14:118.

    Article  CAS  Google Scholar 

  23. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.

    Article  CAS  PubMed  Google Scholar 

  24. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  25. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Published 28 May 2009 (v4.03: 14 June 2010). U.S. Department of Health and Human Services: National Institutes of Health, National Cancer Institute. Available at https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.

  26. Edge SB, Byrd DR, Compton CC, et al. (eds). Malignant melanoma of the uvea. In AJCC Cancer Staging Manual. 7th ed. Springer: New York, 2010, pp 547–60.

  27. KIMMTRAK (tebentafusp-tebn) USPI. Immunocore. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761228s000lbl.pdf.

  28. Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. Ann Oncol. 2014;25:742–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Valsecchi ME, Terai M, Eschelman DJ, et al. Double-blinded, randomized phase II study using embolization with or without granulocyte-macrophage colony-stimulating factor in uveal melanoma with hepatic metastases. J Vasc Interv Radiol. 2015;26:523-32.e2.

    Article  PubMed  PubMed Central  Google Scholar 

  30. de Leede EM, Burgmans MC, Meijer TS, et al. Prospective clinical and pharmacological evaluation of the Delcath system’s second-generation (GEN2) hemofiltration system in patients undergoing percutaneous hepatic perfusion with melphalan. Cardiovasc Intervent Radiol. 2017;40:1196–205.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tong TML, Samim M, Kapiteijn E, et al. Predictive parameters in patients undergoing percutaneous hepatic perfusion with melphalan for unresectable liver metastases from uveal melanoma: a retrospective pooled analysis. Cardiovasc Intervent Radiol. 2022;45:1304–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Meijer TS, Burgmans MC, Fiocco M, et al. Safety of percutaneous hepatic perfusion with melphalan in patients with unresectable liver metastases from ocular melanoma using the Delcath System’s second-generation hemofiltration system: a prospective non-randomized phase II trial. Cardiovasc Intervent Radiol. 2019;42:841–52.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tong TML, Burgmans MC, Speetjens FM, et al. Combining melphalan percutaneous hepatic perfusion with ipilimumab plus nivolumab in advanced uveal melanoma: first safety and efficacy data from the phase Ib part of the Chopin trial. Cardiovasc Intervent Radiol. 2023;46:350–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We thank the patients, their families and caregivers, and the study teams at the participating sites. The authors acknowledge Seth Maxwell and Angela Wharton, who are employees of Delcath Systems, Inc., for their involvement in this study, including contributions to data analysis. All the authors critically reviewed the manuscript and approved the final version before submission, including the authorship list. Editorial support was provided by Preetinder Kaur of Certara under the direction of the authors following Good Publication Practice guidelines (Ann Intern Med. 2022;175:1298–1304) and was funded by Delcath Systems Inc., New York, USA.

Author information

Authors and Affiliations

  1. Departments of Cutaneous Oncology and Sarcoma, Moffitt Cancer Center, Tampa, FL, USA

    Jonathan S. Zager MD, FACS & Junsung Choi MD

  2. Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA

    Jonathan S. Zager MD, FACS & Junsung Choi MD

  3. Thomas Jefferson University, Philadelphia, PA, USA

    Marlana Orloff MD & David J. Eschelman MD, FSIR

  4. European Institute of Oncology, IRCCS, Milan, Italy

    Pier Francesco Ferrucci MD

  5. The University of Tennessee Health Science Center, Memphis, TN, USA

    Evan S. Glazer MD, PhD, FACS

  6. The Ohio State University, Columbus, OH, USA

    Aslam Ejaz MD

  7. University of South Alabama, Mobile, AL, USA

    J. Harrison Howard MD

  8. Medical University of Graz, Graz, Austria

    Erika Richtig MD

  9. Charité Comprehensive Cancer Center, Berlin, Germany

    Sebastian Ochsenreither MD

  10. Stanford University, Stanford, CA, USA

    Sunil A. Reddy MD

  11. Emory University, Atlanta, GA, USA

    Michael C. Lowe MD

  12. Duke University, Durham, NC, USA

    Georgia M. Beasley MD

  13. University Hospital Würzburg, Würzburg, Germany

    Anja Gesierich MD

  14. University Hospital Marburg, Marburg, Germany

    Armin Bender MD & Martin Gschnell MD

  15. University Hospital Zürich, Zürich, Switzerland

    Reinhard Dummer MD

  16. Léon Bérard Center, Lyon, France

    Michel Rivoire MD

  17. Hospital Clínic Barcelona, Barcelona, Spain

    Ana Arance MD, PhD

  18. Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK

    Stephen William Fenwick MD, FRCS & Christian H. Ottensmeier MD, PhD, FRCP

  19. The Clatterbridge Cancer Center, University of Liverpool, Liverpool, UK

    Joseph J. Sacco MD

  20. University Hospital Regensburg, Regensburg, Germany

    Sebastian Haferkamp MD

  21. University Hospital Münster, Münster, Germany

    Carsten Weishaupt MD

  22. Delcath Systems, Inc., Queensbury, NY, USA

    Johnny John MD

  23. University Hospital Southampton NHS Foundation Trust, Southampton, UK

    Matthew Wheater MD, PhD, MRCP

Authors
  1. Jonathan S. Zager MD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlana Orloff MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pier Francesco Ferrucci MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junsung Choi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David J. Eschelman MD, FSIR
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Evan S. Glazer MD, PhD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aslam Ejaz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Harrison Howard MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Erika Richtig MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sebastian Ochsenreither MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sunil A. Reddy MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael C. Lowe MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Georgia M. Beasley MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Anja Gesierich MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Armin Bender MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Martin Gschnell MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Reinhard Dummer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Michel Rivoire MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ana Arance MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Stephen William Fenwick MD, FRCS
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Joseph J. Sacco MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sebastian Haferkamp MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Carsten Weishaupt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Johnny John MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Matthew Wheater MD, PhD, MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Christian H. Ottensmeier MD, PhD, FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan S. Zager MD, FACS.

Ethics declarations

Disclosure

Dr. Jonathan Zager–global principal investigator in the FOCUS phase 3 study and serves on Delcath Systems Medical Advisory Board. Education and Training grant through Delcath. Dr. Marlana Orloff–Advisory Board: Delcath, Replimune. Consultant: Immunocore. Steering Committee: Ideaya. Speaker: Immunocore. Dr. David Eschelman–Received <$5K consulting fees from Delcath. Dr. Evan Glazer–My institution was a site for the clinical trial. I received no direct payment. Delcath paid for the clinical trial to my institution. Dr. J. Howard–I was paid as a consultant to Delcath as a proctor for this trial to ensure new institutions adhered to protocol. Prof. Erika Richtig–Medical University of Graz received payments for conducting the Phase 3 study. Dr. Sebastian Ochsenreither–Advice: Immunocore, Delcath, Janssen. Speakers’ bureau: Immunocore. Dr. Georgia Beasley–Clinical trial funding paid to institution from Replimune, checkmate pharmaceuticals, Philogen, Delcath. Advisory board BMS 10.2023. Dr. Anja Gesierich–University Hospital Würzburg received payments for conducting the Phase 3 study. Professor Reinhard Dummer–intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. Dr. Ana Arance–Consulting or advisory role: Pierre- Fabre, Novartis, Roche, BMS, MSD, Biontech. Speakers’ Bureau: Pierre- Fabre, Novartis, Roche, BMS, MSD. Travel, Accommodations, Expenses: BMS, MSD. Mr. Stephen Fenwick–Liverpool University Hospitals NHS Trust received support for conducting this Phase 3 study from the trial sponsor. Dr. Joseph Sacco–I have been a paid member of advisory boards for Delcath, Replimune and Immunocore. I have received grant funding from Astra Zeneca and BMS (paid to institution). I have had travel and conference attendance paid for by MSD, BMS and Replimune. Dr. Matthew Wheater–Institutional (University Hospital Southampton) funding for conducting a commercial trial. Personal funding for participation in advisory board for Delcath.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 43 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zager, J.S., Orloff, M., Ferrucci, P.F. et al. Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study. Ann Surg Oncol (2024). https://doi.org/10.1245/s10434-024-15293-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1245/s10434-024-15293-x

Search

Navigation