Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial

Abstract

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Keywords

uveal melanoma / liver-directed therapy / immune checkpoint blockade / SIRT / anti-PD-1 / anti-CTLA-4

References

[1] Aronow ME, Topham AK, Singh AD. Uveal melanoma: 5-year update on incidence, treatment, and survival (SEER 1973–2013). Ocul Oncol Pathol 2018; 4(3): 145–151

[2] Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report No. 15. Arch Ophthalmol 2001; 119(5): 670–676

[3] Kujala E, Mäkitie T, Kivelä T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003; 44(11): 4651–4659

[4] Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol 2017; 43(3): 604–611

[5] Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res 2019; 29(6): 561–568

[6] Koch EAT, Petzold A, Wessely A, Dippel E, Erdmann M, Heinzerling L, Hohberger B, Knorr H, Leiter U, Meier F, Mohr P, Rahimi F, Schell B, Schlaak M, Terheyden P, Schuler-Thurner B, Ugurel S, Utikal J, Vera J, Weichenthal M, Ziller F, Berking C, Heppt MV. Clinical determinants of long-term survival in metastatic uveal melanoma. Cancer Immunol Immunother 2022; 71(6): 1467–1477

[7] Koch EAT, Petzold A, Wessely A, Dippel E, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Hohberger B, Kähler KC, Knorr H, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schadendorf D, Schell B, Schlaak M, Terheyden P, Thoms KM, Schuler-Thurner B, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, Heppt MV. 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(13): 3359

[8] Nathan P, Hassel JC, Rutkowski P, Baurain JF, Butler MO, Schlaak M, Sullivan RJ, Ochsenreither S, Dummer R, Kirkwood JM, Joshua AM, Sacco JJ, Shoushtari AN, Orloff M, Piulats JM, Milhem M, Salama AKS, Curti B, Demidov L, Gastaud L, Mauch C, Yushak M, Carvajal RD, Hamid O, Abdullah SE, Holland C, Goodall H, Piperno-Neumann S. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med 2021; 385(13): 1196–1206

[9] Koch EAT, Petzold A, Wessely A, Dippel E, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Kähler KC, Knorr H, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schadendorf D, Schell B, Schlaak M, Terheyden P, Thoms KM, Schuler-Thurner B, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, Heppt MV. Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity. Cancers (Basel) 2022; 14(3): 518

[10] Pires da Silva I, Lo S, Quek C, Gonzalez M, Carlino MS, Long GV, Menzies AM. Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy. Cancer 2020; 126(1): 86–97

[11] Somasundaram R, Zhang G, Fukunaga-Kalabis M, Perego M, Krepler C, Xu X, Wagner C, Hristova D, Zhang J, Tian T, Wei Z, Liu Q, Garg K, Griss J, Hards R, Maurer M, Hafner C, Mayerhöfer M, Karanikas G, Jalili A, Bauer-Pohl V, Weihsengruber F, Rappersberger K, Koller J, Lang R, Hudgens C, Chen G, Tetzlaff M, Wu L, Frederick DT, Scolyer RA, Long GV, Damle M, Ellingsworth C, Grinman L, Choi H, Gavin BJ, Dunagin M, Raj A, Scholler N, Gross L, Beqiri M, Bennett K, Watson I, Schaider H, Davies MA, Wargo J, Czerniecki BJ, Schuchter L, Herlyn D, Flaherty K, Herlyn M, Wagner SN. Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun 2017; 8(1): 607

[12] Somasundaram R, Connelly T, Choi R, Choi H, Samarkina A, Li L, Gregorio E, Chen Y, Thakur R, Abdel-Mohsen M, Beqiri M, Kiernan M, Perego M, Wang F, Xiao M, Brafford P, Yang X, Xu X, Secreto A, Danet-Desnoyers G, Traum D, Kaestner KH, Huang AC, Hristova D, Wang J, Fukunaga-Kalabis M, Krepler C, Ping-Chen F, Zhou X, Gutierrez A, Rebecca VW, Vonteddu P, Dotiwala F, Bala S, Majumdar S, Dweep H, Wickramasinghe J, Kossenkov AV, Reyes-Arbujas J, Santiago K, Nguyen T, Griss J, Keeney F, Hayden J, Gavin BJ, Weiner D, Montaner LJ, Liu Q, Peiffer L, Becker J, Burton EM, Davies MA, Tetzlaff MT, Muthumani K, Wargo JA, Gabrilovich D, Herlyn M. Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. Nat Commun 2021; 12(1): 346

[13] Lindblad KE, Lujambio A. Liver metastases inhibit immunotherapy efficacy. Nat Med 2021; 27(1): 25–27

[14] Rowcroft A, Loveday BPT, Thomson BNJ, Banting S, Knowles B. Systematic review of liver directed therapy for uveal melanoma hepatic metastases. HPB (Oxford) 2020; 22(4): 497–505

[15] Mariani P, Almubarak MM, Kollen M, Wagner M, Plancher C, Audollent R, Piperno-Neumann S, Cassoux N, Servois V. Radiofrequency ablation and surgical resection of liver metastases from uveal melanoma. Eur J Surg Oncol 2016; 42(5): 706–712

[16] Akyuz M, Yazici P, Dural C, Yigitbas H, Okoh A, Bucak E, McNamara M, Singh A, Berber E. Laparoscopic management of liver metastases from uveal melanoma. Surg Endosc 2016; 30(6): 2567–2571

[17] Eldredge-Hindy H, Ohri N, Anne PR, Eschelman D, Gonsalves C, Intenzo C, Bar-Ad V, Dicker A, Doyle L, Li J, Sato T. Yttrium-90 microsphere brachytherapy for liver metastases from uveal melanoma: clinical outcomes and the predictive value of fluorodeoxyglucose positron emission tomography. Am J Clin Oncol 2016; 39(2): 189–195

[18] Gonsalves CF, Eschelman DJ, Adamo RD, Anne PR, Orloff MM, Terai M, Hage AN, Yi M, Chervoneva I, Sato T. A prospective phase II trial of radioembolization for treatment of uveal melanoma hepatic metastasis. Radiology 2019; 293(1): 223–231

[19] Marquardt S, Kirstein MM, Brüning R, Zeile M, Ferrucci PF, Prevoo W, Radeleff B, Trillaud H, Tselikas L, Vicente E, Wiggermann P, Manns MP, Vogel A, Wacker FK. Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: european multicentre study on safety, short-term effects and survival. Eur Radiol 2019; 29(4): 1882–1892

[20] Kirstein MM, Marquardt S, Jedicke N, Marhenke S, Koppert W, Manns MP, Wacker F, Vogel A. Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors. J Cancer Res Clin Oncol 2017; 143(10): 2113–2121

[21] Karydis I, Gangi A, Wheater MJ, Choi J, Wilson I, Thomas K, Pearce N, Takhar A, Gupta S, Hardman D, Sileno S, Stedman B, Zager JS, Ottensmeier C. Percutaneous hepatic perfusion with melphalan in uveal melanoma: a safe and effective treatment modality in an orphan disease. J Surg Oncol 2018; 117(6): 1170–1178

[22] Dewald CLA, Hinrichs JB, Becker LS, Maschke S, Meine TC, Saborowski A, Schönfeld LJ, Vogel A, Kirstein MM, Wacker FK. Chemosaturation with percutaneous hepatic perfusion: outcome and safety in patients with metastasized uveal melanoma. Röfo Fortschr Geb Röntgenstr Neuen Bildgeb Verfahr 2021; 193(8): 928–936

[23] Hughes MS, Zager J, Faries M, Alexander HR, Royal RE, Wood B, Choi J, McCluskey K, Whitman E, Agarwala S, Siskin G, Nutting C, Toomey MA, Webb C, Beresnev T, Pingpank JF. Results of a randomized controlled multicenter phase III trial of percutaneous hepatic perfusion compared with best available care for patients with melanoma liver metastases. Ann Surg Oncol 2016; 23(4): 1309–1319

[24] Meijer TS, Burgmans MC, Fiocco M, de Geus-Oei LF, Kapiteijn E, de Leede EM, Martini CH, van der Meer RW, Tijl FGJ, Vahrmeijer AL. Safety of percutaneous hepatic perfusion with melphalan in patients with unresectable liver metastases from ocular melanoma using the delcath systems’ second-generation hemofiltration system: a prospective non-randomized phase II trial. Cardiovasc Intervent Radiol 2019; 42(6): 841–852

[25] Heppt MV, Amaral T, Kähler KC, Heinzerling L, Hassel JC, Meissner M, Kreuzberg N, Loquai C, Reinhardt L, Utikal J, Dabrowski E, Gesierich A, Pföhler C, Terheyden P, Thoms KM, Zimmer L, Eigentler TK, Kirchberger MC, Stege HM, Meier F, Schlaak M, Berking C. Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study. J Immunother Cancer 2019; 7(1): 299

[26] Piulats JM, Espinosa E, de la Cruz Merino L, Varela M, Alonso Carrión L, Martín-Algarra S, López Castro R, Curiel T, Rodríguez-Abreu D, Redrado M, Gomà M, Rullán AJ, Calvo González A, Berrocal-Jaime A. 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(6): 586–598

[27] Khoja L, Atenafu EG, Suciu S, Leyvraz S, Sato T, Marshall E, Keilholz U, Zimmer L, Patel SP, Piperno-Neumann S, Piulats J, Kivelä TT, Pfoehler C, Bhatia S, Huppert P, Van Iersel LBJ, De Vries IJM, Penel N, Vogl T, Cheng T, Fiorentini G, Mouriaux F, Tarhini A, Patel PM, Carvajal R, Joshua AM. 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(8): 1370–1380

[28] Pelster MS, Gruschkus SK, Bassett R, Gombos DS, Shephard M, Posada L, Glover MS, Simien R, Diab A, Hwu P, Carter BW, Patel SP. Nivolumab and ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study. J Clin Oncol 2021; 39(6): 599–607

[29] Aedo-Lopez V, Gérard CL, Boughdad S, Gautron Moura B, Berthod G, Digklia A, Homicsko K, Schaefer N, Duran R, Cuendet MA, Michielin O. Safety and efficacy of ipilimumab plus nivolumab and sequential selective internal radiation therapy in hepatic and extrahepatic metastatic uveal melanoma. Cancers (Basel) 2022; 14(5): 1162

[30] Blomen CL, Kött J, Hartung TI, Torster LK, Gebhardt C. Combination of immune checkpoint inhibitors and liver-specific therapies in liver-metastatic uveal melanoma: can we thus overcome its high resistance?. Cancers (Basel) 2021; 13(24): 6390

[31] Theurich S, Rothschild SI, Hoffmann M, Fabri M, Sommer A, Garcia-Marquez M, Thelen M, Schill C, Merki R, Schmid T, Koeberle D, Zippelius A, Baues C, Mauch C, Tigges C, Kreuter A, Borggrefe J, von Bergwelt-Baildon M, Schlaak M. Local tumor treatment in combination with systemic ipilimumab immunotherapy prolongs overall survival in patients with advanced malignant melanoma. Cancer Immunol Res 2016; 4(9): 744–754

[32] Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 2015; 1(9): 1325–1332

[33] Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520(7547): 373–377

[34] Brossart P. The role of antigen spreading in the efficacy of immunotherapies. Clin Cancer Res 2020; 26(17): 4442–4447

[35] Najjar YG, Navrazhina K, Ding F, Bhatia R, Tsai K, Abbate K, Durden B, Eroglu Z, Bhatia S, Park S, Chowdhary A, Chandra S, Kennedy J, Puzanov I, Ernstoff M, Vachhani P, Drabick J, Singh A, Xu T, Yang J, Carvajal R, Manson D, Kirkwood JM, Cohen J, Sullivan R, Johnson D, Funchain P, Shoushtari A. Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study. J Immunother Cancer 2020; 8(1): e000331

Acknowledgements

We thank all investigators of the German Dermatologic Cooperative Oncology Group (DeCOG) for their general commitment to the research consortium, in particular to the Committee on Ocular Melanoma, and participation in the ADOReg registry. E.A.T.K. and M.V.H. were supported by the clinician-scientist program awarded by the German Society of Dermatology (DDG) and the Arbeitsgemeinschaft Dermatologische Forschung (ADF). E.A.T.K. received research support by the Hiege Foundation (Deutsche Hautkrebsstiftung) and by the Bavarian Cancer Research Center (BZKF).

Compliance with ethics guidelines

This study was approved by the institutional review board of the medical faculty of the Munich University Hospital (approval number 413-16 UE) and was conducted following the principles of the Helsinki Declaration in its current version. The Patient consent was waived due to retrospective design involving anonymized data from several centers.

Conflict of Interests

M.E.: Personal fees, travel costs and speaker’s honoraria from MSD, AstraZeneca, Janssen-Cilag, Cepheid, Roche, Astellas, Diaceutics; research funding from AstraZeneca, Janssen-Cilag, STRATIFYER, Cepheid, Roche, Gilead; advisory roles for Diaceutics, MSD, AstraZeneca, Janssen-Cilag, GenomicHealth; outside the submitted work. A.G.: Speaker’s honoraria from Allmiral, Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies with Amgen, Array, Bristol-Myers Squibb, Delcath Systems Inc, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. R.G.: Research support: Pfizer, Johnson & Johnson, Novartis, SUN, Amgen, Sanofi, Merck-Serono, Kyowa-Kirin, Almirall-Hermal. Honoraria for lectures: Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, SUN, Pierre-Fabre, Sanofi. Honoraria for advice: Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, SUN, Merck-Serono, Sanofi, Immunocore; outside the submitted work. C.L. received Advisory board, Speekers fee, travel reimbusment from MSD, BMS, Sanofi, Pierre Fabre, Roche, Novartis, Biontech, Almirall Hermal, Sun Pharma, Kyowa Kirin, Merck, Immunocore. F.M.: Travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche; outside the submitted work. K.-M.T.: Honoraria from BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO, Almirall, Galderma, Candela; Consultant or Advisory Role for BMS, MSD, Roche, Novartis, Pierre Fabre, Sun Pharma, LEO, Almirall; Travel support from BMS, MSD, Roche, Novartis, Pierre Fabre, LEO; outside the submitted work. C.P.: Received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO outside the submitted work. S.U.: Research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; outside the submitted work. J.U.: Advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. A.W.: Speaker’s honoraria from Novartis; outside the submitted work. All others authors declare no conflicts of interest.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0993-y and is accessible for authorized users.

Open Access

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

RIGHTS & PERMISSIONS

2023 The Author(s). This article is published with open access at link.springer.com and journal.hep.com.cn