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Frontiers of Medicine

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Front. Med.    2023, Vol. 17 Issue (5) : 878-888    https://doi.org/10.1007/s11684-023-0993-y
RESEARCH ARTICLE
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
Elias A. T. Koch1,2,3,4, Anne Petzold1,2,3,4, Anja Wessely1,2,3,4, Edgar Dippel5, Markus Eckstein2,3,4,6, Anja Gesierich7, Ralf Gutzmer8, Jessica C. Hassel9, Harald Knorr10, Nicole Kreuzberg11, Ulrike Leiter12, Carmen Loquai13, Friedegund Meier14, Markus Meissner15, Peter Mohr16, Claudia Pföhler17, Farnaz Rahimi18, Dirk Schadendorf19, Max Schlaak20, Kai-Martin Thoms21, Selma Ugurel19, Jochen Utikal22, Michael Weichenthal23, Beatrice Schuler-Thurner1,2,3,4, Carola Berking1,2,3,4, Markus V. Heppt1,2,3,4()
1. Department of Dermatology, Uniklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
2. Comprehensive Cancer Center Erlangen—European Metropolitan Area of Nürnberg (CCC ER-EMN), 91054 Erlangen, Germany
3. Deutsches Zentrum Immuntherapie (DZI), Uniklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
4. Bavarian Cancer Research Center (BZKF), Uniklinikum Erlangen, Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
5. Department of Dermatology, Ludwigshafen Medical Center, 67059 Ludwigshafen, Germany
6. Institute of Pathology, Uniklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
7. Department of Dermatology, University Hospital Würzburg, 97080 Würzburg, Germany
8. Skin Cancer Center Minden, Department of Dermatology, Mühlenkreiskliniken AöR, Ruhr University Bochum Campus Minden, 32423 Minden, Germany
9. Skin Cancer Center, Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany
10. Department of Ophthalmology, Uniklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
11. Department of Dermatology and Venereology, Skin Cancer Center at the Center of Integrated Oncology (CIO) Köln Bonn, University Hospital of Cologne, 50937 Cologne, Germany
12. Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, 72056 Tübingen, Germany
13. Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany
14. Skin Cancer Center at the University Cancer Center Dresden and National Center for Tumor Diseases & Department of Dermatology, University Hospital Carl Gustav Carus, 01307 Dresden, Germany
15. Department of Dermatology, Venereology and Allergology, Goethe University, 60590 Frankfurt am Main, Germany
16. Department of Dermatology, Elbeklinikum, 21614 Buxtehude, Germany
17. Department of Dermatology, Saarland University Medical School, 66421 Homburg/Saar, Germany
18. Department of Dermatology and Allergy, Munich University Hospital (LMU), 81377 Munich, Germany
19. Department of Dermatology, University Hospital Essen, 45147 University Duisburg-Essen, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany
20. Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology, Venerology and Allergology, 10117 Berlin, Germany
21. Department of Dermatology, University Medical Center Goettingen, 37075 Goettingen, Germany
22. Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, and DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
23. Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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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     
Corresponding Author(s): Markus V. Heppt   
Just Accepted Date: 15 May 2023   Online First Date: 30 June 2023    Issue Date: 07 December 2023
 Cite this article:   
Elias A. T. Koch,Anne Petzold,Anja Wessely, et al. 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[J]. Front. Med., 2023, 17(5): 878-888.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0993-y
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/878
Parameter Categories Total (n = 182) Cohort A (n = 78) Cohort B (n = 104) P value
Age Median in years 65.2 (17.7–87.6) 63.8 (31.7–85.0) 66.2 (17.7–87.6) 0.31
Sex Female 91 (50%) 36 (46.2%) 55 (52.9%) 0.45
Male 91 (50%) 42 (53.8%) 49 (47.1%)
ECOG performance status 0 96 (52.7%) 48 (61.5%) 48 (46.2%) 0.056
1 16 (8.8%) 3 (3.8%) 13 (12.5%)
2 4 (2.2%) 0 (0%) 4 (3.8%)
3 1 (0.5%) 0 (0%) 1 (1%)
Not indicated 65 (35.7%) 27 (34.6%) 38 (36.5%)
LDH Not elevated 49 (26.9%) 26 (33.3%) 23 (22.1%) 0.56
Elevated 85 (46.7%) 34 (43.6%) 51 (49%)
Not indicated 48 (26.4%) 18 (23.1%) 30 (28.8%)
Sites of metastasis Liver 170 (93.4%) 78 (100%) 92 (88.5%) 0.11
Pulmonary 87 (47.8%) 32 (41%) 55 (52.9%)
Bone 49 (26.9%) 18 (23.1%) 31 (29.8%)
CNS 28 (15.4%) 11 (14.1%) 17 (16.3%)
Lymph node 40 (22%) 16 (20.5%) 24 (23.1%)
Connective tissue 9 (4.9%) 3 (3.8%) 6 (5.8%)
Skin 24 (13.2%) 9 (11.5%) 15 (14.4%)
Disseminated 10 (5.5%) 5 (6.4%) 5 (4.8%)
Other 48 (26.4%) 16 (20.5%) 32 (30.8%)
Number of metastatic sites (at the time of immunotherapy) Median (range) 2.5 (1–8) 2.4 (1–8) 2.7 (1–7) 0.43
Time from metastasis to treatment start Medians in months (range) 11.7 (0–329.7) 14.4 (0–329.7) 8 (0–46.6) 0.297
Treatment lines throughout patient course Median (range) 2 (1–7) 2 (1–7) 2 (1–6) 0.094
Radiation therapy Yes 42 (23.1%) 29 (37.2%) 13 (12.5%) < 0.001
No 96 (52.7%) 33 (42.3%) 63 (60.6%)
Unknown 44 (24.2%) 16 (20.5%) 28 (26.9%)
Liver directed treatment RFA 8 (10.3%)
SIRT 53 (67.9%)
TACE 9 (11.5%)
Chemosaturation 5 (6.4%)
Liver-surgery 1 (1.3%)
Other 2 (2.6%)
ICB therapy Single anti-PD1 54 (29.7%) 19 (24.4%) 35 (33.7%) 0.23
Single anti- CTLA-4 7 (3.8%) 4 (5.1%) 3 (2.9%)
Combined ICB 121 (66.5%) 55 (70.5%) 66 (63.5%)
Tab.1  Baseline characteristics of the study population
Response to ICB (any) Total (n = 182) Cohort A (n = 78) Cohort B (n = 104) Test (A vs. B)
CR 3 (1.6%) 2 (2.6%) 1 (1.0%)
PR 14 (7.7%) 11 (14.1%) 3 (2.9%)
SD 34 (18.7%) 16 (20.5%) 18 (17.3%)
PD 99 (54.4%) 36 (46.2%) 63 (60.6%)
MR 5 (2.7%) 3 (3.8%) 2 (1.9%)
NA 26 (14.3%) 10 (12.8%) 17 (16.3%)
ORR 17 (9.3%) 13 (16.7%) 4 (3.8%) P = 0.0073
DCR 51 (28.0%) 29 (37.2%) 22 (28.2%) P = 0.027
Response to anti-PD1 monotherapy Total (n = 54) Cohort A (n = 19) Cohort B (n = 35) Test (A vs. B)
CR 0 (0.0%) 0 (0.0%) 0 (0.0%)
PR 3 (5.6%) 2 (10.5%) 1 (2.9%)
SD 6 (11.1%) 3 (15.8%) 3 (8.6%)
PD 35 (64.8%) 10 (52.6%) 25 (71.4%)
MR 2 (3.7%) 1 (5.3%) 1 (2.9%)
NA 8 (14.8%) 3 (15.8%) 5 (14.3%)
ORR 3 (5.6%) 2 (10.5%) 1 (2.9%) P = 0.57
DCR 9 (16.7%) 5 (26.3%) 4 (11.4%) P = 0.31
Response to combined ICB Total (n = 121) Cohort A (n = 55) Cohort B (n = 66) Test (A vs. B)
CR 3 (2.5%) 2 (3.6%) 1 (1.5%)
PR 11 (9.1%) 9 (16.4%) 2 (3.0%)
SD 27 (22.3%) 13 (23.6%) 14 (21.2%)
PD 59 (48.8%) 22 (40.0%) 37 (56.1%)
MR 3 (2.5%) 2 (3.6%) 1 (1.5%)
NA 18 (14.9%) 7 (12.7%) 11 (16.7%)
ORR 14 (11.6%) 11 (14.1%) 3 (4.5%) P = 0.017
DCR 41 (33.9%) 24 (30.8%) 17 (25.8%) P = 0.061
Tab.2  Response rates to ICB
Subgroups of cohort A n ORR DCR
A1: LDT before ICB 23 6/23 = 26.1% 11/23 = 47.8%
A2: LDT during ICB 14 2/14 = 14.3% 5/14 = 35.7%
A3: LDT after ICB* 19 1/19 = 5.3% 6/19 = 31.6%
Time of LDT unknown 22 3/22 = 13.6% 6/22 = 27.3%
P value (before vs. during vs. after) Underpowered 0.54
Tab.3  Response rates to ICB in the subpopulations of cohort A
Fig.1  Kaplan–Meier estimates of the patient population for (A) OS of the entire population with a median OS of 14.9 months (CI 95% 12.7–17.8). (B) OS comparing cohort A (red) vs. B (turquoise) with a median OS of 20.1 months (CI 95% 14.1-NR) vs. 13.8 months (CI 95% 9.2–16.0; P = 0.0016). (C) compares CR, PR (red) vs. SD, PD (turquoise) revealing a median OS of NR (NR-NR) vs. 14.3 months (CI 95% 11.3–16.4; P < 0.001). (D) compares CR, PR, SD (red) vs. PD (turquoise) with a median OS of 29 months (20.1-NR) vs. 12.6 months (CI 95% 8.6–15.4; P < 0.001).
Fig.2  Swimmer plots for cohorts A (lower) and B (top) demonstrating the OS for each patient. The color shows the best response to ICB, the symbols depict the reason for treatment discontinuation and the yellow triangle shows the time of tumor progression. If a patient was censored, an arrow is drawn. The red cross marks the time of LDT.
Subgroups of cohort A N (OS) Median OS in months (95% CI) OS after 6 months (95% CI) OS after 12 months (95% CI) OS after 24 months (95% CI)
LDT without SIRT 25 13.4 (8.8-NR) 84.7% (70.1%–100%) 56.4% (37.6%–84.6%) 38.1% (20.8%–69.8%)
Only SIRT 53 23.7 (17.8-NR) 84.0% (74.3%–94.8%) 71.7% (59.6%–86.3%) 46.9% (31.8%–69.1%)
A1 23 18.2 (13.4-NR) 80.3% (64.6%–99.7%) 68.3% (50.0%–93.3%) 48.3% (29.2%–80.0%)
A2 14 26.0 (26.0-NR) 83.3% (64.7%–100%) 74.1% (52.6%–100%) 74.1% (52.6%–100%)
A3 19 23.7 (15.4-NR) 100% 86.3% (70.1%–100%) 48.8% (26.1%–91.3%)
Subgroups of cohort A N (PFS) Median PFS in months (95% CI) PFS after 3 months (95% CI) PFS after 6 months (95% CI)
LDT without SIRT 13 2.6 (2.4–5.3) 38.5% (19.3%–76.5%) 7.7% (1.2%–50.6%)
Only SIRT 36 3.5 (2.3–5.5) 52.8% (38.8%–71.9%) 25.0% (14.2%–44.0%)
A1 14 2.4 (1.9–11.1) 42.9% (23.4%–78.5%) 28.6% (12.5%–65.4%)
A2 9 3.5 (2.5-NR) 55.6% (31.0%–99.7%) 22.2% (6.6%–75.4%)
A3 13 3.5 (2.0-NR) 53.8% (32.6%–89.1%) 15.4% (4.3%–55.0%)
Tab.4  Survival times for the subpopulations of cohort A
Total Cohort A Cohort B Test (Cohorts A vs. B)
Any ICB: Nr. of patients with AE 81/182 (44.5%) 41/78 (52.6%) 40/104 (38.5%) P = 0.081
Any ICB: Nr. of patients with severe AE 46/182 (25.3%) 23/78 (29.5%) 23/104 (22.1%) P = 0.34
Comb. ICB: Nr. of patients with AE 66/121 (54.4%) 33/55 (60%) 33/66 (50%) P = 0.36
Comb. ICB: Nr. of patients with severe AE 42/121 (34.6%) 22/55 (40%) 20/66 (30.2%) P = 0.36
Cohort A1 LDT before ICB Cohort A2 LDT during ICB Cohort A3 LDT after ICB Cohort A Time of LDT unknown
Number of patients with AE 11/23 (47.7%) 10/14 (71.1%) 9/19 (47.4%) 11/22 (50%)
Number of patients with severe AE 7/23 (30.3%) 4/14 (28.6%) 7/19 (36.7%) 5/22 (22.6%)
Tab.5  Occurrence of adverse events
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