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
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.
. [J]. Frontiers of Medicine, 2023, 17(5): 878-888.
Elias A. T. Koch, Anne Petzold, Anja Wessely, Edgar Dippel, Markus Eckstein, Anja Gesierich, Ralf Gutzmer, Jessica C. Hassel, Harald Knorr, Nicole Kreuzberg, Ulrike Leiter, Carmen Loquai, Friedegund Meier, Markus Meissner, Peter Mohr, Claudia Pföhler, Farnaz Rahimi, Dirk Schadendorf, Max Schlaak, Kai-Martin Thoms, Selma Ugurel, Jochen Utikal, Michael Weichenthal, Beatrice Schuler-Thurner, Carola Berking, Markus V. Heppt. 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. Front. Med., 2023, 17(5): 878-888.
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
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
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
Fig.1
Fig.2
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
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
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