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Multicenter Study
. 2019 Nov 13;7(1):299.
doi: 10.1186/s40425-019-0800-0.

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study

Markus V Heppt  1   2 , Teresa Amaral  3   4 , Katharina C Kähler  5 , Lucie Heinzerling  2 , Jessica C Hassel  6 , Markus Meissner  7 , Nicole Kreuzberg  8 , Carmen Loquai  9 , Lydia Reinhardt  10 , Jochen Utikal  11 , Evelyn Dabrowski  12 , Anja Gesierich  13 , Claudia Pföhler  14 , Patrick Terheyden  15 , Kai-Martin Thoms  16 , Lisa Zimmer  17 , Thomas K Eigentler  3 , Michael C Kirchberger  2 , Henner M Stege  9 , Friedegund Meier  10 , Max Schlaak  1 , Carola Berking  18   19
Affiliations
Multicenter Study

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study

Markus V Heppt et al. J Immunother Cancer. .

Abstract

Background: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.

Methods: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.

Results: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).

Conclusions: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.

Keywords: Biomarker; Combined immune checkpoint blockade; Ipilimumab; Nivolumab; Uveal melanoma.

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Conflict of interest statement

Teresa Amaral: grants from Neracare; travel support from Novartis, personal fees and travel support from BMS, outside the submitted work; Carola Berking: speaker’s honoraria from BMS, Immunocore, MSD, Novartis, and Roche, consultant’s honoraria from Amgen, BMS, MSD, Novartis, Pierre Fabre, Roche, and Sanofi-Aventis and travel support from Amgen, BMS, MSD, and Roche; Anja Gesierich: speaker’s honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme and Roche, consultant’s honoraria from Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme, travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis and Roche; Lucie Heinzerling speaker’s/ consultant’s honoraria from BMS, MSD, Novartis, Roche, Amgen, Pierre Fabre, Sanofi-Aventis, Curevac, research grants to institution from Novartis; Markus V. Heppt: speaker’s honoraria and/or consultant’s honoraria from Roche, Novartis, BMS, MSD and travel support from BMS; Katharina C. Kähler: consultant to Roche, BMS, MSD and received travel grants and speaker fees from Roche, BMS, MSD, Novartis, Amgen; Carmen Loquai: advisory for Roche, Amgen, Novartis, BMS, MSD, Ribological, speaker’s honoraria from Roche, BMS, MSD, Novartis, travel reimbursement from Roche, BMS, MSD, Novartis; Max Schlaak: speaker’s honoraria and/ or consultant’s honoraria from Roche, Novartis, BMS, MSD, Kyowa Kirin, Amgen, Pierre Fabre and travel support from BMS; Henner M. Stege: travel support from Novartis and Roche; Patrick Terheyden: speaker’s honoraria from BMS, Novartis, MSD, Pierre-Fabre, Curevac and Roche, consultant’s honoraria from BMS, Novartis, Pierre-Fabre, Merck Serono, Sanofi und Roche and travel support fom BMS, Pierre-Fabre and Roche; Kai-Martin Thoms: speaker’s honoraria from BMS, MSD, Novartis and Roche, consultant’s honoraria from BMS, MSD, Novartis, Roche and Pierre Fabre and travel support from BMS, Novartis, Roche and Pierre Fabre; Jochen Utikal: advisory board or honoraria and travel support from Amgen, BMS, GSK, LeoPharma, MSD, Novartis, Pierre Fabre, Roche, outside the submitted work; Lisa Zimmer: consultant/ honoraria from Roche, BMS, MSD, Novartis, Sanofi, Pierre Fabre and travel support from MSD, BMS, Amgen, Pierre Fabre, Sanofi and Novartis. The remaining authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Kaplan-Meier estimates of the patient population for a progression-free survival (PFS) and b overall survival (OS). The median PFS and OS was estimated to 3.0 months (95% CI 2.4–3.6) and 16.1 months (95% CI 12.9–19.3), respectively. One patient was not included in the Kaplan-Meier analysis for PFS and OS due to missing data
Fig. 2
Fig. 2
a Kaplan-Meier estimates for overall survival (OS) according to ECOG performance status. The median OS was 17.7 months (95% CI 13.1–22.3) for ECOG 0 versus 2.5 months (95% CI 0.0–9.6) for ECOG ≥1. Three patients were not included due to missing data. b Kaplan-Meier estimates for OS according to the prognostic score based on the serum parameters LDH, CRP, and REC. The groups with low and intermediate risk were pooled due to a small number of cases. The median OS was 17.7 months (95% CI 14.7–20.8) in the low plus intermediate group versus 15.4 months (95% CI 12.7–18.2) in the high risk group versus 7.1 months (95% CI 0.0–16.2) in the very high risk group. The p-values indicated were calculated with the log-rank test. One patient was not included due to missing data
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