After enucleation or radiotherapy of the primary lesion, 50% of uveal melanoma (UM) patients develop distant metastases. In contrast to cutaneous melanoma, targeted therapies and checkpoint inhibitors failed to improve overall survival (OS) in UM. Chemoembolization or intrahepatic artery perfusion improved local control, but failed to show OS benefit. The anti-CTLA-4 antibody ipilimumab (IPI), showed limited clinical activity in UM, thus combination therapies may be required. Preclinical experiments in a murine melanoma model indicated that additional radiofrequency ablation(RFA) enhanced antigen presentation and induced durable responses.
We therefore have set-up a phase 1b/2 study to assess safety and efficacy of the combination of RFA and IPI in UM patients with at least 2 unresectable liver lesions. In the phase 1b part patients underwent RFA of one liver lesion and received 4 courses IPI 0,3mg/kg, 3mg/kg or 10mg/kg q3wk in a 3 + 3 design. Primary endpoint of the phase 1b part was safety in terms of dose limiting toxicities per cohort to define the recommended phase 2 dose(RP2D). Primary endpoints of the phase 2 part were confirmed objective response rate (ORR) and disease control rate (DCR) according to RECIST 1.1 (only non-RFA lesions), secondary endpoints were progression free survival (PFS) and OS.
IPI 10mg/kg + RFA was defined as the RP2D. After 19 patients had been treated, the study was amended to adjust the RP2D to IPI 3mg/kg + RFA, because 9 patients (47%) had developed grade 3 colitis. In the 3mg/kg IPI + RFA cohort also 19 patients have been treated, and baseline characteristics were balanced between the cohorts. Treatment related grade ≥3 AEs were seen in 53% of patients in the 10mg/kg cohort versus 32% in the 3mg/kg cohort. No confirmed objective responses were observed; the confirmed DCR was 21% in the 10mg/kg cohort and 11% in the 3mg/kg cohort. Median PFS was 2.8 months and was comparable for both groups, median OS was 13.6 months for the 10mg/kg cohort versus 9.5 months for the 3mg/kg cohort (p = 0.23).
The combination of IPI 3mg/kg +RFA was safe but showed limited clinical activity in UM. However, overall survival seems to be longer compared to other study cohorts of UM patients, especially in the IPI 10mg/kg cohort.
Clinical trial identification
EudraCT Number: 2011-004200-38
Legal entity responsible for the study
J.V. Thienen: Advisory board: MSD, Bristol-Myers Squibb. J.B. Haanen: Advisory role: Bristol-Myers Squibb. MSD, Pfizer, Roche, Novartis, Neon Therapeutics Research grants: Bristol-Myers Squibb, MSD, GSK. C.U. Blank: Advisory board: Bristol-Myers Squibb, MSD, Novartis, GSK, Pfizer, Lilly, Roche Research grant: Bristol-Myers Squibb, Novartis. All other authors have declared no conflicts of interest.