Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients: a single-center experience.
Combination of T cell checkpoint blockade by CTLA-4- and PD-1-blockade is one of the most promising therapies in patients with advanced melanoma. It induces superior response rates when compared with single-agent therapy, but at the cost of a high percentage of grade 3 and 4 adverse events (AEs). This combination therapy was until July 2016 not available in the Netherlands, which prompted several physicians to treat patients with less than standard numbers of courses of ipilimumab followed directly by nivolumab or pembrolizumab.



In this retrospective analysis, patients were included who were treated with two courses (day 0 and 21) anti-CTLA-4 (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22 with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on treatment-related AEs were collected from electronic patient records and scored according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans.



Forty advanced melanoma patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median follow-up (FU) was 51 weeks (range: 4-63 weeks) with a minimum FU of 26 weeks. Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best overall response rate (BORR) was 55% (95% CI 39-70) and disease control rate was 75% (95% CI 59-87). Ongoing responses were observed in 82% of responding patients.



Treatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results warrant further investigation in a prospective randomized controlled clinical trial.
Department of Medical Oncology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
A
A
Meerveld-Eggink
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
E A
EA
Rozeman
Division of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
F
F
Lalezari
Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J V
JV
van Thienen
Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J B A G
JBAG
Haanen
Department of Immunology, Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
C U
CU
Blank
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab
CTLA-4 blockade; PD-1 blockade; checkpoint inhibition; combination therapy; melanoma