Sequential CTLA-4, PD-1 Blockade Proposed For Advanced Melanoma

Advanced melanoma patients may experience less toxicity if given ipilimumab separately to nivolumab or pembrolizumab therapy

medwireNews: A sequential approach to therapy could harness the benefits of combined T cell checkpoint inhibitor blockade while reducing toxicity, suggests a review of patients with advanced melanoma.

Forty patients at The Netherlands Cancer Institute in Amsterdam were treated with two cycles of the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab followed by two infusions of an anti-programmed cell death 1 (PD-1) agent, either nivolumab (n=11) or pembrolizumab (n=29), given 3 weeks apart.

Sequential treatment was offered to these individuals because combined blockade was unavailable in the Netherlands until July 2016, Christian Blank and co-authors from the institution explain in the Annals of Oncology.

After a median of 51 weeks of follow-up, 88% of the patients had experienced treatment-related toxicity, most commonly fatigue, diarrhoea, pruritus and rash. Grade 3 or 4 treatment-related adverse events were reported in 38% of the patients, with 18% affected by colitis, 8% by elevations of lipase or amylase, 5% by elevation of liver enzymes and 5% with maculopapular rash.

Eleven patients required systemic immunosuppression to manage their side effects and six patients ended treatment because of toxicity.

In all, 37 of the patients were assessed for response by imaging, from week 11 or 12 of treatment. The best overall response rate at time of reporting was 55%, with a complete response in 15% and a partial response in 40%. Twenty per cent had stable disease, giving a disease control rate of 75%.

And the authors note that 82% of the patients who responded to treatment have ongoing responses.

“Our data are striking in the light, that in contrast to patients treated in the phase 2 and 3 trials, many of our patients had received prior systemic treatment for advanced disease and/or had (symptomatic) cerebral metastases”, Christian Blank et al emphasize, noting that both characteristics are negative prognostic markers for response and survival with immunotherapy. 

While acknowledging the limitations of their retrospective study, the researchers suggest that their regimen “strongly deserves further investigation, which should take place in a randomized controlled clinical trial comparing the standard combination of ipilimumab and nivolumab to our sequential scheme.”

As well as offering better quality of life, a less toxic combination of CTLA-4 and PD-1 blockade could “create space” for the addition of a third checkpoint inhibitor in patients who did not achieve a complete response with dual therapy, such as a LAG-3 or TIM-3 agent, they hypothesize.


Meerveld-Eggink A, Rozeman EA, Lalezari F, et al. Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced melanoma patients – a single center experience. Ann Oncol; Advance online publication 2 February 2017. DOI:

medwireNews ( ) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2017