“Another concern of the higher risk of severe toxicity associated with close to 60% of patients getting combination of ipilimumab plus nivolumab, is that if they develop a grade 3 or more toxicity that requires high-dose steroids, later on we might have a problem putting these patients into clinical trials – most trials say that patients can’t have had grade 3 or more toxicity that required steroid use,” said Dr Hu-Lieskovan.

Despite the higher levels of toxicity with the combination treatments and the risk of being unable to enroll patients in other trials in the future, there are some indications that certain patients may particularly benefit from this dual treatment approach.

“There’s a recent study showing that the combination works really well with patients who have asymptomatic brain [metastases]. The intracranial response rate to ipilimumab plus nivolumab is actually similar to systemic response rate around 60%, but intracranial response rate to anti–PD-1 single agent is low, around 20%,” said Dr Hu-Lieskovan.

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The paper also showed that the combination treatment was particularly successful in patients with BRAF mutations, with 60% of patients surviving 5 years or more compared with 46% on nivolumab alone and 30% on ipilimumab alone. Without a BRAF mutation, 48% of patients survived 5 years or more compared with 43% and 25% on nivolumab or ipilimumab alone, respectively.

“A large question in the field right now is whether combined PD-1 plus CTLA-4 blockade is worth it, given the added toxicity and upfront cost, when compared to PD-1 blockade alone with nivolumab,” said Alexander Shoushtari, MD, medical oncologist specializing in melanoma at Memorial Sloan Kettering Cancer Center in New York City. “The results of this trial suggest that BRAF-mutated tumors might benefit from the addition of ipilimumab to nivolumab more than BRAF wild-type tumors,” he added.

Another important insight from the work was that patients who had to stop treatment due to intolerable toxicities, their outcome was just as good as those who stayed on the combination treatment for longer.