Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab Feasible In Advanced Melanoma

Phase Ib findings suggest a role for standard-dose pembrolizumab given alongside reduced-dose ipilimumab for the treatment of patients with stage III-IV melanoma

medwireNews: The combination of pembrolizumab given at the standard dose and ipilimumab at a reduced dose is tolerable and has anti-tumour activity in patients with advanced melanoma, the KEYNOTE-029 results indicate.

In the open-label phase Ib trial, 153 patients with unresectable stage III or IV disease were given intravenous pembrolizumab 2 mg/kg alongside intravenous ipilimumab 1 mg/kg every 3 weeks for up to four doses, followed by pembrolizumab at the same dose for a maximum of 2 years.

Over a median follow-up of 17 months, 45% of participants experienced grade 3–4 treatment-related adverse events, with the most common being elevated lipase levels (16%), autoimmune hepatitis (6%), colitis (5%) and elevated amylase levels (4%).

As a result of such toxicities, 9% of patients discontinued the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab and 8% discontinued the cytotoxic T–lymphocyte-associated antigen 4 blocker ipilimumab, and an additional 14% stopped taking both medications.

Immune-mediated adverse events of grade 3 or 4 were reported in 27% of patients, with skin reactions (8%), colitis (7%) and hepatitis (6%) occurring most frequently, and led to the discontinuation of just pembrolizumab and just ipilimumab in 5% and 7% of patients, respectively, and of both study drugs in 9%.

No treatment-related deaths occurred during the course of the study.

Lead author Georgina Long, from the Melanoma Institute Australia in Sydney, New South Wales, and colleagues, who report the results in The Lancet Oncology, point out that the combination “was associated with higher toxicity than that reported for pembrolizumab or ipilimumab monotherapy.”

But the safety profile of this combination “compared favourably with that of reduced-dose nivolumab combined with standard-dose ipilimumab”, they say. The researchers note that 55% of patients receiving the latter combination in the KEYNOTE-067 trial experienced grade 3–4 treatment-related adverse events after a median 9 months of follow-up, compared with 45% over 17 months in their trial.

Writing in an accompanying commentary, Michael Postow, from the Memorial Sloan Kettering Cancer Center in New York, USA, interjects a note of caution. “Since this trial was not randomised, comparison of these results to other related studies is inherently difficult because of differing patient populations”, he says.

With regard to efficacy, 61% of study participants achieved an objective response, of which 15% were complete responses and 46% were partial. The estimated 12-month progression-free and overall survival rates were 69% and 89%, respectively.

Describing the objective response rate as “impressively high” and the efficacy results as “preliminarily encouraging”, the commentator points out, however, that the effect of ipilimumab on overall survival is known to be dose-dependent and that “this overall survival improvement was seen without an increase in obvious short-term efficacy, such as objective response.”

Therefore, longer-term follow-up than that currently reported and randomised data “will be needed to truly assess whether or not the reduced ipilimumab dose affects overall survival in combination with anti-PD-1 [treatment]”, Michael Postow writes.


Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol; Advance online publication 17 July 2017. doi:

Postow M. Reduced-dose ipilimumab with standard-dose pembrolizumab: is less more? Lancet Oncol; Advance online publication 17 July 2017. doi:

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