Efficacy and Safety of Combination Pembrolizumab and Reduced-Dose Ipilimumab for Patients With Advanced Melanoma

Jeffrey S. Weber, MD, PhD


February 22, 2018

Hello. This is Dr Jeffrey Weber, medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center in New York City.

Today I would like to discuss a paper by Georgina Long and colleagues,[1] recently published in Lancet Oncology, which describes the results of an open-label phase 1/2 clinical trial (KEYNOTE-029) of 153 patients with metastatic melanoma who had not previously received immunotherapy and were treated with a novel regimen of pembrolizumab at the then-standard dose of 2 mg/kg every 3 weeks and with the addition, for the first four induction doses, of ipilimumab, the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody, at a dose of 1 mg/kg—a relatively low dose of ipilimumab compared with that used in Bristol-Myers Squibb's CheckMate 067 trial,[2] which led to the approval of that regimen.

In the current KEYNOTE-029 study,[1] a total of 153 patients were given pembrolizumab and low-dose ipilimumab, with a median follow-up of 17 months. Interestingly, a very high proportion of patients (72%) received all four doses of the induction therapy, and 42% of the patients went on to receive maintenance therapy. Only about 14% of patients discontinued therapy due to treatment-related adverse events, and the rate of grade 3/4 immune-related adverse events was relatively favorable at 27%, which is about half of what we see when we use the higher dose of ipilimumab with nivolumab in the regimen described in the CheckMate 067 trial.[2]

Interestingly, in the KEYNOTE-029 trial, hypothyroidism occurred in about 16% of patients (which suggests to me that the investigators were really monitoring patients for this by frequently checking thyroid function) and hyperthyroidism in 11% of patients.[1] With the checkpoint inhibitors, patients often develop hyperthyroidism, then a classically burned-out thyroid that leads to hypothyroidism, so there may have been a significant overlap between those two.

The good news is that the clinical efficacy data in this trial were outstanding. The response rate was a robust 61%; the estimated 1-year overall survival was 89%, and the estimated 1-year progression-free survival was 69%.[1] These are very good numbers that compare quite favorably to the use of a more toxic regimen of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg during the four-dose induction, because there is a median relapse-free survival of about 11.5 months, which, of course, would compare favorably with an estimated median progression-free survival of 69% in the current KEYNOTE-029 trial.[1]

The survival at 1 year in the CheckMate 067 study was in the 80%-85% range,[2] which again is quite similar to the estimated 1-year survival of 89% in the current KEYNOTE-029 trial.[1] All in all, putting it together, this suggests that what we call flip-dose ipilimumab and PD-1 (programmed cell death-1) blockade—this time, of course, with pembrolizumab instead of nivolumab—appears to be a very useful regimen with a robust response rate and very good initial efficacy numbers. Of course, in the CheckMate 067 trial we have 3-year survival data that have just been updated in the New England Journal of Medicine by Wolchok et al,[3] and in the current KEYNOTE study we do not have very long follow-up; as I indicated, median is only about 17 months. However, these are very encouraging data, and the study will go on to a phase 2 trial comparing various doses and schedules of both pembrolizumab and ipilimumab.

Again, this is Dr Jeffrey Weber reporting. Please feel free to send your comments and questions. Thank you very much for your attention.


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