PD-1 blockade in advanced melanoma
medwireNews: The safety and efficacy of the programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab in patients with melanoma formed a key part of the Melanoma and Skin Cancer proffered paper session at the European Cancer Congress in Vienna, Austria. This report summarises two presentations from the session.
Improved efficacy with sequential nivolumab, ipilimumab compared with ipilimumab followed by nivolumab in advanced melanoma
F Stephen Hodi (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) presented the results of the phase II CheckMate 064 trial  of sequential nivolumab followed by ipilimumab versus treatment with ipilimumab then nivolumab in patients with unresectable stage III or IV melanoma. In both treatment arms, the second drug was followed by nivolumab therapy until disease progression or unacceptable toxicity.
At week 25, the objective response rate was 41.2% for the 68 patients who received nivolumab first and 20.0% for the 70 who received ipilimumab first. This was consistent with the progression rates, said Hodi, which were a corresponding 38.2% and 60.0%.
Overall during the induction periods, treatment-related side effects of at least grade 3 occurred in 50.0% and 42.9% of participants in the nivolumab first and ipilimumab first treatment arms, respectively. And there were no treatment-related deaths.
When the treatment periods were considered individually, the incidence of high-grade toxicity was lower in the nivolumab first than in the ipilimumab first group during the first induction period (7 vs 24%), but higher during the second induction (52 vs 28%) and the continuation period (38 vs 22%).
Hepatic adverse events of grade 3 or above were more common in patients given nivolumab first compared with those treated with ipilimumab first, at 15% versus 4%.
Hodi concluded that their study findings “may help inform the choice of initial treatment approaches in advanced melanoma.”
Caroline Robert, from the Institut Gustave Roussy in Paris, France, who discussed the study expressed her surprise and disappointment at the findings. She noted that the response rates in this study were not too different from those reported in the monotherapy arms of the recent Larkin et al  trial that compared concurrent nivolumab and ipilimumab with nivolumab alone and ipilimumab alone in advanced melanoma.
And considering the response rates together with the safety data, Robert said that she “did not see a clear benefit” for the sequential design, but added that the study encourages us to consider different trial profiles, including using a lower dose of ipilimumab or giving the drugs intratumourally.
T-VEC plus pembrolizumab well-tolerated in stage IIIb, IV melanoma
Georgina Long (University of Sydney, New South Wales, Australia) presented preliminary safety findings from the phase Ib part of the MASTERKEY-265 study  in which 21 previously untreated patients with unresectable stage IIIb or IV melanoma were given the oncolytic virus talimogene laherparepvec (T-VEC) plus pembrolizumab.
Study participants initially received just T-VEC by intralesional injection for 5 weeks before the addition of pembrolizumab on day 36. All patients were followed up for a minimum of 6 weeks from when the first dose of T-VEC plus pembrolizumab was delivered. And no dose-limiting toxicities were observed during this period. Moreover, at the time of this analysis, 19 patients were continuing treatment with both agents, while one was receiving pembrolizumab alone, having discontinued T-VEC as there were no remaining injectable lesions. The remaining patient died during the course of the study owing to progressive disease.
“All patients had at least one adverse event, regardless of attribution”, said Long, adding that the most common treatment-related toxicity of any grade was rash (43%), which is higher than the rates reported with single-agent T-VEC or pembrolizumab. Pyrexia, fatigue and chills of any grade were also common, occurring in 43%, 38% and 33% of participants, respectively. And four patients reported grade 3 adverse events, including anaemia, hyperglycaemia, macular and generalised rash, and headache.
The dual therapy was well-tolerated and as such “warrants further investigations”, the speaker concluded. She added that they will be presenting efficacy data later in the year.
The discussant Dirk Schadendorf, from University Hospital Essen in Germany, remarked that T-VEC, with its “unique mode of action”, is interesting, but previous studies have shown that its systemic effects are not sufficient to cure patients.
He also said that T-VEC requires the presence of injectable lesions, and these are found in just 20–30% of patients.
But Schadendorf concluded that the efficacy data for the combination therapy are awaited.
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1. Hodi FS, Gibney G, Sullivan R, et al. An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064). Presented at: European Cancer Congress; Vienna, Austria: 25–29 September 2015; 23LBA
2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23–34
3. Long G, Dummer R, Ribas A, et al. Safety data from the phase 1b part of the MASTERKEY-265 study combining talimogene laherparepvec (T-VEC) and pembrolizumab for unresectable stage IIIB--IV melanoma. Presented at: European Cancer Congress; Vienna, Austria: 25–29 September 2015; 24LBA