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Pembrolizumab superior to ipilimumab in advanced melanoma

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October 3, 2017

Patients with advanced melanoma treated with pembrolizumab demonstrated higher 2-year survival rates than those treated with ipilimumab, according to long-term follow-up of the KEYNOTE-006 study.

Further, patients derived greater survival benefit from pembrolizumab (Keytruda, Merck) with fewer grade 3 to grade 4 treatment-related adverse events than with ipilimumab (Yervoy, Bristol-Myers Squibb).

“The final analysis showed that pembrolizumab treatment resulted in twice the percentage of patients alive and without disease progression compared with ipilimumab,” Jacob Schachter, MD, director of the Ella Institute for Treatment and Research of Melanoma at Sheba Medical Center in Israel, and colleagues wrote.

The analysis included 834 patients from 87 academic cancer centers around the world. Researchers randomly assigned patients 1:1:1 to receive 10-mg/kg doses of pembrolizumab every 2 weeks (n = 279) or every 3 weeks (n = 277), or 3-mg/kg ipilimumab every 3 weeks for four doses (n = 278).

Pembrolizumab treatment continued for 2 years or until disease progression, intolerable toxicity or patient/investigator decision to discontinue. Patients could discontinue pembrolizumab treatment after 6 months of therapy with complete response and if multiple RECIST v1.1 scans supported the response.

Researchers performed tumor imaging at 12 weeks then every 6 weeks up to 48 weeks and every 12 weeks thereafter.

OS served as the primary endpoint of the final analysis.

A total of 811 patients (median age, 62 years) received treatment.

The median time on treatment was 28.1 weeks (range, 0.1-108.1) for patients who received pembrolizumab every 2 weeks; 24 weeks (range, 0.1-111.1) for pembrolizumab every 3 weeks; and 9 weeks (range, 0.1-13.1) for ipilimumab.

The median follow-up was 22.9 months; researchers followed all patients for a minimum of 21 months.

At the Dec. 3, 2015 data cutoff, 383 patients had died. Fifty-two patients who received pembrolizumab every 2 weeks and 38 who received pembrolizumab every 3 weeks remained on treatment.

Median OS was not reached among patients treated with pembrolizumab and was 16 months for those treated with ipilimumab. Researchers reported HRs for OS of 0.68 (95% CI, 0.53-0.87) for pembrolizumab every 2 weeks, and 0. 68 (95% CI, 0.53–0.86) for every 3 weeks.

Fifty-five percent of patients in both pembrolizumab groups achieved 2-year OS, compared with 43% of patients assigned ipilimumab.

Median PFS was 5.6 months (range, 3.4-8.2) among patients who received pembrolizumab every 2 weeks, 4.1 months (range, 2.8-2.98) for every 3 weeks and 2.8 months (range, 2.8-2.9) for ipilimumab.

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Researchers reported objective response rates of 37% (95% CI, 31-43) among patients treated every 2 weeks, 36% (95% CI, 30-42) among patients every 3 weeks and 13% (95% CI, 10-18) among patients treated with ipilimumab. This included complete response rates of 12% among patients treated every 2 weeks, 13% for every 3 weeks and 5% for ipilimumab. Partial response occurred among 25% of patients treated every 2 weeks, 23% for patients every 3 weeks and 8% for ipilimumab.

Researchers observed no differences in response rates between pembrolizumab schedules.

Grade 3 to grade 4 treatment-related events occurred more frequently within the first 18 weeks among patients treated with ipilimumab. Grade 3 to grade 5 toxicities occurred in 17% of both pembrolizumab groups and 20% of the ipilimumab group.

These findings highlight the advantages of pembrolizumab over ipilimumab, according to Kilian Wistuba-Hamprecht, PhD student in the department of dermatology at University Medical Centre Tuebingen, Centre for Medical Research in Germany, and Graham Pawelec, MA, PhD, professor of experimental immunology in the department of internal medicine at University Medical Centre Tuebingen and cancer solutions consultant at Health Sciences North Research Institute in Ontario, Canada.

“Given the substantiated superiority of pembrolizumab over ipilimumab, it is reasonable to ask whether the use of ipilimumab should be discontinued,” Wistuba-Hamprecht and Pawelec wrote in a related editorial. “Mitigating against doing so are the promising results now being reported for combined treatment with both CTLA-4 and anti-PD-1 antibodies.”

Combined ipilimumab and nivolumab (Opvido, Bristol-Myers Squibb) yielded better PFS and ORR compared with either drug alone, they added.

The evaluation of combined pembrolizumab and ipilimumab is ongoing in phase 1 clinical trials.

However, toxicities may be higher with combination therapy.

“The main task for the future will be to better understand the mechanisms that underlie checkpoint inhibition with different antibodies against other targets, and to predict which patients will respond best to each regimen,” they wrote. – by Melinda Stevens

Disclosures: Schachter reports personal fees from Bristol-Myers Squibb and Merck Sharp & Dohme outside of the study. Please see the full study for a list of all other authors’ relevant financial disclosures. Wistuba-Hamprecht and Pawelec report no relevant financial disclosures.

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