Pembrolizumab Survival Benefit Proves Durable in Patients With Advanced Melanoma

Anti–PD-1 Immunotherapy Improves Outcomes Regardless of Prior Treatment

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With new immunotherapies available for the treatment of advanced melanoma, an important question is how best to combine and sequence them. Long-term follow-up from the KEYNOTE-001 trial suggests that pembrolizumab (Keytruda) can improve survival in newly diagnosed patients and in those treated previously with ipilimumab (Yervoy).

At 36 months, 40% of patients with advanced melanoma treated with pembrolizumab were alive, and the overall survival rate was similar in both ipilimumab-treated patients and those who had not received prior ipilimumab.

Challenging Disease

“Advanced melanoma is still a very challenging cancer, which is why it is so remarkable that such a large proportion of patients see a long-term benefit from this therapy. These data support the use of pembrolizumab as a standard of care in patients with advanced disease regardless of prior treatment,” stated Caroline Robert, MD, PhD, Head of the Dermatology Unit at the Institut Gustave-Roussy, Paris. Dr. Robert presented these data at a press briefing held in advance of the 2016 ASCO Annual Meeting, where the new data will be presented (abstract 9503, being presented June 6, 2016).1

Advanced melanoma is still a very challenging cancer, which is why it is so remarkable that such a large proportion of patients see a long-term benefit from this therapy.
— Caroline Robert, MD, PhD

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Pembrolizumab is an anti–programmed cell death protein 1 (PD-1) antibody approved for the treatment of advanced melanoma regardless of prior treatment in more than 50 countries. In the KEYNOTE-002 trial, pembrolizumab achieved superior progression-free survival compared with chemotherapy in ipilimumab-refractory melanoma. In KEYNOTE-006, pembrolizumab proved to be superior to ipilimumab with regard to both overall and progression-free survival in advanced melanoma.

Study Details

KEYNOTE-001, a phase Ib trial, enrolled 655 patients treated in three different cohorts: pembrolizumab at 2 mg/kg every 3 weeks, pembrolizumab at 10 mg/kg every 3 weeks, or pembrolizumab at 10 mg/kg every 2 weeks. During the study, the optimal dose was deemed to be 2 mg/kg every 3 weeks. Patients were treated with pembrolizumab until disease progression, intolerable toxicity, or investigator decision.

At baseline, 24% were BRAF V600 mutation–positive, 78% had stage M1c disease, 38% had elevated lactate dehydrogenase, 75% had received more than one prior therapy, and 52% had been treated previously with ipilimumab.

At a median follow-up of 32 months, 358 patients (55%) had died. At 36 months, the overall survival rate was 40%, and the median overall survival was 24.4 months.

Survival rates differed somewhat based on prior melanoma therapy. The 3-year survival rate was higher among treatment-naive patients, at 45%. Three-year survival rates were the same among those previously treated with ipilimumab and those who were not (41% in both groups).

The average time on pembrolizumab therapy was 11.3 months. “Some patients have been on pembrolizumab for more than 3.5 years, and 21% of patients in the trial are still receiving it,” Dr. Robert said.

A total of 95 patients (15%) achieved a complete response. Among them, 61 (64%) stopped treatment after complete response. Median duration of treatment was 23 months, and response duration ranged from 17 to 43 months. Only 2 of the 61 patients who stopped treatment after complete response experienced disease progression. One of the two has been restarted on therapy, but it is too early to evaluate response, Dr. Robert said.

Further Considerations

Dr. Robert cautioned that this is only a single-arm, early-phase trial, but she noted that the encouraging survival data suggest that pembrolizumab is of benefit regardless of previous treatments.

Overall, pembrolizumab was well tolerated, with adverse events that were consistent with other clinical trials of this therapy. The most common treatment-related adverse events were fatigue (40%), pruritus (28%), and rash (23%). Only 8% of patients stopped pembrolizumab because of side effects.

In a matter of a few years, these [anti–PD-1] therapies have truly transformed the outlook for patients with melanoma and many other hard-to-treat cancers.
— Don S. Dizon, MD, FACP

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Don S. Dizon, MD, FACP, ASCO spokesperson and moderator of the press briefing, said: “These findings are incredibly exciting. It’s incredibly encouraging that we could potentially see a cure.”

He continued: “New therapies that block the PD-1 pathway are extending survival for many patients and, for some, may offer the prospect of living longer than ever after a diagnosis of advanced melanoma. In a matter of a few years, these therapies have truly transformed the outlook for patients with melanoma and many other hard-to-treat cancers.”

Pembrolizumab vs Nivolumab

During the question-and-answer session that followed the press briefing, Dr. Robert was asked whether there are differences between pembrolizumab and nivolumab (Opdivo) that would influence treatment selection. She replied that both immunotherapies were quite similar, with similar response rates and comparable types and rates of grade 3 adverse events.

“Pembrolizumab is given every 3 weeks, and nivolumab is given every 2 weeks The scientific basis for these intervals is not clear, and maybe this will be revisited. Honestly, I don’t see differences between these two drugs at this time,” she told listeners.

Role of Pembrolizumab in Melanoma

  • Pembrolizumab, an anti–PD-1 immunotherapy, improved long-term survival in patients with advanced melanoma.
  • Survival rates were similar in ipilimumab-treated and ipilimumab-naive patients, suggesting that pembrolizumab can extend survival in advanced melanoma regardless of previous treatments.

Although a large randomized trial would be needed to compare both drugs, she didn’t think that would be the most important area of study going forward. “It would be more exciting to look at combinations of immunotherapy,” she commented.

“The country, reimbursement status, and price of the drugs will affect the choice between them. Also, a patient who prefers a 3-week interval might choose pembrolizumab, whereas an individual who wants to be followed more closely might choose an every-2-week drug,” she pointed out. ■

Disclosure: The KEYNOTE trials are funded by Merck. Dr. Robert has been a consultant or advisor for Bristol-Myers Squibb, Roche, Merck, Amgen, Novartis, and GlaxoSmithKline. Dr. Dizon reported no potential conflicts of interest.


1. Robert C, Ribas AQ, Hamid O, et al: 3-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. 2016 ASCO Annual Meeting. Abstract 9503. To be presented June 6, 2016.