Use of anti-programmed death 1 (PD-1) monoclonal antibodies, including pembrolizumab (Keytruda, Merck), in the treatment of advanced melanoma has, to much acclaim, changed the management of the disease. But the downside of the data is that most patients do not respond to treatment, a pooled analysis of an early-phase study confirms.
Of 581 patients with measurable disease at baseline, 194 patients, or 33% of the overall cohort, achieved an objective response to several different dosing regimens of pembrolizumab, Antoni Ribas, MD, PhD, from the University of California, Los Angeles, and his colleagues report in their analysis, published in the April 19 issue of JAMA.
Similarly, 60 of 133 patients (45%) who were treatment-naïve at baseline achieved an objective response, defined as either a complete or partial response.
The numbers, which come from the KEYNOTE-001 phase 1 study of pembrolizumab, indicate that a majority of patients are nonresponders.
Furthermore, only 8% of the patients achieved a complete response.
"Despite the clinical benefit in the responding subgroup, the overall efficacy results...point to the limitations of anti-PD-1 monotherapy in treatment of patients with advanced melanoma," Shailender Bhatia, MD, and John Thompson, MD, both from the Fred Hutchinson Cancer Research Center in Seattle, write in an accompanying editorial.
Median progression-free survival was only 4 months (range, 4.1 - 6.9 months) in the study, they point out, and at 12 months, the progression-free survival rate was 35%.
"This suggests failure of the host immune system to adequately control melanoma tumors in two-thirds of all patients within the first year," Drs Bhatia and Thompson write.
"Even among the responders, disease progression was observed in 26% of patients," they add.
Still, the editorialists are encouraged by this class of therapy.
"Although most patients may not experience the ideal outcome of durable complete remission with current regimens, these immune checkpoint blocking agents provide hope for patients and represent a solid foundation for future research."
The first cohort consisted of 135 patients with advanced melanoma — 87 who had not previously received ipilimumab and 48 who had — who were assigned to sequential, nonoverlapping, regimens. Treatment consisted of pembrolizumab 2 mg/kg every 3 weeks or pembrolizumab 10 mg/kg every 2 or every 3 weeks until disease progression
The second cohort involved 520 patients with the same diagnosis who were randomized to one of three groups: 226 ipilimumab-naïve patients received pembrolizumab — 2 or 10 mg/kg — every 3 weeks until disease progression, as did 294 patients previously treated with ipilimumab, and a mixed group of ipilimumab-naïve and ipilimumab-treated patients received pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks.
Overall, 35% of the patients were free of disease progression at 12 months, as were 52% of those who received pembrolizumab as their initial treatment, Dr Ribas reported.
Median overall survival was 23 months, but for patients who received pembrolizumab as their initial therapy, it was 31 months.
At 12 months, almost two-thirds of the overall cohort was still alive; at 24 months, almost half were still alive. In the treatment-naive cohort, 73% were alive at 12 months and 60% were alive at 24 months.
Investigators detected no real differences in antitumor activity among the various treatment doses and schedules.
However, they did find that smaller median tumor size at baseline was associated with higher objective response rates to pembrolizumab. Specifically, those with a baseline tumor burden below the median had an objective response rate of 43%, regardless of whether or not they had previously received ipilimumab.
In the 510 patients with both measurable disease at baseline and at least one tumor measurement after baseline, 71% exhibited some decrease in their target lesions (median decrease, 36%), Dr Ribas and colleagues report.
In the smaller group of 121 treatment-naive patients with both measurements, 79% had a decrease in tumor size (median decrease, 54%).
Still, Much Better Than in the Past
"Pembrolizumab was generally well tolerated, without clear evidence of a dose- or regimen-related increase in toxicities," Dr Ribas pointed out.
There was also no difference in the toxicity profile between patients who had previously been treated with ipilimumab and those who had not. The median duration of treatment was 24 weeks, and the most common toxicities related to treatment were fatigue, pruritus, and rash.
Treatment was discontinued because of adverse events in 4% of patients.
It is important to celebrate the good news that these immune checkpoint inhibitors have brought to the treatment of advanced melanoma, when previously there were only rare responses to interleukin-2, Dr Thompson told Medscape Medical News.
"We've had follow-up now out to almost 10 years in some patients treated with ipilimumab, and some patients do achieve durable remission," he explained.
Follow-up for patients treated with pembrolizumab is approaching 5 years, he added, and an estimated 35% to 40% of patients who have received the PD-1 antibody are still alive at 5 years.
"This is a lot better than the statistics we quoted 10 years ago, so the first positive point is that remissions to immune checkpoint inhibitors can be durable," he said.
It will be important to delve into the biology of melanoma and determine why some patients do not respond to this class of agent.
Currently, a number of researchers are evaluating biomarkers in the hopes of identifying patients who are likely to respond to these agents. Tumors that stain positive for PDL-1, for example, have a higher likelihood of responding to PD-1 inhibitors. This can help physicians more easily determine which patients are likely to respond.
Efforts are also being made to identify gene-expression profiles of melanoma tumors to predict which tumors will respond.
"Certain melanomas have gene-expression patterns that make a tumor a 'cold' tumor," Dr Thompson explained. "It's not inflamed so it doesn't elicit immune cells to move into the tumor to attack the melanoma."
"As a consequence, the PD-1 antibodies are not very effective in such tumors," he added.
However, it might be possible to turn a cold tumor into a hot, or inflamed, one.
"And if we can do that successfully, the tumor would hopefully be responsive to the PD-1 inhibitors," Dr Thompson said.
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