Pembrolizumab Works in Melanoma After Ipilimumab

Zosia Chustecka

July 23, 2014

The investigational programmed death (PD) inhibitor pembrolizumab (MK-3475, Merck & Co), which has produced results in melanoma that have been described as "pretty darned impressive," has also been shown to work in patients with advanced disease who have stopped responding to ipilimumab (Yervoy, Bristol-Myers Squibb). These patients currently have few therapeutic options, and use of pembrolizumab in this patient population could be the first approved indication for this product.

An application for US Food and Drug Administration approval for pembrolizumab use in patients with advanced melanoma previously treated with ipilimumab has been granted priority review by the agency, with an action date of October 28.

The drug is also awaiting approval in Europe.

Results showing efficacy in this patient population, in a total of 173 patients with ipilimumab-refractory disease, were published in the July 15 issue of the Lancet.

The results "are another important advance in the rapidly evolving landscape of cancer immunotherapy," comment experts in an accompanying editorial.

Treatment of melanoma has never been this promising.

They "add to the burgeoning literature on the potential of PD-1 blockade to improve outcomes in patients with metastatic melanoma," write the editorialists, Shailender Bhatia, MD, and John Thompson, MD, from the University of Washington and the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center. "Treatment of melanoma has never been this promising," they comment.

Pembrolizumab is one of a few investigational PD inhibitors under development that have shown highly promising results in melanoma and are also being investigated in many other cancer types, generating particular excitement in lung cancer. The other products include nivolumab (Bristol-Myers Squibb/Ono), which has recently been approved in Japan for use in melanoma, and also MPDL-3280A (Roche/Genentech/Chugai) and MED14736 (AstraZeneca/MedImmune).

Results in Refractory Patients

The results for pembrolizumab in refractory melanoma come from an expansion cohort of the phase 1 KEYNOTE-001 study, which was funded by the manufacturer (Merck & Co). This study initially enrolled 135 patients with nonrefractory melanoma and 48 patients who had previously been treated with ipilimumab. Encouraging results, reported last year (N Engl J Med. 2013;369:134-144), led the researchers to expand the study.

The expansion cohort now being reported, by an international group of authors led by Caroline Robert, MD, from the Gustave-Roussy Institute in Paris, comprised patients with advanced melanoma who had progressed on ipilimumab (178 patients enrolled, 173 treated). This cohort included 31 patients (18%) who tested positive for BRAF mutations, and who had also been also been treated with a BRAF inhibitor (dabrafenib; Tafinlar, GlaxoSmithKline) and vemurafenib (Zelboraf, Roche) or a MEK inhibitor (trametinib; Mekinist, GlaxoSmithKline), or both. For these patients there is currently no effective treatment, the researchers note.

All patients received treatment with pembrolizumab, either at a dose of 2 mg/kg or 10 mg/kg, administered ever 3 weeks by an intravenous infusion lasting 30 minutes. Treatment continued until disease progression, intolerable toxicity, or consent withdrawal.

The 2 doses of the drug had a "similar substantial anticancer activity," the researchers note.

The overall response rate (ORR) was 26% at both doses, and the responses were long lasting, with 88% of responses ongoing at the time of analysis, at a median follow-up of 8 months.

This long-lasting response is similar to what has been reported with other immunotherapies, the researchers comment.

These immunotherapies can also have a delayed response, and previous studies with pembrolizumab have shown cases in which the initial response was seen after 11 months, and complete responses occurring at 16 months.

This delayed response may explain why in this study there was only a 1% complete response rate at the 8-month analysis. "With additional follow-up, it is possible that there will be more complete responses," the authors comment.

The Kaplan–Meier estimates for progression-free survival at 24 weeks were 45% for the 2 mg/kg group and 37% in the 10 mg/kg group, and the estimates for overall survival at 1 year were 58% in the 2 mg/kg group and 63% in the 10 mg/kg group.

Overall, the responses to pembrolizumab in this population of patients with refractory melanoma are lower than those previously reported for pembrolizumab in melanoma patients who were treatment-naïve or had not previously received ipilimumab, the researchers note. They are in line with those reported with nivolumab in ipilimumab-treated melanoma patients, they add.

But there was efficacy in this patient population, they note, and they conclude that pembrolizumab "could be an effective treatment option for patients with ipilimumab-refractory advanced melanoma, a population for whom there are few effective treatment options."

The editorialists add that the latest results confirm that PD inhibition is a distinct therapeutic approach from that of CTLA-4 blockade (the mechanism of action of ipilimumab), even though both are immunotherapies and immune checkpoint inhibitors. "The lack of durable benefit with ipilimumab does not seem to preclude benefit from subsequent PD-1 blockade, which shows non-cross-resistant potential of these immune therapies for improving outcomes in patients with metastatic melanoma," Dr. Bhatia and Dr. Thompson write.

Small Subgroup of BRAF-mutant Melanoma Patients

The researchers note that for the small subgroup (18%) of patients who had progressed on ipilimumab and also had BRAF-mutant melanoma and had previously been treated with BRAF and/or MEK inhibitors, the response rate appeared to be lower than that seen in the remainder of the cohort. The ORR was 19% in the BRAF-mutant subgroup compared with 28% in the rest of the patients. However, they note that the 95% confidence intervals for these subgroups overlapped, and also because of the small numbers involved, these findings should be interpreted with caution.

The editorialists also urge caution; the responses to pembrolizumab in this small patient subgroup "seem encouraging, but the small number of patients (n = 31) does not allow a conclusive assessment." It also may be that rapid progression of disease after development of resistance to BRAF or MEK inhibitors could compromise performance status or organ function or both, which would preclude further immunotherapy, they add.

Pembrolizumab Generally Well Tolerated

Pembrolizumab was "generally well tolerated," and the overall safety profiles were similar for the 2 doses, Dr. Robert and colleagues report. The most common drug-related adverse events of any grade were fatigue, pruritus, and rash. Grade 3 or 4 adverse events considered to be immune-related occurred in 3 patients, and included autoimmune hepatitis, maculopapular rash, and pancreatitis. In addition, grade 3 or 4 adverse events considered to be drug-related and of "special interest" included diarrhea, hypophysitis, pneumonitis, and rash. In total, 4 patients discontinued because of these adverse events.

"Potentially immune-mediated adverse events were generally manageable with treatment interruption and corticosteroid treatment," the researchers comment.

Dr. Robert reports serving as an adviser for Merck, as well as other pharmaceutical companies, as have several of the coauthors. Six of her coauthors are employees of Merck. Dr. Bhatia and Dr. Thompson have conducted research that has been funded by Merck.

Lancet. Published online July 15, 2014. Abstract, Editorial


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