PD-1 Inhibitors Effective in Hodgkin Lymphoma

Two immunotherapy drugs are showing promise for treating patients with Hodgkin lymphoma (HL) who failed to respond to other therapies, according to results from phase I trials presented at the annual meeting of the American Society of Hematology in San Francisco, CA, in December.

Both studies tested programmed death 1 (PD-1) inhibitors in patients with classic HL. In one trial of 23 patients who received nivolumab (Opdivo; Bristol-Myers Squibb), the objective response rate was 87%, with 17% achieving a complete response and 70% a partial response; the remaining 13% had stable disease (N Engl J Med 2014 December 6 [Epub ahead of print]). In another trial of 29 patients treated with pembrolizumab (Keytruda; Merck), the overall response rate was 66%, with 21% achieving a complete response and 45% a partial response after 12 weeks (available at https://ash.confex.com/ash/2014/webprogram/Paper75615.html).

About half of the responses seen in the nivolumab trial occurred within 8 weeks of starting treatment, says Philippe Armand, MD, PhD, an oncologist at Dana-Farber Cancer Institute in Boston, MA, and senior author of the study. While the median overall survival had not yet been reached, 48% of patients were still in remission at the time the data were analyzed, some for over a year.

“Most patients have had ongoing responses but it's too early to get a sense of durable responses,” says Armand. “At the time of data lock, one patient was still in complete remission without any further treatment, but we still don't know how long the effects will last or whether you can stop the drug at some point.”

Based on the study results, the FDA designated nivolumab as a breakthrough therapy for HL, and a large phase II study is under way. In December, the drug received FDA approval for inoperable or advanced melanoma.

In the pembrolizumab trial, some patients who did not achieve complete or partial response experienced stable disease, notes first author Craig Moskowitz, MD, clinical director of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center in New York, NY. Twenty of the 29 patients are still undergoing treatment.

“Almost all patients had evidence of tumor shrinkage,” says Moskowitz. “Including patients with stable disease, we saw a clinical benefit rate of 86%.”

Classic HL frequently harbors amplification of chromosome 9p24.1 that leads to increased expression of PD-L1 and PD-L2, which then engage the PD-1 receptor to temporarily shut down the immune response, says Armand.

“When we analyzed 10 patient biopsies,” says Armand, “all of the tumors had this genetic amplification and increased expression of ligands PD-L1 and PD-L2, which seems to be the basis for vulnerability to PD-1 blockade in these patients.”

Pembrolizumab has been approved for metastatic melanoma and has shown promise for treating other cancers.

Overall, the results suggest that PD-1 inhibitors should be tested in patients with other types of lymphoma, such as large cell lymphoma, says Moskowitz.

“The safety profile of these drugs is quite good, with very little grade 3 or 4 toxicity,” he says. “Our results should encourage continued research with PD-1 inhibitors for a variety of patients with HL.”

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