PD-1 Blockade Moves Into Hematology


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Philippe Armand, MD, PhD

Catherine M. Bollard, MBChB, MD

Craig H. Moskowitz, MD

Strategies that target tumor cells using the immune system are extremely exciting. I see this as a way forward in how we will revolutionize treatments in hematology.

—Catherine M. Bollard, MBChB, MD

The promise of the programmed death receptor-1 (PD-1) inhibitors seen in solid tumors, especially melanoma, may hold true for at least one hematologic malignancy, according to studies presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.

At a press briefing, data from phase I studies were presented for nivolumab1 and pembrolizumab (Keytruda)2 in patients with classical Hodgkin lymphoma who had shown disease progression on prior treatment. Response rates were 87% to single-agent nivolumab and 66% to pembrolizumab. The results provide strong evidence that drugs that enhance the ability of the immune system to fight cancer may work well in hematologic malignancies.

Press briefing moderator Catherine M. Bollard, MBChB, MD, bone and marrow transplant specialist at Children’s National Health System and the George Washington University in Washington, DC, commented, “Strategies that target tumor cells using the immune system are extremely exciting. I see this as a way forward in how we will revolutionize treatments in hematology.”

Nivolumab

The findings for nivolu­mab were presented by Philippe Armand, MD, PhD, of the Dana-Farber Cancer Institute in Boston. They were simultaneously published in The New England Journal of Medicine.3

“Nivolumab could be safely administered to patients with relapsed or refractory classical Hodgkin lymphoma. Treatment resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated,” Dr. Armand said at the press briefing.

The phase I study included 23 patients with classical Hodgkin lymphoma, almost all of whom had undergone at least three lines of therapy, including stem cell transplant and brentuximab vedotin (Adcetris); 35% had received at least six. Patients received nivolumab at 3 mg/kg every 2 weeks until tumor progression.

High Response Rates

Responses were observed in 87% of patients, including 100% of patients who had not undergone a stem cell transplant and 80% who did have a transplant but had not received brentuximab vedotin. Complete responses were observed in 17% overall, but in 60% of brentuximab vedotin–naive patients. The stable disease rate was 13%.

At 24 weeks, 86% of patients were progression-free. At the time of the data-lock, 48% of responses were ongoing, and 43% of patients were still on treatment. “We have patients in remission now for more than 1 year,” Dr. Armand said.

Grade 3 drug-related adverse events were observed in 22% of patients; there were no grade 4 events. Two patients (9%) discontinued treatment due to adverse events.

“Overall, nivolumab has been used in a thousand or so patients in clinical trials of solid tumors, and the safety profile here mirrors what those studies showed,” Dr. Armand said. “Interestingly, there was no apparent increase in lung toxicity, which we worry about because many patients had other treatments that can cause lung injury.”

The efficacy of nivolumab in this study prompted the U.S. Food and Drug Administration to designate the drug a “breakthrough therapy” for relapsed Hodgkin lymphoma, and a larger multinational phase II trial is underway.

The drug may be effective in these patients because they harbor genetic abnormalities in chromosome 9p24, which leads to overexpression of PD-1 ligands. Correlative studies showed that all the tumors in this study had this genetic profile. “Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade,” Dr. Armand concluded.

Pembrolizumab

The results of the KEYNOTE-013 study of pembrolizumab in patients who progressed after brentuximab vedotin treatment were presented by Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, New York.

The study evaluated 29 patients who received pembrolizumab 10 mg/kg every 2 weeks. More than half the patients had received at least five prior lines of treatment; all had received brentuximab vedotin, and two-thirds had undergone stem cell transplant.

Responses (all partial responses) were observed in 66% patients, including 75% who had received a transplant and 44% who did not. The median duration of response was not reached. “The waterfall plot was really quite good,” Dr. Moskowitz observed. “Almost all patients had some evidence of tumor shrinkage.”

Importantly, the clinical benefit rate (including stable disease) was 86%, he noted, indicating that this is an important outcome. “Many patients had stable disease on pembrolizumab. In fact, some who have been on treatment the longest had stable disease [ie, not an objective response],” he added. 

Grade 3 or higher treatment-related adverse events were rare and included axillary pain, hypoxia, joint swelling, and pneumonitis in one patient each. There were no grade 4 events or treatment-related deaths.

What’s Next?

When asked what will come next for these agents in Hodgkin lymphoma, Dr. Moskowitz commented, “They have high single-agent activity, but we would like to see how they play in the sandbox with our standard therapies.”  

The investigators agreed that the drugs are very similar, and the differences in response rates are more likely due to the biologic heterogeneity of the patients rather than differences in the drugs’ efficacy.  “My gut feeling is that at the end of the day, response rates will be similar, though toxicity profiles may be slightly dissimilar,” Dr. Moskowitz said. ■

Disclosure: Dr. Bollard reported honoraria from Cellmedica. Dr. Armand reported consultancy with Merck, research funding from Merck and Bristol-Myers Squibb. Dr. Moskowitz reported research funding from Merck. For full disclosures of the study authors, view the study abstracts at www.hematology.org.

References

1. Armand P, Ansell SM, Lesokhin AM, et al: Nivolumab in patients with relapsed or refractory hodgkin lymphoma: Preliminary safety, efficacy and biomarker results of a phase I study. ASH Annual Meeting. Abstract 289. Presented December 8, 2014.

2. Moskowitz CH, Ribrag V, Michot JM, et al: PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: Preliminary results from a phase 1b study (KEYNOTE-013). ASH Annual Meeting. Abstract 290. Presented December 8, 2014.

3. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. December 6, 2014 (early release online).



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