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Impressive response rates with new PD-1 inhibitors
VBCC - December 2014, Vol 5, No 10 - ASH 2014 Highlights
Wayne Kuznar

San Francisco, CA—Two programmed cell death receptor-1 (PD-1) inhibitors—the investigational drug nivo­lumab and the recently approved pem­bro­lizumab (Keytruda)—produced dramatic responses in patients with Hodg­kin lymphoma in phase 1 clinical trials. Complete or partial responses were reported by up to 87% of patients who had exhausted other treatment options, providing solid evidence that targeting the immune system can be effective in hematologic malignancies, similar to solid tumors. The data were presented at the 2014 American Society of Hematology meeting.

“Strategies that target tumor cells using the immune system are extremely exciting,” said Catherine M. Bollard, MBChB, MD, Blood and Marrow Transplant Specialist, Children’s National Health System, and Professor of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC. “I see this as a way forward in how we will revolutionize treatments in hematology.”

Nivolumab
Nivolumab was tested in 23 patients with Hodgkin lymphoma, 87% of whom had received previous treatment with at least 3 regimens, including stem-cell transplant and brentuximab vedotin (Adcetris). In all, 35% of the patients had received at least 6 previous regimens. All tumors had genetic abnormalities involving 9p24.1, leading to overexpression of the PD-1 ligands. Nivolumab 3 mg/kg was administered every 2 weeks until disease progression or severe toxicity.

“Treatment resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated,” said lead investigator Philippe Armand, MD, PhD, Senior Physician, Hematologic Malignancies, Dana-­Farber Cancer Institute, Boston.

Responses were seen in the 100% of patients who had not undergone a stem-cell transplant and in 80% who had a transplant but did not receive brentuximab. At an average of 40 weeks, the complete response rate was 17% overall, and 60% in brentuximab-naïve patients. Another 13% of patients had stable disease.

The progression-free survival rate was 86% at 24 weeks. At the time of data assessment, 48% of the responses were ongoing, and 43% of patients were still receiving treatment. Some patients have been in remission for >1 year, said Dr Armand.

The safety profile of nivolumab mirrored that in solid tumors. Overall, 22% of patients had grade 3 drug-related adverse events (AEs); no deaths or drug-related grade 4 AEs were reported. Two patients discontinued treatment as a result of AEs.

“There was no apparent increase in lung toxicity, which we worry about, because many patients had other treatments that can cause lung injury,” Dr Armand said.

In May of this year, the FDA granted nivo­lumab a breakthrough therapy designation for relapsed Hodgkin lymphoma.

Pembrolizumab
Pembrolizumab was evaluated in 29 heavily pretreated patients with classic Hodgkin lymphoma who had progressed after treatment with brentuximab vedotin. Craig H. Mosko­witz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, presented the results of the trial at the meeting.

The response rate was 66%, reported Dr Moskowitz, with complete responses in 21% of the patients and partial responses in 45%. Responses occurred in 75% of the patients with previous stem-cell transplant and in 44% of those who were transplant-ineligible or who had refused transplant.

The median time to response was 12 weeks, and the median duration of response was not reached. “Almost all patients had some evidence of tumor shrinkage,” Dr Moskowitz said.

The clinical benefit rate, which includes stable disease, was 86%. “Many patients had stable disease on pembrolizumab. In fact, some who have been on treatment the longest had stable disease,” he said.

Pembrolizumab 10 mg/kg was administered every 2 weeks until progressive disease, excessive toxicity, or the completion of 24 months of therapy. Overall, 52% of the patients had received at least 5 previous lines of treatment. All patients had previously failed therapy with brentuximab, and 69% had stem-cell transplant failure.

There were 4 treatment-related grade ≥3 AEs—1 patient each with axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 AEs or treatment-related deaths.

Pembrolizumab and nivolumab have individually demonstrated single-­agent activity in patients with Hodgkin lymphoma, said Dr Moskowitz, commenting on these results. He noted that future evaluations in combination with standard therapies, or even as maintenance treatment to enhance the posttransplant immune response will be important.

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Last modified: December 23, 2014
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