January 2015, Vol. 2, No. 1
PD-1 Inhibitor–Based Immunotherapy the Newest Breakthrough in Hodgkin Lymphoma
Two PD-1 inhibitors – the investigational drug nivolumab and the recently approved pembrolizumab – 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.
“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 was tested in 23 patients with Hodgkin lymphoma, 87% of whom had received previous treatment with at least 3 regimens, including stem cell transplantation and brentuximab vedotin. 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, MA.
Responses were seen in 100% of patients who had not undergone stem cell transplantation 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-naive 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 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 because 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,” Armand said.
In May 2014, the FDA granted nivolumab breakthrough therapy designation for relapsed Hodgkin lymphoma.
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 City, presented the results of the trial at the meeting.
The response rate was 66%, reported Moskowitz, with complete responses in 21% of the patients and partial responses in 45%. Responses occurred in 75% of the patients who had undergone previous stem cell transplantation and in 44% of those who were transplant-ineligible or who had refused a 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,” 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 disease progression, 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 activity in patients with Hodgkin lymphoma, said 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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