Photo courtesy of ASH
Philippe Armand, MD
SAN FRANCISCO—Two monoclonal antibodies that block the programmed death-1 (PD-1) pathway are showing promise in early phase trials in relapsed/refractory classic Hodgkin lymphoma (cHL).
Nivolumab prompted an 87% overall response rate (ORR) in heavily pretreated patients, and pembrolizumab elicited a 66% ORR in patients who had failed prior treatment with brentuximab vedotin.
These results were presented in 2 abstracts at the 2014 ASH Annual Meeting.
The rationale for using PD-1 blockade in cHL is that these patients frequently have an alteration in chromosome 9p24.1, which leads to increased expression of the PD-1 ligands, PD-L1 and PD-L2. The ligands engage the PD-1 receptors on activated T cells, inducing T-cell exhaustion. More than 85% of cHL tumors overexpress PD-L1.
Craig H. Moskowitz, MD, who presented the data on pembrolizumab at the meeting, sees nivolumab and pembrolizumab as being very similar.
“My gut feeling is that, at the end of the day, the response rates will be very similar,” he said. “The complete response rates will be similar. I think the toxicity profiles may be slightly dissimilar, and we’ll have to see what happens when these studies are both peer-reviewed.”
Nivolumab
Philippe Armand, MD, of Dana-Farber Cancer Institute in Boston, presented data on nivolumab in cHL (abstract 289), which was an independent expansion cohort of a phase 1b study in hematologic malignancies.
The 23 cHL patients received nivolumab at 3 mg/kg on weeks 1 and 4, then every 2 weeks.
Patients were a median age of 35 years (range, 20 to 54), and about two-thirds had received 4 or more prior systemic therapies. Seventy-eight percent had prior autologous stem cell transplant, and 78% had prior treatment with brentuximab.
“These were extensively pretreated patients” Dr Armand said, “with few options available.”
Twenty patients responded, for an ORR of 87%. Four patients (17%) achieved a complete response (CR), 16 (70%) had a partial response, and 3 (13%) had stable disease.
There were no progressions. And, at 24 weeks, the progression-free survival was 86%.
There were no life-threatening adverse events (AEs), no drug-related deaths, and no drug-related grade 4 AEs. Twenty-two patients (96%) experienced an AE, 18 (78%) had a drug-related AE, 5 (22%) had a grade 3 drug-related AE, and 2 (9%) patients discontinued treatment due to a drug-related AE.
The 2 events leading to discontinuation were myelodysplastic syndromes with grade 3 thrombocytopenia and grade 3 pancreatitis. The other grade 3 drug-related AEs were lymphopenia, increased lipase, GI inflammation, pneumonitis, colitis, and stomatitis.
“Overall, nivolumab has been used in thousands of patients already on clinical trials in solid tumors,” Dr Armand said. “And, overall, this safety profile mirrors that from what we expected in solid tumors.”
“But the interesting thing about that, from our standpoint, is that there was no apparent increase in the incidence of lung toxicity, which is something we worry about for those patients because many of them had had radiation or other drugs that can cause lung injury.”
This study was recently published in NEJM. It was funded by Bristol-Myers Squibb, the company developing nivolumab, and others.
Based on results of this study, the US Food and Drug Administration (FDA) granted nivolumab breakthrough therapy designation to treat HL. The drug recently gained FDA approval to treat advanced melanoma.
Pembrolizumab
Dr Moskowitz, of Memorial Sloan Kettering Cancer Center in New York, presented data on pembrolizumab as abstract 290.*
Investigators enrolled 31 patients onto the cHL cohort of the Keynote 013 trial. Patients were a median age of 32 years (range, 20 to 67).
All patients had failed therapy with brentuximab vedotin, 69% failed prior stem cell transplant, and 28% were transplant ineligible. Patients had to have an ECOG performance status of 0 or 1 and could not have autoimmune disease or interstitial lung disease.
Patients received 10 mg/kg of pembrolizumab intravenously every 2 weeks for up to 24 months or until progression.
Twenty-nine patients were evaluable for efficacy. The ORR was 66%, with a CR rate of 21% and a partial response rate of 45%. Twenty-one percent of patients had stable disease, and 14% had progressive disease. So the clinical benefit rate was 86%.
The median time to response was 12 weeks, and the median duration of response ranged from 1 to 185 days, but the median had not yet been reached.
Nine patients (31%) discontinued therapy, 1 (3%) due to an AE, 7 (24%) due to disease progression, and 1 (3%) after achieving a CR. Twenty patients (69%) were still on therapy at the time of the presentation, and 1 patient went on to transplant.
Sixteen patients (55%) experienced 1 or more treatment-related AE of any grade. Those occurring in 2 or more patients included hypothyroidism (10%), pneumonitis (10%), constipation (7%), diarrhea (7%), nausea (7%), hypercholesterolemia (7%), hypertriglyceridemia (7%), and hematuria (7%).
Treatment-related AEs of grade 3 or higher included axillary pain (3%), hypoxia (3%), joint swelling (3%), and pneumonitis (3%). Three patients experienced 4 grade 3 or higher AEs. There were no grade 4 treatment-related AEs or treatment-related deaths.
“In my opinion,” Dr Moskowitz concluded, “these results support continued development of pembrolizumab in Hodgkin lymphoma.”
“I think that these drugs are here to stay. Where we are going to put them in the armamentarium in Hodgkin lymphoma remains to be seen.”
This study was funded by Merck Sharp & Dohme Corp., the company developing pembrolizumab.
*Information in the abstract differs from that presented at the meeting.