January 2015, Vol. 2, No. 1
Will PD-1 Blockers Have a Role in Hematologic Cancers?
The checkpoint inhibitors – the anti-CTLA-4 agent ipilimumab and the PD-1 blockers nivolumab and pembrolizumab (with others coming) – have shown promise in multiple solid tumors and are showing hints of activity in hematologic malignancies as well. But according to early research, their use in hematology may be somewhat more limited.
At a special session devoted to these emerging agents, Stephen Ansell, MD, of the Mayo Clinic, Rochester, MN, declared immune therapies “the new frontier” in cancer. “It holds real promise, and it’s only the beginning of a new wave.”
Checkpoint inhibitors are “taking the brakes off the immune system,” blocking signals that keep T cells from attacking tumors and correcting the unfavorable environment that keeps T cells suppressed, he explained.
Ronald Levy, MD, of Stanford University, Stanford, CA, noted that pharmaceutical companies are rapidly taking advantage of “the plethora of targets” described by immunologists. “Each target and antibody is the subject of a clinical development path for a number of companies,” he said. “The future holds an amazing array of new drugs that will unleash the T-cell immune response that’s always been lurking there.”
“Ipilimumab and PD-1 blockers are the subject of enormous excitement, and they are not redundant, so we may be able to combine them for enhanced effect. We are already seeing responses, dramatically so, in ways we could not have predicted,” he noted.
But Levy doubted that checkpoint inhibitors will have a prominent place in the treatment of most hematologic malignancies based on lackluster responses observed in most tumor types. Instead, he predicted their benefit may be reserved for a malignancy, Hodgkin lymphoma, that is tailor-made for the mechanism of action of these drugs. In this cancer, the results were, he said, “amazing.”
For example, in a phase 1 study of the CTLA-4 inhibitor ipilimumab in 13 patients who progressed after allogeneic transplant and a median of 7 prior therapies, the clinical benefit rate was 36% (Abstract 3964). The 1 responder had Hodgkin lymphoma. Three patients with lymphoid malignancies achieved stable disease. The most impressive finding was the lack of acute graft-
versus-host disease, he said.
And in a phase 1 study of the PD-1 blocker nivolumab in 54 patients with relapsed/refractory lymphoid malignancies, the overall response rate was 28% in B-cell lymphomas and 17% in T-cell lymphomas. There were no responses in multiple myeloma patients (Abstract 291).
“If we are looking for an efficacy signal, I don’t think we are blown away by this,” he suggested.
“Amazing” Results in Hodgkin Lymphoma
In contrast to these results, nivolumab and pembrolizumab made an impressive showing in Hodgkin lymphoma, a disease in which there is increased PD-1 ligand expression. “Here, we have a perfect situation for PD-1 blockade to work,” he said. “We have a target that is overexpressed by the tumor cells. When we take the brakes off the interaction between the PD-L1 ligand and the T cells, amazing things happen.”
In a phase 1 trial of nivolumab in 23 patients with relapsed/refractory Hodgkin lymphoma, the objective response rate was 87%, and 17% of these were complete responses (Abstract 289). The responses were durable; at 24 weeks, progression-free survival was 86%. A similar study of pembrolizumab in 15 patients (Abstract 290) confirmed the effectiveness of blocking this interaction, he said.
But there is still an obstacle for PD-1 blockers to be breakthrough drugs, even in Hodgkin lymphoma. “The problem is that lots of Hodgkin lymphoma patients are cured already” with standard therapies, he pointed out.
“If we use PD-1 blockers only in relapsed/refractory patients, that’s a small use of these drugs. How to move this very active regimen up front in competition with all our other treatments, in a disease that we already treat very successfully, will be an interesting challenge,” he said.
Administration of T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) persist over the long term and induce durable remissions in children with relapsed/refractory acute lymphocytic leukemia (ALL). Complete responses were achieved in 92% of recipients of CTL109 cells who were enrolled in a phase 1/2a study, [ Read More ]
On September 4, 2014, the FDA approved pembrolizumab for use in advanced or unresectable melanoma following progression on prior therapies. This approval was based on clinical data from the phase 1b KEYNOTE-001 trial and made pembrolizumab the first anti–PD-1 antibody to gain approval in the United States for any solid [ Read More ]