Checkpoint Inhibitors in Hematologic Cancers: An Overview From ASH 2015

Theodore Bosworth

Disclosures

January 25, 2016

When immune checkpoint inhibitors receive regulatory approval for the treatment of hematologic cancers, which appears very likely, their efficacy may in many cases be tied to an additional therapy.

Immune checkpoint inhibitors are monoclonal antibodies that block proteins, called "checkpoints," expressed by tumor cells to inhibit the immune response. The development of this therapy for hematologic cancers has lagged behind that of solid tumors, but new data at the 2015 ASH annual meeting suggest the promise may be similar.

In solid tumors, several checkpoint inhibitors have now been granted regulatory approval for single-agent use in advanced disease. The most recent approvals, granted to both nivolumab and pembrolizumab, were for single-agent use in advanced non-small cell lung cancer. As yet, no checkpoint inhibitor has been granted an indication for a hematologic cancer or lymphoproliferative disorder, but it appears that at least some of the approvals, when they are granted, will be for a checkpoint inhibitor in combination with a second agent.

In multiple myeloma, for example, the activity of checkpoint inhibitors by themselves has been relatively unimpressive, according to Stephen M. Ansell, MD, PhD, Chair, Lymphoma Group, Mayo Clinic, Rochester, Minnesota. However, in early-phase trials presented at the American Society of Hematology (ASH) annual meeting, very high rates of activity were seen when a checkpoint inhibitor was combined with an immunomodulatory drug (IMiD). As a participant in a symposium that addressed the promise of checkpoint inhibitors, Dr Ansell suggested that the optimal use of checkpoint inhibitors in hematologic cancers, as well as solid tumors, will probably be when these agents are employed with at least one other therapy.

Two studies on checkpoint inhibitors in multiple myeloma presented at the ASH meeting evaluated pembrolizumab in combination with an IMiD. In the multicenter phase 1 KEYNOTE-023 study,[1] enrollment was limited to patients in whom at least two prior therapies that included an IMiD and a proteasome inhibitor had failed. A dose-determination design was used to incrementally escalate doses of pembrolizumab and lenalidomide in order to determine the maximally tolerated doses; study enrollment was then expanded in a dose-confirmation phase, which administered a 28-day cycle of 200 mg pembrolizumab every 2 weeks, 25 mg lenalidomide on days 1 through 21, and 40 mg dexamethasone weekly.

The overall response rate (ORR) in the 17 heavily pretreated evaluable patients was 76%. There were no complete responses (CRs), but four patients achieved a very good partial response (VGPR). In addition, several responses were durable, with ongoing disease control still observed more than 8 months after therapy was initiated, reported the lead author, Jesus San Miguel, MD, PhD, Clínica Universidad de Navarra, Pamplona, Spain. This pattern of durable responses is similar to that previously reported in subsets of patients with solid tumors treated with checkpoint inhibitors, according to Dr San Miguel, who has led several instrumental studies in multiple myeloma.

Significant adverse events on this regimen included one case of grade 3 tumor lysis syndrome, one case of grade 3 infectious pneumonia, and several cases of grade 3 or 4 neutropenia. However, all patients recovered without treatment discontinuation. Dr San Miguel characterized the safety profile as tolerable and the overall potential of this regimen as sufficiently promising to warrant further clinical studies.

In a second study, 24 patients with relapsed or refractory multiple myeloma were evaluated on a 28-day cycle of pembrolizumab plus the IMiD pomalidomide.[2] Except for the substitution of 4 mg of pomalidomide, the treatment schedule in this study, a phase 2 evaluation, was the same as that used in the phase 1 study with lenalidomide. The ORR was 50%, according to data presented by Ashraf Z. Badros, MD, University of Maryland, Baltimore. This included three near CRs and two VGPRs. Most patients without an objective response had stable disease. Only two progressed after therapy was initiated.

Grade 3 or higher hematologic toxicities, such as neutropenia and lymphopenia, were again observed, but most nonhematologic adverse events, including fatigue, constipation, dyspnea, and itching, were tolerated without dose reductions. Although autoimmune-mediated adverse events, including two cases of hypothyroidism, two cases of transaminitis, and one case of pneumonitis, produced a signal of caution, the authors maintained that the safety profile was acceptable and that the promising antitumor activity warrants a randomized trial.

However, not all hematologic cancers require a second agent to generate significant antitumor activity. As previously reported, high rates of single-agent activity with checkpoint inhibitors have been observed in Hodgkin lymphoma.[3]

In an update from this study presented at the ASH meeting,[4] the ORR produced by nivolumab alone (3 mg/kg every 2 weeks) in 23 patients with relapsed or refractory Hodgkin lymphoma was 87%. Six patients (26%) achieved a CR, 5 (22%) were able to proceed to a stem cell transplant, and durable responses include remissions persisting more than 1.5 years after treatment was initiated.

A second multicenter phase 1 study, this one conducted with pembrolizumab, produced similar results.[5] In 31 evaluable patients, five (16%) achieved a CR, 15 (48%) a partial response, and seven (23%) stable disease. Again, after a median follow-up of almost 1 year, nearly one half remained on treatment. Side effects in the study with pembrolizumab, as in the study with nivolumab, included grade 3 hematologic toxicities as well as immune-related toxicities, such as hypothyroidism, but these were generally considered manageable and acceptable in the context of the benefit in a group of patients with diminishing treatment options.

If confirmed in registration trials, these data could lead to US Food and Drug Administration approval of nivolumab, pembrolizumab, or both as single agents in advanced Hodgkin lymphoma. This would follow the pattern already established in solid tumors, but Dr Ansell, along with other experts speaking at the 2015 ASH annual meeting, predicted that the ultimate application of these agents is in combination regimens.

Durable responses have been observed in only a subset of even the most sensitive cancers, whether these are hematologic or solid tumors.

Durable responses have been observed in only a subset of even the most sensitive cancers, whether these are hematologic or solid tumors. Checkpoint inhibition has provided proof-of-principle evidence that immunoregulatory signals can be manipulated, but durable control or cure of cancer in most patients appears to require at least a second hit.

The premise that immunoregulatory signaling is complex and redundant was the primary theme of the symposium on the tumor microenvironment in which Dr Ansell participated. Both nivolumab and pembrolizumab target the specific checkpoint protein programmed death ligand 1, but there are other checkpoint proteins, including cytotoxic T-lymphocyte–associated protein 4, which is targeted by ipilimumab. Although experimental evidence predicts greater immune response when multiple checkpoint proteins are inhibited, even this step may not be enough if the silencing of checkpoints is not followed by activation of T regulatory or natural killer cells.

In explaining how the tissue microenvironment may account for insufficient activation of immunoregulatory cells, Dr Ansell described a T-cell population with an "exhausted" phenotype, characterized by limited proliferative activity and impaired cytokine production. He described the goal of immunotherapies as "reeducating" the signals that affect immune function suppression and activation, a goal that is likely to involve therapies acting on two or more signaling systems.

Alan G. Ramsay, PhD, King's College, London, United Kingdom, who participated in the same symposium, provided a similar perspective. Like Dr Ansell, he predicted that the future of checkpoint inhibition in hematologic cancer will involve combination strategies that permit regulation of multiple signaling pathways, not just those involving checkpoints. Although the excitement over checkpoint inhibitors is well deserved, Dr Ramsay maintained that there is even greater promise when it becomes clear how to extend the benefit of a single checkpoint inhibitor to a greater proportion of patients by combining it with an additional agent.

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