Role of Checkpoint Inhibition in Most Hematologic Cancers Unclear, But Potential Remains

Saad Z. Usmani, MD

Checkpoint inhibition may have demonstrated promising findings in some hematologic malignancies, such as Hodgkin lymphoma, but PD-1/PD-L1 inhibitors have caused safety concerns when added to immunomodulatory agents in others, specifically multiple myeloma.

In Hodgkin lymphoma, the FDA approved nivolumab (Opdivo) in March 2016 for the treatment of patients with classical disease that has relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin (Adcetris). The decision marked the first PD-1 inhibitor approved for a hematologic malignancy.

Meanwhile, in multiple myeloma, the FDA in September 2017 placed partial clinical holds on 3 trials—the phase III CheckMate-602, phase I CheckMate-039, and phase II CA204142 studies—assessing nivolumab-based combinations in patients with relapsed/refractory disease. These were based on safety concerns previously reported in 2 pembrolizumab (Keytruda)-based studies in myeloma, KEYNOTE-183 and KEYNOTE-185, which led to the FDA placing clinical holds on them in July 2017.

However, in December 2017, clinical holds on 2 of the nivolumab trials, CheckMate-039 and CA204142, were lifted.

While the role of immunotherapy has not yet been determined in multiple myeloma, Saad Z. Usmani, MD, explained that other combination strategies with checkpoint blockade are being explored across the hematologic malignancy field.

OncLive: You lectured on immunotherapy for B-cell malignancies and multiple myeloma. What did you share with the audience?

Earlier studies have showed minimal efficacy with checkpoint inhibitors in B-cell malignancies and even less in multiple myeloma. Can you speak to how efforts have evolved since then?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Usmani, director of clinical research (hematologic malignancies), director of plasma cell disorders, clinical associate professor of medicine, University of North Carolina at Chapel Hill, Levine Cancer Institute, Atrium Health, discussed the current state of immune checkpoint inhibitors in hematologic cancers, recent setbacks, and ongoing studies that could further shape the landscape.Usmani: My presentation covered some of the emerging and future immunotherapy strategies for B-cell malignancies, as well as multiple myeloma. These would include not just the monoclonal antibody-based strategies, but also cellular therapy—based strategies, including T-cell receptor (TCR) T cells, CAR T cells, and bispecific monoclonal antibodies. [I also provided] some of the historic perspective efficacy data, as well as safety profile issues, and where we are heading in the field with regards to those technologies. In terms of the PD-1/PD-L1 pathway, we have seen efficacy first in the Hodgkin lymphoma realm; the original clinical observations were published a little more than 3 years ago in the New England Journal of Medicine, and that was with nivolumab in advanced patients with Hodgkin lymphoma.

Since then, several clinical trials have explored early relapse, frontline strategies, and the posttransplantation realm. It looks like, in each of those strategies, there is good activity utilizing PD-1 and PD-L1 inhibitors.

In myeloma, we only have clinical data with pembrolizumab in combination with lenalidomide (Revlimid)/dexamethasone as well as pomalidomide (Pomalyst)/dexamethasone. These data were generated in small single-center phase I/II trials. The phase III trials were held by the FDA in the summer of 2017. Subsequently, checkpoint inhibition was deemed not safe with immunomodulatory drugs. However, newer clinical trials combining checkpoint inhibitors with other drug classes in myeloma are ongoing.

Is there a high percentage of patients with these malignancies who have PD-1/PD-L1 expression?

Is it too early to comment on combination studies of checkpoint inhibitors plus CAR T-cell therapy?

Could chemotherapy be the one constant regimen in the hematologic malignancy field?

What other exciting data are you looking forward to seeing?

Overall, the field has moved. When it comes to PD-1/PD-L1 pathway inhibition, there are all sorts of exploration of other checkpoint pathways, like CTLA-4, OX40, etc. Some of those checkpoint inhibition strategies are making their way into early-phase clinical trials, as well. There are. Although the absolute expression levels may vary, but the expression level for PD-L1 is fairly high in most B-cell neoplasms. Those clinical trials are just happening now, so it is a little early. However, that would be one strategy to keep those T cells going and not getting exhausted. Other strategies may actually be utilizing the CRISPR technology to enable T cells to live longer and avoid exhaustion. I believe so; that is a fair point to make. When it comes to immunotherapy, until we hone the technology and learn how to minimize and manage the side effects from some immunotherapy approaches, chemotherapy will be the mainstay of treatment for [patients with] hematologic malignancies. I would be interested in hearing a little more about dual-target CAR T-cell strategies and the strategies to keep the T cells from getting exhausted and burnt out. It is also important to note that creating the product itself—that whole process—and the time it takes to make CAR T-cell therapies is less than ideal for a lot of patients who have more aggressive relapses, or their disease is just growing at a rapid pace. These patients don’t have a lot of temporizing measures before they get that strategy. I am looking forward to hearing about ways we can minimize the time it takes for us to make the product and, therefore, making that process more expeditious for our patients.

What is the timeline for dual-targeted CAR T-cell therapy approaches?

This is an exciting time to be a hematologic malignancies researcher and a clinical trialist, so we are looking forward to some of these investigations. When patients are relapsing with diffuse large B-cell lymphoma or Hodgkin lymphoma, they don’t have good outcomes and they don’t have a lot of good options available. The same is true for patients with double-refractory myeloma; their overall survival is fairly poor.We will probably see the earliest clinical trials in the next 12 to 18 months and the results will probably [read out] in the next 3 to 5 years.

FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA® (pembrolizumab) in Patients with Multiple Myeloma. Published August 31, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed May 3, 2018.