February 2016, Vol. 5, No. 1

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Checkpoint Inhibitors in Lymphoma: A New Universe

Philippe Armand, MD

ASH 2015, ASH Highlights

philippe-armand98pxImmunotherapy is generating great excitement in melanoma and non–small cell lung cancer (NSCLC). FDA approvals of checkpoint inhibitors in these tumor types, as well as encouraging preliminary results in other solid tumors, have paved the way for studying them in hematologic cancers.

Philippe Armand, MD, Dana-Farber Cancer Institute, Boston, MA, discussed early studies in lymphomas with checkpoint inhibitors.

Results thus far with nivolumab in lung cancer and melanoma showcase the durability of response with checkpoint inhibitors, he explained. “This apparent durability of response is what is most exciting and has come to characterize checkpoint blockade,” he said.

Studies of nivolumab, a programmed death-1 (PD-1) inhibitor, suggested that responses are confined to PD-1 ligand 1 (PD-L1)-positive tumors. This opened the hunt for other PD-L1–positive tumors and led to studies in Hodgkin lymphoma (HL), he explained.

“The pathophysiology of HL is unique. Studies have shown that classic HL frequently harbors PD-1,” he said. “HL may have a genetically driven hardwired dependence on PD-L1 for survival. Based on this, HL was included in the expansion cohorts of phase 1 trials of nivolumab and pembrolizumab.”

In young, heavily pretreated patients with HL, objective response rates were about 87% with nivolumab and 65% with pembrolizumab.

“Putting the data together, most HLs have some shrinkage of tumor as the best response, and responses tend to be durable: 2 years with nivolumab and 1.5 years with pembrolizumab,” he continued.

Most of the HL patients who responded had PD-L1 expression. Results have been confirmed in large phase 2 studies. Ongoing studies are being conducted in first salvage, frontline, and posttransplant settings.

“No doubt checkpoint inhibitors will be an impor­tant arrow in our quiver,” Armand said.

Primary mediastinal B-cell lymphoma (PMBL) may also be a target for PD-1 blockade, he continued. The genetics of this lymphoma are similar to those of HL, with PD-L1 expression seen in 70%. This tumor may be sensitive to PD-1 blockade. Pembrolizumab is being studied in PMBL in a phase 1 trial, and a phase 2 study is being launched.

Nivolumab was studied in a small phase 1 trial of 11 patients with diffuse large B-cell lymphoma (DLBCL), but responses and durable responses were seen less frequently than in HL, he said. “It may be possible to tease out subsets of DLBCL patients who will respond by using PD-L1 expression,” Armand suggested.

What Lies Beyond PD-L1?

Testing for PD-L1 is controversial. There is no standardized assay or threshold cutoff for positive tumors. Further, PD-L1 is a dynamic marker that can change from the archived tumor sample to initiation of treatment.

“Our ability to predict PD-L1 positivity on the basis of a snapshot of archival tissue may not be valid,” Armand told the audience.

PD-L2 is being studied as a potential biomarker for PD-1 blockade.

To complicate the issue, with experience it has become clear that PD-L1–negative patients with solid tumors respond to PD-1 blockade. PD-L1 may not predict a survival benefit in melanoma or in NSCLC.

“We don’t really know yet what PD-L1 positivity and PD-L1 negativity mean,” he stated.

“PD-L1 is not the whole story. Studies suggest that the tumor microenvironment is playing an important role,” he continued.

“For now, PD-L1–positive tumors are generally good targets for checkpoint inhibitors. But PD-L1 positivity is not the only answer. We need to continue to discover how to broaden these treatments.

“We are really entering a new universe. We sense that checkpoint inhibitors will be broadly useful in oncology. The possibility of combining these drugs with other drugs opens a whole avenue of study.

“Checkpoint inhibitors can be combined with chemotherapy and radiotherapy, with immunomodulatory drugs in multiple myeloma, and with other novel therapies such as CAR T cells, bispecific antibodies, and vaccines.

“This field is too big to fail. This will change the treatment paradigm for classic HL as monotherapy or in combination therapy,” he stated.

“Our mission is to find what works best in the greatest number of patients in the fastest time possible. We need to leverage and feed this immense field of endeavor. We need to commit to that going forward.” he concluded.

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