Checkpoint Inhibitors in Lymphoma: A New Universe

February 2016, Vol 7, No 1

Immunotherapy is generating great excitement in melanoma and non–small-cell lung cancer (NSCLC). The 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 these therapies in hematologic cancers.

At ASH 2015, Philippe Armand, MD, PhD, Senior Physician, Hematologic Oncology, Dana-Farber Cancer Institute, Boston, discussed early studies of treating patients with lymphoma with checkpoint inhibitors.

Thus far, the results with the anti–PD-1 inhibitor nivolumab (Opdivo) in lung cancer and in melanoma showcase the durability of response with checkpoint inhibitors, Dr Armand explained. "This apparent durability of response is what is most exciting and has come to characterize checkpoint blockade," he said.

Hodgkin Lymphoma

Studies of nivolumab suggested that the 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, Dr Armand explained.

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

In young, heavily pretreated patients with Hodgkin lymphoma, the objective response rates were approximately 87% with nivolumab and 65% with pembrolizumab.

"Putting the data together, most Hodgkin lymphomas 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," Dr Armand continued.

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

"No doubt, checkpoint inhibitors will be an important arrow in our quiver," Dr 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 Hodgkin lymphoma, with frequent PD-L1 expression seen in 70% of patients. 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 the responses and durable responses were seen less frequently than in Hodgkin lymphoma, Dr Armand said.

"It may be possible to tease out subsets of DLBCL patients who will respond by using PD-L1 expression," he suggested.

What Lies Beyond PD-L1?

Testing for PD-L1 expression is controversial. "Our ability to predict PD-L1 positivity on the basis of a snapshot of archival tissue may not be valid," Dr Armand told attendees.

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

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

"We don't really know yet what PD-L1 positivity and PD-L1 negativity mean," Dr Armand 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," Dr Armand added. "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."

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

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