PD-1 Checkpoint Inhibitors Harness the Immune System to Treat Lymphomas

A new class of drugs, known as immune checkpoint inhibitors, is providing new perspective on how to treat relapsed and refractory lymphomas, according to three abstracts presented at the 56th ASH Annual Meeting.

“It has long been known that tumor cells induce an immunosuppressant microenvironment, which contributes to the failure of patients to mount effective immune responses against their cancer,” said John Gribben, MD, DSc, FMedSci, the Chair of Medical Oncology at Barts Cancer Institute, Queen Mary University of London. The programmed cell death 1 pathway is one such immune checkpoint: increased expression of the programmed death-ligand 1 on tumor cells inhibits immune cell activation via interaction with the programmed death 1 receptor (PD-1) on the surface of T cells.

“Despite what is known about expression of these molecules on hematologic malignancies, the clinical program [for PD-1 checkpoint inhibitors] is more established in solid tumors, in which there are already licensed indications,” Prof. Gribben noted. Nivolumab and pembrolizumab, both monoclonal antibodies that inhibit PD-1, are now demonstrating their utility as exciting new therapeutics that improve the ability of the immune system to fight against relapsed and refractory blood cancers.

“These agents merit urgent further development,” Prof. Gribben told ASH Clinical News. “The results presented clearly demonstrate that the promise of tumor immunology treatment approaches is now coming to fruition and could revolutionize the way that we treat these cancers in the future.”

Nivolumab Study Confirms the Importance of PD-1 in HL

“This is one of the first studies of PD-1 inhibition in hematologic malignancies, and the first dedicated study in Hodgkin lymphoma,” said Philipe Armand, MD, PhD, from the Dana-Farber Cancer Institute in Boston, who presented promising preliminary results from a phase 1 trial of nivolumab in 23 heavily pretreated patients with Hodgkin lymphoma (HL).

Results showed an overall response rate (ORR) of 87 percent, including a complete response rate (CR) of 17 percent.

These response rates “are higher than in any other tumor type to date,” noted Dr. Armand. Progression-free survival (PFS) was 86 percent at 24 weeks, but duration of response has yet to be determined. All tumors studied showed genetically defined overexpression of PD-1 ligands.

The drug’s toxicity was similar to that seen in solid tumors: 22 percent of patients experienced a grade 3 treatment-related adverse event, and 78 percent experienced a treatment-related adverse adverse event of any grade. No grade 4 treatment-related events or treatment-related deaths occurred.

Based on these results, the U.S. Food and Drug Administration granted nivolumab breakthrough status in relapsed classical HL. “The studies [presented at the annual meeting] may pave the way for broader and earlier use of PD-1 blockade in Hodgkin lymphoma, with the hope of increasing the cure rate,” Dr. Armand told ASH Clinical News.

Nivolumab Treatment Shows Modest Activity in Other Lymphoid Malignancies

The same phase 1 study also investigated the use of nivolumab in patients with other relapsed or refractory lymphoid malignancies, including 29 patients with B-cell non-HL (B-NHL), 23 patients with T-cell non-HL (T-NHL), and 27 patients with multiple myeloma (MM).

Treatment effect was found to be tumor-dependent, although the mechanisms behind these differences in response remain an ongoing area of investigation.

The ORR was 28 percent (CR = 7%) for B-NHL, and 17 percent (CR = 0%) for T-NHL. Nivolumab showed no clinical activity in patients with MM. Again, toxicity profiles were similar to those seen in solid tumors.

“These findings demonstrate that giving anti-PD1 in hematologic malignancies is safe and expands the potential diseases where PD-1 inhibitors may play a role,” said lead study author Alexander Lesokhin, MD, of the Memorial Sloan Kettering Cancer Center in New York, NY. “Modest single-agent activity in non-Hodgkin lymphoma suggests that anti-PD1 may be best used in combination therapy with other agents that have activity in each individual lymphoma.”

Pembrolizumab is Safe and Effective in Heavily Pretreated HL

Finally, Craig Moskowitz, MD, also from Memorial Sloan Ketering Cancer Center in New York, presented exciting preliminary data for a hard-to-treat patient population. The phase 1b study examined pembrolizumab in 29 patients with HL after failure of brentuximab vedotin. Nearly 70 percent of patients had also failed prior autologous stem cell transplantation.

Results showed an ORR of 66 percent, including a CR rate of 21 percent. The clinical benefit rate was 86 percent, but duration of response has yet to be determined. Pembrolizumab was well tolerated – only three patients experienced grade 3 treatment-related adverse events, and no grade 4 treatment-related adverse events or treatment-related deaths occurred – supporting the continued development of pembrolizumab in patients with HL, Dr. Moskowitz and colleagues concluded.


References

Armand P, Ansell SM, Lesokhin AM, et al. “Nivolumab in patients with relapsed or refractory Hodgkin lymphoma – preliminary safety, efficacy and biomarker results of a phase I study.” Abstract #289. Presented at the American Society of Hematology Annual Meeting, December 8, 2014.

Lesokhin AM, Ansell SM, Armand P, et al. “Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies.” Abstract #291. Presented at the American Society of Hematology Annual Meeting, December 8, 2014.

Moskowitz CH, Ribrag V, Michot J, et al. “PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013).” Abstract #290. Presented at the American Society of Hematology Annual Meeting, December 8, 2014.

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