Promising Activity Seen With Nivolumab in Refractory Classical Hodgkin Lymphoma

Philippe Armand, MD, PhD

Most patients with classical Hodgkin lymphoma (cHL), having previously failed three or more therapies, responded to the immunotherapy nivolumab in a small phase I trial.

The PD-1 inhibitor has been granted breakthrough therapy designation by the FDA as a result, and is now being investigated in a large phase II trial, according to the authors of the study. Lead author Philippe Armand, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented the findings December 6 during the 2014 Annual Meeting of the American Society of Hematology.

A checkpoint inhibitor, nivolumab works by inhibiting the PD-1 receptor that sits on the surface of cancer cells. The receptor, thought to be excessively engaged in cHL due to amplification of genetic material at the chromosomal area known as 9p24.1, dampens the body’s immune response to the cancer cells. More specifically, the binding of the PD-L1 and PD-L2 ligands to PD-1 receptor-positive activated T cells induces T cell exhaustion, a reversible inhibition of T cell activation and proliferation, the investigators wrote in the abstract presented at ASH.

Nivolumab, they noted, is a fully human IgG4 monoclonal PD-1 blocking antibody that potentiates anti-tumor T cell activity.

The presentation at ASH was the first ever to report data on PD-1 antibody for the treatment of cHL, the authors wrote, adding that, in the past, nivolumab has demonstrated promising results in solid-tumor cancers. Last year, the FDA granted a fast-track review to nivolumab as a potential treatment for non—small cell lung cancer, renal cell carcinoma, and melanoma, and this year, the agency granted priority review to the drug as a therapy for previously treated patients with advanced melanoma.

Our data are encouraging for Hodgkin lymphoma patients with relapsed or treatment-resistant disease, and the remarkable response rate seen in this study validates the scientific hypothesis that Hodgkin lymphoma relies heavily on the PD-1 pathway for survival, Armand said. We hope that further development of this drug can lead to improved outcomes for patients afflicted with this cancer.

In the phase I study, 23 patients with cHL—whose median age was 35, and who had been treated with three or more therapies, in many cases stem cell transplant and/or brentuximab vedotin—were added as a separate cohort to a larger study investigating nivolumab in lymphoma and multiple myeloma. The patients received a 3 mg/kg intravenous infusion of nivolumab every 2 weeks until their tumors progressed or they experienced excessive toxicity.

The primary endpoint was safety; overall response rate (ORR), progression-free survival (PFS), anti-tumor activity, and expression of immunomodulatory proteins in tumor biopsies, marked the main secondary endpoints.

In June, after an average follow-up of 40 weeks, 20 of 23 patients in the study demonstrated a complete response (4 patients) or a partial response (16 patients) to nivolumab. The remaining 3 patients (13%) had stable disease. Tumor burden was reduced in all 23 patients at one or more efficacy assessments during treatment with nivolumab. Their PFS rate at 24 weeks was 86% (95% CI, 62-95%). Median overall survival has not been reached.

Among the 18 patients who had previously failed brentuximab vedotin, the ORR was 89% (16/18), with 6% (1/18) achieving complete response and 83% (15/18) partial response, Armand continued.

The drug’s toxicity mirrored that observed in other solid-tumor cancers. Drug-related adverse events (AEs) occurred in 78% of patients, most commonly rash (22%), decreased platelet count (17%), diarrhea, nausea, pruritus, fatigue, and pyrexia (each at 13%), the authors reported. Twenty-two percent of patients experienced drug-related grade 3/4 AEs, and two patients experienced one serious AE each that led them to leave the trial (grade 3 myelodysplastic syndrome and grade 3 pancreatitis).

Although investigators expected to see an increase in lung toxicity in patients who had received prior potentially lung-damaging treatments, that side effect did not materialize, Armand said.

In addition to the two patients who discontinued due to toxicities, 6 of 23 patients elected to discontinue study treatment to undergo stem cell transplantation, and 4 patients discontinued due to disease progression. Ten patients continued on the study as of June 16, 2014, and have now been in remission for more than a year, Armand said.

In an analysis using tumor samples from 10 patients in the trial, investigators, as anticipated, found evidence of genetic abnormalities to 9p24.1 resulting in amplified expression of the PD-L1 and PD-L2 ligands, Armand said.

Based on their results, the study investigators deemed nivolumab safe and tolerable, with an 87% response rate, in this patient population:

The frequent and long-lasting responses in heavily pretreated, relapsed/refractory patients, including those who have failed brentuximab vedotin, highlight the importance of the PD-1 pathway in cHL, and the genetically defined sensitivity to PD-1 blockade in this disease.

Armand P, Ansell SM, Lesokhin AM, et at. Nivolumab in patients with relapsed or refractory Hodgkin lymphoma - preliminary safety, efficacy and biomarker results of a phase I study. Presented at: Annual Meeting of the American Society of Hematology; December 5-9, 2014; San Francisco, California. Abstract 289.

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