With less than 10,000 patients diagnosed with Hodgkin lymphoma each year and a cure rate of approximately 75% to 80%, drug development for this disease was never a priority for pharmaceutical companies. So when the antibody-drug conjugate brentuximab vedotin (Adcetris) was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of relapsed Hodgkin lymphoma, with a response rate of 75%, many observers thought that mission was accomplished. Clinical trials incorporating brentuximab vedotin with different chemotherapy regimens proliferated, with many trials reporting encouraging early results.

Simple, Naked Antibody

Consequently, it was beyond all expectations that another highly active drug would be identified so quickly, earning a Breakthrough Therapy designation from the FDA. What was more surprising is that this active drug, nivolumab (Opdivo), is a simple, naked antibody that reactivates the patient’s own immune cells. With a few malignant cells residing among an overwhelming number of reactive, inflammatory immune cells, Hodgkin lymphoma was cancer’s poster child for illustrating the failure of immune surveillance. On the other hand, it was also a cancer model for exploring novel immune therapy. After many failures, a successful treatment strategy has emerged.

As reported by Ansell and colleagues¹ and reviewed in this issue of The ASCO Post, nivolumab, an antibody that blocks the ability of programmed cell death protein 1 (PD-1) to interact with its natural ligands (PD-L1 and PD-L2) produced a response rate of 87%, with an acceptable safety profile. The response rate was exceptionally high, even among patients whose disease progressed after therapy with brentuximab vedotin.

Furthermore, most responses were swift, occurring within the first 2 to 3 months. However, like many drugs tested in multiply relapsed patients, the vast majority of responses were partial, indicating that in this setting, single-agent nivolumab is unlikely to cure patients with relapsed Hodgkin lymphoma.

Next Steps

So what is next? In the short-term, nivolumab (and other PD-1/PD-L1 targeted antibodies) will need to be combined with brentuximab vedotin and chemotherapy in different disease settings—post-transplant, pretransplant, and even with front-line chemotherapy regimens. We also need to learn more about the exact mechanism of action, mechanisms of resistance, and biomarkers for patient selection for this class of drugs, so we can develop rationally designed mechanism-based combination regimens.

Furthermore, we need to define the optimal duration of therapy for those who achieve complete remissions. In the long run, careful exploration of novel chemotherapy-free and radiation therapy–free combination regimens will need to be performed in a multistep process. The goal for such novel regimens should be clear: higher activity and better safety than the existing therapy. In this new paradigm, brentuximab vedotin and nivolumab are building blocks, as we continue to identify other novel targeted agents.

After more than 4 decades of neglect, drug development for Hodgkin lymphoma is back on track. Until we cure every single patient with Hodgkin lymphoma, and ensure that cured patients will enjoy a normal and healthy life, the fat lady should continue to refuse to sing. ■

Disclosure: Dr. Younes has received honoraria from Seattle Genetics, Millennium, and Takeda.

Reference

1. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311-319, 2015.