PD-1 Immunotherapy Combos May Be Next Step in Hodgkin Lymphoma Therapy

Anas Younes, MD

The prospect of combining PD-1 inhibitors with existing therapies, particularly brentuximab vedotin, is emerging as the most exciting new development in advancing the treatment of patients with Hodgkin lymphoma, raising the possibility of improving the cure rates in a disease where standard strategies have already produced notable results, according to Anas Younes, MD.

Younes, a medical oncologist who is chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, is among the nation’s leading experts in developing new treatments for patients with Hodgkin and non-Hodgkin lymphomas. In an interview with OncLive, Younes said that nivolumab and pembrolizumab, which are both monoclonal antibodies targeting the PD-1 immune checkpoint, have demonstrated promise in early clinical trials among patients with Hodgkin lymphoma who have had multiple relapses.

“Both showed very good tolerance but also remarkable activity exceeding 60% or 70% response rates,” said Younes. “Some of these responses are really durable. This has generated tremendous excitement about further developing these agents and about the potential of combining them with other nonchemotherapeutic agents.”

When it comes to identifying partners for these immunotherapies, a regimen that would pair a PD-1 inhibitor with brentuximab “is the most exciting combination” to explore, said Younes. A phase I/II trial is scheduled to be launched combining brentuximab with nivolumab in an estimated 60 patients with relapsed or refractory Hodgkin lymphoma after failure of frontline therapy.¹

Strategies to Enhance Outcomes

Current Landscape

“There is interest now in combining brentuximab vedotin with checkpoint inhibitors—two active agents,” he said. “Whether this will be sufficient by itself or would still need to be combined with chemotherapy would be the next step in drug development with Hodgkin lymphoma.” He said new combinations initially would be evaluated in the relapse setting and then tested in earlier lines of treatment. “It makes a lot of sense to combine them since each one has high single-agent activity,” Younes added. “We need to learn about the safety and efficacy of this combination.”Standard therapies have improved outcomes dramatically during the past several decades for patients with Hodgkin lymphoma, a relatively rare cancer that is expected to result in an estimated 9000 new cases in the United States this year, according to the American Cancer Society.² Approximately 95% of cases are categorized as classical Hodgkin lymphoma.

The overall 5-year and 10-year survival rates have reached 85% and 80%, respectively, with outcomes varying by stage. The 5-year survival rate is approximately 90% among patients with stages I or II disease, about 80% among individuals at stage III, and about 65% for patients at stage IV. Younes said about half of new patients are diagnosed at stages I or II, with the remainder presenting at the more advanced stages.

Those outcomes have been achieved with an armamentarium that includes first-line chemotherapy and radiation therapy regimens, and second-line autologous stem-cell transplantation (ASCT) therapy.

PD-1 Inhibitors

In 2011, the FDA approved brentuximab as a treatment for patients with relapsed Hodgkin lymphoma after the failure of ASCT or multiagent chemotherapy regimens; the antibody—drug conjugate that targets CD30 was the first new therapy approved for the malignancy since 1977. In August, brentuximab moved forward in the treatment timeline when the FDA approved a new indication for the agent to be used after ASCT consolidation therapy for patients at high risk of relapse or progression.Nivolumab, which has gained FDA approvals in melanoma and non—small cell lung cancer (NSCLC), was designated as a breakthrough therapy in Hodgkin lymphoma in May 2014 after promising early clinical trial findings in patients with relapsed and refractory classical Hodgkin lymphoma.

In January 2015, Ansell et al reported that 20 of 23 patients (87%) with heavily pretreated Hodgkin lymphoma achieved an objective response to nivolumab therapy dosed at 3 mg/kg of body weight every 2 weeks, including 17% with a complete response.³ Most of the patients had previously been treated with ASCT and brentuximab.

The most frequently reported drug-related adverse events (AEs) of any grade were rash (22% of patients) and decreased platelet count (17%). Five patients (22%) experienced AEs of grade 3 severity, consisting of one AE in each of five categories: decreased lymphocyte count, increased lipase level, stomatitis, myelodysplastic syndrome, and pancreatitis.

Nivolumab has continued to demonstrate durable responses after more than a year of follow-up, researchers reported in June.⁴ The median duration of response for patients with Hodgkin lymphoma ranged from 9 weeks to more than 91 weeks.

A larger registrational trial, CheckMate205, is continuing into nivolumab monotherapy in classical Hodgkin lymphoma after transplant failure.⁵ The study seeks to enroll 240 patients.

Pembrolizumab, which also is approved in melanoma and NSCLC, is not as advanced in the development process for Hodgkin lymphoma as nivolumab but has demonstrated activity in early clinical trials and remains under study in the malignancy.

Brentuximab

In a phase Ib study, pembrolizumab generated responses in 66% of 29 patients with heavily pretreated classical Hodgkin lymphoma, including six patients (21%) who achieved a complete remission.⁶ The most frequently reported AEs were grade 1/2 respiratory events (20%) and thyroid disorders (20%).While the checkpoint immunotherapy agents make progress, so does brentuximab. In the phase III AETHERA trial, brentuximab was evaluated in 329 patients with unfavorable risk or primary classical Hodgkin lymphoma who had undergone ASCT.

Investigators found that treatment with brentuximab reduced the risk of disease progression for this patient population by 43% compared with placebo.⁷ The median progression-free survival with brentuximab vedotin was 42.9 months versus 24.1 months (P = .0013).

The researchers said that approximately half of all patients with unfavorable risk factors relapse after ASCT, and these findings paved the way for the expanded indication for brentuximab in this population that the FDA approved earlier this year.

Reaching for Better Outcomes

Brentuximab also is being evaluated in the phase III ECHELON-1 trial as frontline therapy in an approximately 1040 patients with advanced Hodgkin lymphoma.8 In the multicenter, international trial, patients are being randomized to receive either brentuximab plus the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) versus the standard chemotherapy combination of AVD plus bleomycin (ABVD).Younes said the focus of research into Hodgkin lymphoma is “basically pushing the cure rate of an already highly curable disease.” “This is almost unheard of in cancer therapy,” said Younes. “Everybody is focusing on the highly unmet need patient population and rightly so—we need to bring up the cure rate of cancer that has a very low survival, and that’s where most drug development is focusing. We are in an unusual and fortunate situation where we can push the cure rate even higher. Hopefully, at one point we can cure everybody.”

He said that if clinicians are able to introduce safe and effective new agents earlier in the treatment paradigm, patients might be able to forgo transplants or be treated with less intensive chemotherapy or radiation therapy regimens.

“It is possible to replace, defer, or delay the need for transplant if these new combinations prove to be effective in the relapsed setting,” said Younes. “Or, if we improve the cure rate by introducing [new therapies] in the front-line setting, the need for second-line therapy including transplant will become less and less important.

Younes urged practicing oncologists and hematologists to consider helping their patients enroll in appropriate clinical trials.

“There are highly effective agents available for patients with relapsed lymphoma in a clinical trial setting and unless patients are enrolled in these trials, we will not be able to advance the field,” said Younes. “Even though it’s a curable cancer, I think oncologists and patients should continue to try to participate in these novel clinical trials.

References

1. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02572167.
2. What are the key statistics about Hodgkin disease? American Cancer Society website. www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-key-statistics. Revised March 4, 2015. Accessed October 16, 2015.
3. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma [published online December 6, 2014]. N Engl J Med. 2015;372(4):311-339.
4. Timmerman J, Armand P, Lesokhin AM, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: updated results of a phase 1 study (CA209-039). Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 010.
5. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02181738.
6. Moskowitz CH, Ribrag V, Michot JM, 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). Presented at: 56th Annual Meeting of the American Society of Hematology; December 5-9, 2014; San Francisco, California. Abstract 290.
7. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial [published online March 19, 2015]. Lancet. 2015;385(9980):1853-1862.
8. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01712490.