Novel Agents Show Impressive Activity in Hodgkin Lymphoma

Jane N. Winter, MD

The recent breakthrough designation of brentuximab vedotin (Adcetris) for the first-line treatment of patients with classical Hodgkin lymphoma could potentially allow for another option for select populations, such as elderly patients, who have demonstrated promising responses.

In the ECHELON-1 trial, the combination of brentuximab vedotin plus AVD (adriamycin, vinblastine, and dacarbazine) (AVD) reduced the risk of disease progression or death by 23% (HR, 0.770; P = .035). Two-year overall survival data favored the combination when compared to with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD)) in an interim analysis.

Immunotherapy agents have also been displaying efficacious results in patients with classical Hodgkin lymphoma, with ongoing trials ofFDA-approved PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) producing promising results.

“We have identified the fact that Hodgkin lymphoma is genetically poised to be sensitive to checkpoint inhibition,” said Jane N. Winter, MD.

During a presentation at the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Winter, professor of medicine, Division of Hematology/Oncology, Feinberg School of Medicine at Northwestern University, discussed immunotherapy in the treatment of patients with Hodgkin lymphoma.

OncLive^®: Can you please give an overview of your presentation on immunotherapy in Hodgkin lymphoma?

In an interview during the meeting, Winter shared her insight on the progress of the above-mentioned agents, emphasizing the importance of clinical trials in this disease.Winter: For Hodgkin lymphoma, we have new agents that are available. Recently, we have been trying to balance long-term toxicities as well as acute toxicities with efficacy. There is a long way to go, particularly for some subgroups of patients, and especially for the elderly. The overall outcomes for patients over the age of 60 are poor, with approximately 50% only surviving 5 years with conventional therapy. Also, for younger patients, there are unmet needs with many patients failing upfront and salvage therapy. The So much so that the issue of increased efficacy in the frontline setting, as well as the issue of reducing long-term toxicities, including secondary malignancies, and cardiovascular disease, are foremost in our consideration.

Checkpoint inhibition is well known to those wwho treat patients with ho create solid tumors, and only more recently to those of us who treat those with hematologic malignancies. It has been recognized that tumors dampen the immune response through the PD-1/PD-L1/PD-L2 axis, and that it is possible to intercept that pathway with antibodies. Uniquely, Hodgkin lymphoma, through a genetic abnormality, is especially sensitive to this strategy. The over expression of PD-L1 and PD-L2 ligand is a result of amplification that occurs genetically, and interception with an anti—-PD-1 antibody has shown to be exceptionally effective. Phase I and II studies have now shown that response rates are very high in relapsed patients, both those who have failed upfront therapy as well as those that who have relapsed after autologous stem cell transplant (ASCT). Often, these are patients who have previously been treated with brentuximab vedotin.

Brentuximab vedotin is a new kid on the block. It has been given breakthrough status for upfront therapy in combination with chemotherapy for Hodgkin lymphoma. This agent has been approved for some time now for treatment post-ASCT for patients who relapse, as well as for those who are not eligible for ASCT. It is a new alternative to conventional therapy, or something that can be added to conventional therapy—as demonstrated in the recent ECHELON-1 study.

Checkpoint inhibition provides us with an alternative approach for treating patients. Going forward, we hope to be able to capitalize on the use of 2 new strategies for the treatment of patients with Hodgkin lymphoma. Specifically, in the elderly, we have recently shown that upfront therapy with brentuximab vedotin followed by chemotherapy provides excellent outcomes, and that data will be presented at the ASH Annual Meeting by Andy Evans from our group.

An alternative for elderly patients may be therapy that includes checkpoint inhibition. We have launched 2 new clinical trials using pembrolizumab—1 of 2 checkpoint inhibitors approved for Hodgkin lymphoma—in both the upfront setting as well as in combination with chemotherapy for relapsed patients. For those who have relapsed after post initial therapy, or have proven to be refractory, pembrolizumab is given in combination with ICE (ifosfamide, carboplatin and etoposide )(ICE) chemotherapy with a PET scan following 2 cycles as the primary endpoint. That study is up and running and actively accruing patients.

We have also just launched a second trial, which targets both elderly and younger patients with newly-diagnosed Hodgkin lymphoma. Those patients receive pembrolizumab as a single agent for 3 cycles and then undergo a PET scan. We are interested in seeing how effective checkpoint inhibition alone will be in the upfront setting. Patients will then proceed to receive chemotherapy AVD—omitting the bleomycin, which is associated with significant pulmonary toxicity. These patients go on to receive a number of cycles, 2 to 4, either a total of 4 or 6 cycles of AVD, and, in some instances, will receive maintenance pembrolizumab for up to 2 years.

These are new approaches. —There are others investigating combinations of checkpoint inhibition and chemotherapy, and there are also studies looking at combinations of checkpoint inhibition with brentuximab vedotin.

Brentuximab vedotin is a “new kid on the block.” It has been given breakthrough status for upfront therapy in combination with chemotherapy for Hodgkin lymphoma. This agent has been approved for some time now for treatment post-ASCT for patients who relapse, as well as for those who are not eligible for ASCT. It is a new alternative to conventional therapy, or something that can be added to conventional therapy—as demonstrated in the recent ECHELON-1 study.

Are there any strategies that you can recommend to physicians on managing the toxicities associated with checkpoint inhibition?

Are there any differences with nivolumab and pembrolizumab in this setting?

These are exciting times. We are looking forward to seeing the full data set from the ECHELON-1 trial and also from the elderly trial, both using brentuximab vedotin upfront, and we are hoping that introducing checkpoint inhibition will also help increase efficacy and reduce long-term toxicity for these patients. Going forward, there will be issues of toxicities associated with checkpoint inhibition. It is reassuring that the recent overview of patients treated on a [CheckMate] nivolumab studies presented by Dr Michelle Fanale at the [14th International Conference on Malignant Lymphoma], showed very little toxicity among those patients. So, Therefore, perhaps we are seeing a better toxicity profile in the patients with Hodgkin patients lymphoma than we see in patients with solid tumors patients. I do worry about using this strategy as a part of upfront treatment for patients, particularly young patients for whom we do not want to see long-term issues.There are very minor differences at this point. They are really interchangeable in terms of efficacy and side effect profiles. There are many others that are being developed by other companies, so we will likely be seeing quite a number of checkpoint inhibitors.

What do you hope community oncologists take took from your talkdiscussion and could possibly , and perhaps use in clinical practice?

Nivolumab was available earlier, so perhaps practicing hematologists have more experience with it. Most community physicians have been using these agents in patients with solid tumors patients for some time now, so they are more familiar and comfortable with them than the academic hematologist. I am hopeful that they will be open to enrolling patients on clinical trials [and] recognize that we have made great progress in Hodgkin lymphoma, but we are not there yet. Particularly This is particularly because this disease aeffects young patients who hope to live very long lives. Curing 80% of patients does not quite make it, and burdening the others with long- term complications, cardiovascular disease, breast cancer, and second malignancies, is not acceptable.

We are hopeful that [community oncologists] will be open to enrolling in clinical trials referring their patients, sharing their patients with us and other centers so that we can move forward and rapidly incorporate these new agents into treatment. [An example of this is] such as the ECHELON-1 study, which that accrued and moved rapidly that and resulted in a breakthrough designation.

Ansell SM, Connors JM, Park SI, O’Meara MM, Younes A. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin Lymphoma. Blood. 2012 120:798.