Hodgkin Lymphoma Field Evolving With Immunotherapy, Adjustments to Standard Approaches

David J. Straus, MD

Since the FDA approval of nivolumab (Opdivo) in May 2016, researchers continue to explore the agent as well as its fellow PD-1 inhibitor, pembrolizumab (Keytruda), in various treatment settings for patients with Hodgkin lymphoma.

In 12-month follow-up results of the phase II CheckMate-205 trial presented at the 2016 ASH Annual Meeting,¹ patients with classical Hodgkin lymphoma (cHL) who received brentuximab vedotin (Adcetris) after autologous hematopoietic stem cell transplantation (AHSCT) treated with nivolumab had an overall response rate (ORR) of 67.5%, with a duration of response of 13.1 months (95% CI, 8.7-NA). The median progression-free survival was 14.8 months.

Results from a separate CheckMate-205 cohort supported the FDA’s approval of nivolumab for patients with cHL who relapse or progress after AHSCT and posttransplantation brentuximab vedotin.

In December 2016, the FDA granted a priority review to a supplemental biologics license application for pembrolizumab as a treatment for patients with refractory cHL or those who have relapsed after ≥3 lines of therapy. This is based on findings from the phase II KEYNOTE-087 and phase Ib KEYNOTE-013 trials, which evaluated pembrolizumab for the proposed indication in the application.²

OncLive: Can you provide a recap of your talk on Hodgkin lymphoma?

In an interview, David J. Straus, MD, an internist and hematologic oncologist at Memorial Sloan Kettering Cancer Center, provides an overview on recent findings and future directions in Hodgkin lymphoma. Straus spoke on these topics during the 2016 OncLive^® State of the Science Summit on Hematologic Malignancies.Straus: The first portion was on overall results in a rare type of Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma, which is about 5% of Hodgkin lymphoma. It is different biologically, as well as clinically, from cHL in that it is a lymphoma with a mature B-cell phenotype. It also has a behavior with an excellent prognosis, but late recurrences—somewhat akin to low-grade B-cell non-Hodgkin lymphoma (NHL). This is a disease where there is no evidence of a decreased survival at diagnosis. Also, there are little data to suggest that any treatment affects the overall outcome.

This was a look at patients who relapse after initial treatment on various studies of the German Hodgkin Study Group, which puts a lot of patients on treatment. They had various protocols that they use for cHL. They ended up with 99 patients who relapsed after their initial treatment. They did not include patients who transformed to an aggressive NHL, which is the clearest indication for treatment.

The bottom line was that everybody did great. They used various treatments, including autologous transplant. The survivals were close to 90% to 100% for whatever they did. In these 99 patients, they only had 10 deaths, 5 of which were due to nodular lymphocyte-predominant Hodgkin lymphoma and 5 due to treatment, including 3 secondary malignancies, 1 infection, and 1 pulmonary failure.

The other 3 abstracts I covered pertained to the use of checkpoint inhibitors. Two of them had really been tested extensively and involved the PD-1 inhibitors pembrolizumab and nivolumab. Both of these have excellent, high response rates in very heavily pretreated patients after autologous transplants and usually after brentuximab vedotin.

The 2016 ASH Annual Meeting was the first time both of these were presented in full form. Nivolumab was actually published by my colleague Eunice L. Kwak, MD, PhD. The excellent results led to an accelerated FDA approval for nivolumab in patients with Hodgkin lymphoma who relapse after autologous transplant and who fail brentuximab vedotin.

Both the pembrolizumab and nivolumab trials had 3 cohorts. Basically, they were relapse/refractory patients after autologous transplants, most of whom had brentuximab vedotin, which is the label for nivolumab, but some of them did not have brentuximab vedotin. There were some patients who were not candidates for transplants; most of them were older patients who, for 1 reason or another, were not fit to undergo transplant.

The bottom line is that they all showed an ORR of around 65% in all cohorts in both drugs, within the complete response rate of about 22%. They had longer follow-up data than had been shown before, which demonstrated durable responses. Most of the responses occurred after 2 to 3 months.

The last one was a combination of nivolumab with brentuximab vedotin prior to transplant in relapsed patients after first-line treatment. They gave 4 cycles of the 2 drugs together. In the first cycle, they staggered the drugs. In the second, third, and fourth cycle, they gave them together. Approximately 20% of patients on this follow-up had gone on to autologous transplant. They had good stem cell collection. The ORR was quite impressive at around 90%, and there was around a 60% to 65% complete response rate—which is very impressive.

Are there any ongoing studies that have the potential to change practice?

What is interesting about this is that we have 2 newer regimens. Nivolumab is not chemotherapy; it is immunotherapy. Brentuximab vedotin is chemotherapy, but it's a new delivery system—an antibody-drug conjugate—that delivers the drug to the tumors. That is very intriguing and provocative; perhaps we do not have to give people high-dose regimens such as ICE (ifosfamide, carboplatin and etoposide), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), and DHAP (dexamethasone, high-dose cytarabine, and cisplatin). Perhaps you could get away with this type of treatment before transplant.We want to achieve a PET complete response with the use of ESHAP or ICE prior to transplant because we have shown that the outcomes are much better if the PET is negative prior to the transplant. If you can achieve that with what is in these heavy-duty chemotherapy regimens, that would be very interesting. However, these are early data and it has to be confirmed in other trials, as well as further follow-up data.

Nivolumab and pembrolizumab are very exciting because, for the first time ever, there is a treatment that works that is not chemotherapy. Even brentuximab vedotin is a kind of chemotherapy; it is a better delivery system, but it's still chemotherapy.

If pembrolizumab gets approved, will there be any sequencing challenges? How would you decide what therapy to use first?

Now, you have drugs with a high response rate that are not chemotherapy. There are real opportunities for this. The question is going to be how to introduce these drugs as early as possible into people who you can possibly identify as being the 10% to 15% of patients who are truly chemotherapy resistant.I believe nivolumab’s label is for use in patients who relapse after transplant following failure to brentuximab vedotin. I suspect the filing for pembrolizumab may be similar. They say, at the present time, they have very similar response rates and very similar toxicity profiles. More data may be important to see which one might be preferable.

Reflect on the data that we heard at the 2016 ASH Annual Meeting. If you jumped ahead 5 or 10 years, what does the landscape for Hodgkin lymphoma look like?

It should be pointed out that we are talking about a very small number of patients. This is not going to be a big moneymaker for the companies because the number of patients who relapse after transplant and brentuximab vedotin who are available for this are a small number of patients. At the present time, I don't see a big difference between these drugs.We've been curing this disease for 40 years. Seventy percent of patients are cured with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The biggest thing that we can do is to eliminate radiation therapy when it's not needed. That's the thing that has the biggest effect on long-term outcome. This is because these patients, after 10 years, begin to get toxicities particularly related to radiation therapy, led by second primary cancers and followed by cardiovascular disease.

We actually have looked at our long-term results and we found, after 5 years or so, the deaths due to Hodgkin lymphoma plateau. Deaths due to other causes begin to be picked up after 10 years and, after 20 years, they exceed those due to Hodgkin lymphoma.

The things that are not causes of mortality are also causes of serious morbidity in the survivors, namely second prior cancers and cardiovascular events. The biggest thing we can do to improve this is to get rid of radiation therapy and, if it’s necessary, to use it safely.

I published a viewpoint in JAMA Oncology entitled, “Radiation Therapy for Hodgkin Lymphoma: Can It Be Administered More Safely if Necessary?" We argue for drastically reduced treatment ports that will reduce the off-target effects of other organs, in the case of mediastinal radiation to the heart, lungs, and breasts. I don't know if this can be done, but this is a direction the radiation oncologist should go in.

Limiting and eliminating radiation therapy is the most important thing we can do to improve long-term outcomes. There is a real opportunity now for immune-based therapies and better chemotherapy to improve the results in initial treatment. The ECHELON-1 study is a randomized phase III trial of 1240 patients comparing ABVD—which we've been using for 40 years—with brentuximab vedotin plus AVD. The trial has completed accrual. We are all interested to see if, for the first time in 40 years, actually adding a new drug to the backbone of the regimen we have been using will improve response and progression-free survival upfront.

References

1. Timmerman J, Engert A, Younes A, et al. Checkmate 205 update with minimum 12-month follow up: a phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 1110.
2. Chen RW, Zinzani PL, Fanale MA, et al. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study. J Clin Oncol. 34;2016 (suppl; abstr 7555).