Immunotherapy Demonstrates Early Promise Across Lymphoma Subgroups

Stephen M. Ansell, MD, PhD

Checkpoint inhibitors are making their way through the treatment paradigm of lymphomas with 2 FDA approvals in the last year. Now, combinations are likely next, as early results demonstrate encouraging activity across various subtypes.

In a cohort of the phase I CheckMate-039 trial that was presented during the 2016 ASH Annual Meeting, the efficacy and safety of the PD-1/CTLA-4 inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy), was evaluated in patients with Hodgkin lymphoma (n = 31), B-cell non-Hodgkin lymphoma (NHL; n = 15), T-cell NHL (n = 11), multiple myeloma (n = 7), and primary mediastinal B-cell lymphoma (n = 1 in the safety arm only). The median number of prior therapies was 4.

At a median follow-up of 11.4 months, results showed that the overall response rates with the combination for patients were as follows: 74% in Hodgkin lymphoma, 20% in B-cell NHL, 9% in T-cell NHL, and 0% for multiple myeloma. Complete responses (CRs) occurred only in the Hodgkin lymphoma cohort, in which the CR rate was 19%.

Regarding safety, the most common treatment-related adverse events (TRAEs) across the overall population were fatigue (26%), pyrexia (23%), and diarrhea (18%). Twenty-nine percent of patients experienced a grade ≥3 TRAE and 48% had a serious AE.

The FDA approved nivolumab in May 2016 for the treatment of patients with classical Hodgkin lymphoma who relapsed or progressed after autologous hematopoietic stem cell transplantation and brentuximab vedotin (Adcetris). The PD-1 inhibitor pembrolizumab (Keytruda) was approved by the FDA in March 2017 for the treatment of both adult and pediatric patients with classical disease Hodgkin lymphoma who are refractory or have relapsed after 3 or more lines of therapy.

OncLive: What did you cover in your presentation at the meeting?

During the 2017 OncLive^® State of the Science Summit on Hematologic Malignancies, Stephen M. Ansell, MD, PhD, chair of the Lymphoma Group at Mayo Clinic, lectured on the state of immunotherapy in lymphoma. In an interview, he shared insight on the potential these agents could have, ongoing clinical trials, and where this blends in with chimeric antigen receptor (CAR) T-cell therapy.Ansell: It is an exciting time in the treatment of patients with lymphoma because we are learning how to optimize the immune system and get it to target the tumor. What I focused on is, first, the understanding of what is fundamentally wrong with the tumor and why is it that the immune system lets the cancer cell have a free pass and doesn’t actually target it.

There has been a lot of work done showing that there are suppressive cells that stop the immune system from being active, but there are also exhausted cells that have been active and almost activated for too long, so that they have become significantly run down and are unable to get off to the cancer cell in an effective fashion.

What work are we doing right now to accomplish this?

That is what has led into some of these newer novel immunotherapy treatments. These are ways in which we want to wake up the immune system, get it far more effective, and make it get off to the cancer cell in a much more effective fashion. One of the very exciting things is that blocking PD-1, which is 1 of the receptors that are on exhausted cells, has proven very effective in certain kinds of lymphoma—Hodgkin lymphoma in particular. The results have been very promising, with very high response rates. What has also been exciting is that subsequent studies have validated what was seen in the phase I study. In the phase II trials of nivolumab and pembrolizumab, the high response rates have remained high.

But, almost more importantly, patients can remain on the drug for an extended period of time and they continue to benefit. Many patients have been on therapy, even up to and beyond 2 years, and remain in remission and are tolerating the treatment well.

We have seen PD-1/CTLA-4 inhibitor combinations in solid tumors. Could it happen in hematologic malignancies?

What to do next? The new area of research is understanding exactly how the PD-1 blockade works, but also understanding how we can combine this with other therapies. Whether it is with other immune-based therapies or chemotherapy, what is the best way forward? There are lots of trials in progress to really understand that. Yes. In fact, a phase I clinical trial was completed utilizing that exact combination in lymphomas in general. That was presented at the 2016 ASH Annual Meeting. Interestingly, the response rates remain high at around 74% for the combination.

It must be exciting to see this explosion of immunotherapy in hematologic malignancies. What is your take on it?

However, what is challenging is that the response rates for PD-1 alone in the phase I trial were also extremely high and the phase II trials have shown it to be very high, too. The question is how much more does CTLA-4 add to the effective results that are seen with PD-1 blockade alone? We really don’t know that, and to answer that question is going to take a randomized controlled trial. It is very exciting, and it is great to see. For years, many of us had said the immune system matters and the number of immune cells present in the tumors have to mean something. A lot of vaccine and immune-activation approaches were tried but without much success. It has been very gratifying to see that by reversing some of the exhaustion problems just result in very excellent results.

How do we see checkpoint inhibitor immunotherapy blending into the paradigm with CAR T-cell therapy? Could these therapies be combined?

There is a lot to build on, because the immune system in hematologic malignancies is clearly interacting with the tumor cell in a much more profound way. If we can use that even more effectively than we are using it right now, my hope is that we will see patients cured in far greater numbers. Everything is on the table and everything is an option. CAR T cells are highly effective therapies and are very promising, but 1 of the challenges with CAR T cells is that the significant activation often results in exhaustion. One of the important things might be to reverse exhaustion or prevent it—and immune checkpoint therapies can do that.

At this point, what do you think community oncologists need to know about immunotherapy in the lymphoma field?

The challenge, however, is to balance that with the potential toxicities because these very activated cells on their own are causing significant toxicities. If you were to take the leash off and let them do even more, that could be even more toxic. But, as we have learned already to manage the toxicities of CAR T cells, we will learn how to manage combinations and I see a lot of promise in the future. At this point, the use of immune checkpoints is something that a community oncologist is pretty comfortable with in melanoma, lung cancer, and those arenas. Now, with both pembrolizumab and nivolumab approved in Hodgkin lymphoma, that is another excellent tool for relapsed patients and the results are excellent. My hope is that community oncologists are aware of that data.

However, they might also look to the future to see how might these agents move into earlier lines of treatment. Although they are not ready for primetime, my hope is that they will partner with folks that are doing some of those trials and consider enrolling patients on studies that will let us come to the next question which is, how well do these combinations work?

Ansell S, Gutierrez ME, Shipp MA, et al. A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 183.