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.
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.
OncLive: What did you cover in your presentation at the meeting?
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.
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.
What work are we doing right now to accomplish this?
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.
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.
We have seen PD-1/CTLA-4 inhibitor combinations in solid tumors. Could it happen in hematologic malignancies?
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.