Novel Combination Strategies Explored in Two Phase III NHL Studies

John Leonard, MD

The treatment landscape for patients with non-Hodgkin lymphoma (NHL) has gone through a significant transformation in recent years, with the approvals of ibrutinib (Imbruvica), idelalisib (Zydelig), and lenalidomide (Revlimid). Many of these agents have demonstrated single-agent activity, with combination strategies currently under exploration.

In the phase III SELENE study, ibrutinib is being explored in combination with either bendamustine plus rituximab (Rituxan) or R-CHOP for previously treated patients with follicular lymphoma (FL) or marginal zone lymphoma. In the phase III AUGMENT trial, lenalidomide is being explored with rituximab versus placebo plus rituximab in patients with relapsed/refractory indolent iNHL.

Together these large trials, along with smaller investigations, hope to uncover more efficacious treatments for patients with NHL. Additionally, smaller investigations are exploring these agents as monotherapies for patients with other types of hematologic malignancies, such as Waldenström's macroglobulinemia (WM).

OncLive: What are some of the exciting therapies currently being investigated for NHL?

To discuss the development of these therapies for patients with hematologic malignancies, OncLive spoke with John P. Leonard, MD, medical oncology, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, who is an investigator for the ongoing SELENE and AUGMENT studies, along with several other clinical trials.Leonard: We have been looking at ibrutinib plus chemotherapy. Ibrutinib is active and approved for certain patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It also has activity in follicular and other indolent lymphomas. The next step, really, is to say “what happens if we add it to chemotherapy. Can we improve outcomes for patients?” There is some preliminary data that say this may be helpful in CLL.

In the SELENE study, we are taking patients that have relapsed with FL or other indolent lymphomas and randomizing them to receive either chemotherapy with or without ibrutinib to see how that may impact progression-free survival. The goal is to control the disease better and longer without significantly added toxicity.

We also have a number of new studies looking at other agents, including idelalisib, which is active in recurrent FL and CLL. At the 2015 ASCO Annual Meeting, we presented data that showed that in WM idelalisib had response rates in about 20 patients that were upwards of 60% to 70% and it was well-tolerated.

Can you discuss the combination of lenalidomide and rituximab in NHL?

Obviously, larger numbers of patients need to be investigated, but this represents another option for patients. There are not many approved drugs for WM because it is a rare disease. Ibrutinib is now approved in WM, so I think that will be looked at a little more. The biology of WM ties very nicely to an inhibitor of those pathways. Treating WM in a much more targeted, precise way as opposed to simply giving chemotherapy is certainly the way of the future.There are a number of ongoing studies of lenalidomide and rituximab in NHL. Lenalidomide has a 30% response rate in a number of different lymphoma subtypes, including FL, MCL, and CLL, and diffuse large B-cell lymphoma.

There are a number of phase II studies that have looked at lenalidomide and rituximab as part of upfront therapy or in relapsed patients. One of those studies, known as the AUGMENT trial, is a randomized trial in patients with recurrent FL. Patients are randomized to get either single-agent rituximab or lenalidomide and rituximab. The goal is to see if adding lenalidomide has greater efficacy than the single-agent, as well as to assess the toxicity profile of the combination.

What is the potential impact of the AUGMENT trial for patients?

What are future treatment goals in NHL?

This trial is ongoing and is still accruing; however, we do have some data from other studies that suggest that the combination is very promising. We reported a study of lenalidomide alone compared to lenalidomide and rituximab, which showed that two drugs are better than one in recurrent/relapsed FL. It is encouraging, and now we are moving onto the phase III trial. FL is a chronic lymphoma. Patients respond to treatment and then they relapse. Certainly, trying to give them a more durable remission, if it is associated with a good quality of life, would be an appropriate goal. If the combination does improve the chance for a clinical response and lengthen that response, it would be extremely beneficial to patients. We have two broad paradigms in lymphoma treatment. One is aggressive lymphoma that requires aggressive treatments with the goal to cure. For those patients who are cured, the goal is to limit the number of treatments required so they can have easier treatments.

For those who are not cured, the goal is to come up with better treatments to improve their prognosis. In the indolent lymphomas, we are not expecting to cure patients, but if we can give them a longer survival with a good quality of life and have options to treat them if their disease is recurrent, that is an ideal strategy.