Novel Regimens Generate Excitement in Lymphoma Treatment Paradigms

Narendranath Epperla, MD, MS

Novel agents and combinations have shaken up the treatment paradigms for patients with advanced classical Hodgkin lymphoma and non-Hodgkin lymphoma (NHL), according to Narendranath Epperla, MD, MS.

For example, the addition of brentuximab vedotin (Adcetris) to standard 3-drug chemotherapy (A+AVD) resulted in a statistically significant 31% reduction in the risk of disease progression or death versus a 4-drug chemotherapy regimen (ABVD) at 4 years in patients with newly diagnosed, advanced-stage classical Hodgkin lymphoma (HR, 0.691; 95% CI, 0.542-0.881; P = .003), according to updated data from the phase III ECHELON-1 trial presented at the 2019 ASH Annual Meeting.1

“In Hodgkin lymphoma, based on longer follow-up [from the ECHELON-1 trial], brentuximab vedotin plus AVD is superior to conventional ABVD in terms of modified progression-free survival. We can be comfortable giving this regimen in practice given its response rate and durability of response, regardless of the patient’s PET status,” noted Epperla.

In NHL, the latest developments in the treatment paradigms of follicular lymphoma and mantle cell lymphoma (MCL) have proved equally exciting.

“There is a lot of excitement in follicular lymphoma in the frontline and relapsed settings with combinations of CD20-directed monoclonal antibodies and lenalidomide (Revlimid), be it rituximab (Rituxan) or obinutuzumab (Gazyva),” said Epperla. “In MCL, CAR T-cell therapy is a very exciting option in patients who fail ibrutinib (Imbruvica).”

In an interview during the 2019 OncLive^® State of the Science SummitTM on Hematologic Malignancies, Epperla, hematologist at The Ohio State University (OSU) Comprehensive Cancer Center—James, and assistant professor in the Department of Internal Medicine, Division of Hematology, at The OSU College of Medicine, reflected on recent advances in Hodgkin lymphoma and NHL.

OncLive: Could you provide background on the ECHELON-1 trial in Hodgkin lymphoma?

Epperla: The phase III ECHELON-1 trial is a landmark study that compared brentuximab vedotin plus AVD versus ABVD in the frontline treatment of patients with classical Hodgkin lymphoma. Patients were randomized 1:1 to each arm. The primary endpoint of the trial was modified progression-free survival (PFS), which was defined as the need for second-line therapy, progression, or death. In the initial analysis, which was reported at a median follow-up of 24.6 months, the modified PFS was better in patients who received A+AVD versus ABVD. At the 2019 ASH Annual Meeting, updated data were presented. At a median follow-up of 43 months, the data showed that patients who received the brentuximab vedotin regimen had superior modified PFS compared with ABVD, irrespective of the interim PET status.

Are you using brentuximab vedotin in practice?

We use patient selection to determine who would benefit from brentuximab/AVD versus ABVD. Given the data, I believe that A+AVD is an appealing option for smokers who have underlying lung injury, chronic obstructive pulmonary disease, or asthma. My preference would be A+AVD over ABVD [in that case]. An additional subset analysis suggests that younger patients seem to derive more benefit [with A+AVD]. However, [the study] was not powered to determine [these differences].

How do the safety profiles of A+AVD and ABVD compare?

One of the big risks with brentuximab vedotin is peripheral neuropathy. In the updated analysis, we saw an improvement in [the resolution] of this event in the majority of patients.

You also gave a presentation on NHL at the OncLive^® State of the Science Summit™. Starting with follicular lymphoma, what advances have we seen?

In the follicular realm, we have the data from the phase III RELEVANCE trial, which compared the combination of lenalidomide and rituximab (R²) with rituximab and chemotherapy in the frontline setting. RELEVANCE was designed as a superiority study. Although the trial failed to meet its primary endpoint, the 3-year PFS [was comparable between the 2 arms]. Patients who received R² had an interim 3-year rate of PFS of 77% versus 78% in those who received rituximab and chemotherapy. In other words, R² squared is a very promising option for patients in the frontline setting. As such, I always discuss this regimen with my patients. At the 2019 ASH Annual Meeting, we saw data with the combination of obinutuzumab, a newer CD20-directed monoclonal antibody, with lenalidomide in the frontline setting. We saw very impressive overall response rates (ORR) and PFS. The 2-year estimated PFS in the single-center phase II study was more than 95%.

Nathan H. Fowler, MD, of The University of Texas MD Anderson Cancer Center, presented the phase I/II results with the combination of obinutuzumab and lenalidomide in the relapsed/refractory setting. Here, too, we saw very impressive outcomes with an ORR of 100%. The 2-year estimated PFS was 73%. The benefit with the combination was noted in all 3 subgroups: in patients who progress within 2 years of starting therapy, patients who are refractory to prior rituximab, and those who received ≥3 prior lines of therapy. These are 3 difficult subsets to treat, and we saw an improvement in response rates in all of them [with the combination]. However, a high risk of neutropenia was observed, so we have to be aware of that toxicity. The data are still early; the median follow-up is only 17 months. I'm looking forward to the updated analysis.

Given the promise of obinutuzumab, will rituximab continue to play a role in the treatment of these patients? If so, where do you see rituximab biosimilars fitting into the paradigm?

If the data stand once it matures, I believe that obinutuzumab has the potential to replace rituximab going forward. At this point in time, however, rituximab still has a place in the treatment paradigm. Biosimilars are comparable [with biologic agents]. As such, these products can replace conventional rituximab alone with any of our chemotherapy backbones or normal agents.

Could you highlight other exciting triplets that have been evaluated in follicular lymphoma?

At the 2019 ASH Annual Meeting, we saw data with the combination of obinutuzumab, lenalidomide, and polatuzumab vedotin (Polivy). Again, we saw very impressive response rates and PFS. The data are still early, but they look very promising.

Are other notable emerging approaches being explored in this space?

Bispecific antibodies have been of particular interest. The bispecific antibodies for CD3 and CD20 are very potent. The response rates are very impressive in relapsed/refractory follicular lymphoma. I'm very excited to see how sequencing pans out for these agents. CAR T-cell therapy is also showing a role in follicular lymphoma. The future is very bright in this disease.

Switching to MCL, could you discuss the novel agents that have emerged in recent years?

One of the subtypes of lymphoma that has seen a tremendous influx of agents is MCL. In terms of novel agents, we’re talking about the BTK inhibitors ibrutinib, acalabrutinib (Calquence), and zanubrutinib (Brukinsa). A slew of other BTK inhibitors are also being studied.

In addition, we’ve seen encouraging data with the BCL-2 inhibitor venetoclax (Venclexta) in combination with BTK inhibitors. These novel agents are now being moved into the frontline setting and being tested with rituximab and lenalidomide. We’re also seeing combinations of [CDK4/6 inhibitors] and BTK inhibitors. There is a lot of excitement in MCL; many B-cell receptor targeted agents are being used.

Zanubrutinib was recently approved in MCL. How do you see this agent fitting into the paradigm?

Zanubrutinib definitively has activity in MCL. [When considering its use], one has to weigh the risk-benefit ratio with regard to patient demographics, such as underlying heart issues and increased susceptibility to bleeding. We have to consider the patient’s comorbidities before proceeding with ibrutinib, acalabrutinib, and zanubrutinib. The data [with zanubrutinib] need to mature. Longer follow-up is needed to see if the durability of response is still maintained with the agent.

CAR T-cell therapy has also generated a lot of excitement in this space. Could you discuss the data presented from the ZUMA-2 trial at the 2019 ASH Annual Meeting?

A few years ago, the outcomes of patients who progressed on BTK inhibitors were very dismal. The overall survival for these patients was between 5 and 10 months. CAR T-cell therapy gives patients a new treatment option.

At the 2019 ASH Annual Meeting, we saw the data from the ZUMA-2 trial. Patients had to have relapsed several times, including on an anthracycline and a BTK inhibitor, in order to be included in the study. Notably, a proportion of patients had a TP53 mutation; however, only a minor proportion of patients had a blastoid [variant] and had morphic variants. These specific subtypes of MCL are the toughest to treat.

In the trial, patients were given a single infusion of treatment. The ORR was 93%, which is very impressive. Moreover, a very high proportion of complete response rates was reported. It’s an exciting time in MCL. Previously, I used to bridge patients with ibrutinib and take them to transplant. Now, when patients fail BTK inhibitors, we can give them CAR T-cell therapy.

Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the ECHELON-1 study. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 4026. bit.ly/34ru1Og.