Pipeline Updates Advance Paradigms Across Lymphomas

Matthew S. McKinney, MD

Swapping bleomycin with brentuximab vedotin (Adcetris) has proved to be superior to the standard 4-drug chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with Hodgkin lymphoma. However, the toxicity associated with the antibody-drug conjugate is a remaining challenge, as is choosing which patients should receive it, said Matthew S. McKinney, MD.

“The downside of adding brentuximab vedotin [in the frontline setting] is increased toxicity— mainly febrile neutropenia to the point where you have to introduce growth factor with each cycle of therapy,” explained McKinney, who is an assistant professor of medicine at Duke University School of Medicine. “There is also more neuropathy, and we have seen liver toxicity as well.”

In follicular lymphoma, there are 3 FDA-approved PI3K inhibitors that are similar at first glance, but a deeper dive into their toxicity profiles and mechanisms of action can help determine which one of them is appropriate to use for a given patient, McKinney added.

Meanwhile, in mantle cell lymphoma (MCL), research efforts are being dedicated to chemotherapy-free induction therapy in relapsed/refractory disease, such as the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence). Furthermore, the use of active surveillance is also being further explored in the space, especially in patients with particularly indolent disease.

“In MCL, there clearly is a population that is appropriate for a watch-and-wait strategy—that represents about 10% to 15% of newly diagnosed patients,” explained McKinney.

In an interview at the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, McKinney discussed exciting treatment advances made in Hodgkin and non-Hodgkin lymphoma (NHL), specifically the compelling research in follicular lymphoma and MCL.

OncLive: What are some of the key developments that have been made in Hodgkin and NHL?

McKinney: [In my presentation,] spoke about Hodgkin lymphoma, mainly frontline management in extensive-stage disease. The main topic I covered was how we got to where we are as far as the current National Comprehensive Cancer Network guidelines for treatment. I covered aspects of the RATHL trial, in which we investigated dropping bleomycin after 2 cycles of ABVD when patients are in complete remission (CR). The other big topic was using brentuximab vedotin early in the frontline treatment of patients with extensive-stage disease, mainly the data coming from the ECHELON-1 study and other smaller studies.

I also switched gears to talk about follicular lymphoma, namely starting with obinutuzumab (Gazyva), which is a novel CD20-directed antibody with potentially increased efficacy in the frontline setting when paired with chemotherapy. I also discussed the increased adverse events (AEs) associated with that therapy and what its role may be.

Finally, I focused on the recent FDA approvals of 3 different PI3K inhibitors for relapsed/refractory follicular lymphoma, going from idelalisib (Zydelig) to the more recent drugs copanlisib (Aliqopa) and duvelisib (Copiktra). There are differences between these drugs in terms of toxicity, as well as other considerations.

Could you expand on the importance of the RATHL study?

RATHL was a large, multicenter, randomized trial evaluating standard ABVD chemotherapy versus a plan where patients who achieve a CR after 2 cycles of ABVD had bleomycin eliminated. Basically, what this study found was that it did miss its primary endpoint by a little bit. There is a lot of concern in the Hodgkin lymphoma community that this was a very arbitrary endpoint. When you look at the overall outcome, it's very clear that dropping bleomycin after 2 cycles of therapy almost completely eliminates the risk of severe bleomycin-related toxicity.

While it did miss its primary endpoint, the RATHL data have been taken on to eliminate egregious bleomycin-related lung toxicity, such as pneumonitis. This chemotherapy program without bleomycin still seems to contain all the benefits of standard ABVD.

Are there other, similar strategies being explored?

The other main strategy in that regard is to substitute bleomycin with brentuximab vedotin, which has been FDA approved for several years as a subsequent line of therapy in relapsed/refractory Hodgkin lymphoma. An open question was how incorporation of brentuximab vedotin impacts frontline outcomes in Hodgkin lymphoma. The ECHELON-1 study was developed to test this, looking at standard ABVD versus an altered ABVD backbone with bleomycin being replaced by brentuximab vedotin. The study was also a little difficult to understand because it used a composite progression-free survival endpoint. When you look at long-term data with that, there was a significant difference in the 2 arms in terms of Hodgkin lymphoma control and lack of disease progression or treatment failure.

It is important for the treating physician to be aware of [the toxicity of brentuximab vedotin]. Those are all considerations. In that trial, the converse was that there was very little lung toxicity in the brentuximab vedotin arm. Therefore, in patients who have a higher risk of treatment failure, the brentuximab vedotin regimen is a reasonable approach to consider. There may certainly be a subgroup analysis that may be helpful for us to determine which patients should receive which therapy.

Is there other research being done with brentuximab vedotin in this space?

The other interesting topic is the idea of sequential brentuximab vedotin. There was a very nice abstract presented at the 2017 ASH Annual Meeting that was subsequently published in Blood. It looked at giving older patients with advanced Hodgkin lymphoma 2 doses of brentuximab vedotin followed by a modified chemotherapy backbone. In patients who reach a CR, there was more brentuximab vedotin consolidation at the end of treatment.

The interesting thing is that the CR rate in that study was approximately 90% near the end of chemotherapy backbone treatment, but most of the patients on that trial were able to complete all their therapy with very few AEs. I certainly think we've been waiting on a program like that for a long time, and some of the elderly patients whom you're more afraid to give bleomycin to can benefit from these sequential schemes.

Nivolumab (Opdivo) is also FDA approved in Hodgkin lymphoma. Have any other checkpoint inhibitors shown promise?

Pembrolizumab (Keytruda) has also been used in this setting; most of the checkpoint inhibitors have been used in advanced disease. Hodgkin lymphoma typically overexpresses PD-1 and PD-L1 checkpoints, along with a molecule called JAK2. This is certainly an attractive target. The main questions out there are whether there are novel combinations we can use in the advanced setting. Also, in early-stage disease, is there a role for consolidation or another incorporation of checkpoint inhibitors, such as nivolumab or pembrolizumab? For broad use, we don't know that information, but there are exciting studies looking at this now.

Could you discuss the PI3K inhibitors available in follicular lymphoma? How do they differ from one another?

In follicular lymphoma, the delta isoform of PI3K has been very important, and all these inhibitors clearly hit that target very potently. Where I believe there is some difference between these drugs in terms of how they are used is that there is a spectrum of the PI3K molecules they hit. Clearly, copanlisib is different from the other 2 in that it has a lot of efficacy across PI3K-alpha and -beta isoforms as well. Molecules such as duvelisib may hit other PI3K isoforms, such as delta or gamma, more so than idelalisib. All of those agents are effective in most relapsed/refractory follicular lymphomas.

The other thing to look at is the way the drugs are administered. Both idelalisib and duvelisib are oral medications taken twice daily, whereas copanlisib is a once weekly intravenous infusion. That's a very important consideration for patients. Sometimes patients have different wishes in terms of how they want to take medicine. [There is also] the issue of insurance as well.

There are certain AEs that are distinct to the PI3K inhibitors as a class. The biggest difference among the 3 approved inhibitors is that copanlisib tends to cause more hyperglycemia. In the most recent trial published in the Journal of Clinical Oncology, there was a 30% grade 3/4 hyperglycemia rate with the drug. That's an important consideration because older patients may already have diabetes. Aside from that, there are smaller differences in AEs, such as diarrhea and colitis. I don't know that it's clear whether there's any significant differences between the drugs across those lines.

Switching to MCL, what therapies are on the rise?

A lot of research is being done to work toward a chemotherapy-free induction in relapsed/refractory therapies. The BTK inhibitors ibrutinib and acalabrutinib are very exciting and very effective in this population. Using BTK inhibitors and drugs like lenalidomide (Revlimid) combined with CD20-directed antibodies will be very important. The other important frontline consideration is investigating which induction approach is best, and there are studies looking at this.

The other question in that setting has to do with the role of consolidation transplant, namely in the setting of minimal residual disease [-negative] patients. An open [National Cancer Institute] cooperative group study that we're participating in is evaluating this. There's an ongoing study looking at ibrutinib with or without venetoclax (Venclexta) in the second-line setting for the BTK inhibitor-naïve population—that's a very exciting combination.

Finally, the last thing to consider, especially in highly refractory MCL, is CAR T-cell therapy. The response rates with CAR T cells have been good, but we need more readouts for some of the larger trials. MCL is an exciting field to be in right now.

How do you determine which patients with MCL are fit for the “watch-and-wait" approach?

My approach is to first figure out if the patient has symptoms and if they need treatment to address that immediately. Some of the molecular markers in MCL are also important, and we'll often take a step in looking at p53 mutations or checking whether an MCL looks like a blastoid variant. That helps further define that they are not an indolent population.

Beyond that, it's a clinical judgement based on the pathology markers. The literature shows that you don't lose anything by observing these patients for a period of time, especially in the indolent patients. It saves them months, and even years, of treatment.