Hamlin Discusses Practice-Changing Data in Lymphoma

Paul A. Hamlin, MD

The 2017 ASH Annual Meeting brought to light the expansive impact that chimeric antigen receptor (CAR) T-cell therapy has had on patients with large cell lymphoma, but it also highlighted how much work remains in this space, according to Paul A. Hamlin, MD.

In the longer follow-up of the phase II ZUMA-1 trial, axicabtagene ciloleucel (axi-cel; Yescarta) maintained a complete remission rate of 40% with a median follow-up of 15.4 months for patients with refractory, aggressive non-Hodgkin lymphoma (NHL). In the updated assessment, which was a 1-year follow-up of ZUMA-1, 42% of patients treated with axi-cel remained progression free and 56% were alive. The 18-month progression-free survival (PFS) rate was 41% and the 18-month overall survival rate was 52%.

“This longer-term follow-up suggests that patients can achieve durable remissions, but we still don’t know if it can replace autologous stem cell transplant [ASCT] or be a curative treatment,” says Hamlin.

Axi-cel was approved by the FDA in October 2017 as a treatment for adults with relapsed or refractory NHL. Moreover, a priority review to a supplemental biologics license application for tisagenlecleucel (Kymriah), another CAR T-cell product, was granted in January 2018 for use in adult patients with relapsed/ refractory diffuse large B-cell lymphoma who are ineligible for or relapse after ASCT.

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In an interview at the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Hamlin, chief, Medical Oncology Service, Memorial Sloan Kettering Cancer Center, discussed exciting updates from the 2017 ASH Annual Meeting throughout the large cell lymphoma space, as well as other advances on the horizon.Hamlin: I spoke about updates from the 2017 ASH Annual Meeting as they relate to large cell lymphoma. I discussed where the field is moving in terms of better molecular characterization of disease and how that is going to inform our decision making in the future.

We are developing more targeted therapies that are actionable based on the underlying driving mutations, and less based on cell origin. Some work that was presented at the 2017 ASH Annual Meeting looked at the ability to further characterize prognostic groups within the cell of origin categorized based on the mutational landscape. That helps to further identify groups that may do better versus worse and have targets that make rational drug combinations reasonable to pursue.

At the same time, we are seeing the maturation of studies that were initiated in past years based on cell of origin. [The basis] for those who are not as familiar with large cell lymphoma, [is that] we know we can characterize biology based on germinal center biology or nongerminal center biology. They have different biologic pathways that are activated in each of those disease processes with potential targets in both.

It happens that in the activated B-cell biology, we have a larger canopy of options. Those studied in the last few years were mostly looking at the addition of a drug to an R-CHOP rituximab (Rituxan), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) backbone.

The large randomized studies that have been performed—some that are reported, and some that are completing accrual and awaiting results—have looked at bortezomib (Velcade), lenalidomide (Revlimid), and ibrutinib (Imbruvica). All have a potential advantage and an activating B-cell biology or nongerminal center biology.

At the 2017 ASH Annual Meeting, when we started to think about therapeutic interventions for large cell lymphoma, we did not have any landmark studies that have moved us away from R-CHOP, which has been a frustration over the last 15 years. In the relapsed large cell lymphoma setting, there were exciting data coming out that relate to drugs such as antibody-drug conjugates as well as CAR T cells.

One antibody-drug conjugate, polatuzumab vedotin, is an anti-CD79b agent, which is similar to brentuximab vedotin. It was utilized in a randomized phase II study with a bendamustine and rituximab (BR) backbone. It was comparative with a BR arm in patients with relapsed large cell lymphoma. What was exciting about this study is that BR, which is not a terribly active agent regimen for relapsed large cell lymphoma, saw nearly a tripling in the response rate and complete response rate.

When we looked at outcome measures, the PFS was almost 3 times as good as a survival advantage. This wasn’t a large randomized phase III trial, but it suggests that antibody- drug conjugates may have enough activity and be agnostic to the cell of origins. They worked equally in those with germinal and nongerminal center phenotypes to benefit our patient population.

I found those to be provocative data, and they are the basis for an upfront phase III study looking at that antibody-drug conjugate as a substitute for vincristine in the R-CHOP backbone. We are aiming toward improving R-CHOP going forward.

CAR T-cell therapy is another big story in the large cell lymphoma space that was reported across all the different products that are out there. We had previously seen that CAR T cells can be active in relapsed large cell lymphoma and that response rates can be meaningful. The big question was, “Are they durable?” We had updated data from the ZUMA-1 study that suggest that patients can achieve durable remissions. We now have follow-up that is approaching 1.5 years, which is an important landmark in large cell lymphoma. That is usually when events start to happen, at least in the upfront setting.

In that study, we can see about 30% to 40% of patients who respond to CAR T-cell therapy are maintaining their response as they get out further. The other 2 studies had follow-up that is much more modest, in the 6-month range, but we are still seeing one-third of patients who have ongoing durable responses. The big question with CAR T cells is, “How applicable will they be in a larger setting outside of clinical trials when we have an intent-to-treat analysis and start to look at the denominator of all the patients who are potentially eligible and whether or not it can take the place of autologous stem cell transplant?” Those studies are underway.

The other provocative data that were presented at the 2017 ASH Annual Meeting were ways to modify CAR T cells to make them safer or more efficacious. In that regard, we know that there is cytokine release syndrome (CRS) and neurotoxicities that are created with activated T cells. In this case, we were able to show that by using a drug like tocilizumab (Actemra), you can abrogate the CRS, although the neurotoxicity does appear to be persistent.

In a similar proof-of-concept report, the idea of using checkpoint inhibitors to augment a T-cell response makes intuitive sense, but there is a concern that you could augment toxicity in this setting. At least the initial small reports do suggest that you can reengage those CAR T cells after a loss of response in a proportion of patients and you can extend the duration of the CAR T cells to improve outcomes.

Will we get to a point where we have sequencing challenges with CAR T-cell therapy?

We can anticipate that we will see increased use of these agents in the population at large and we will start to modify the treatment regimens to make them safer.We are there now. The issue with CAR T cells is that there are many options. We are still unsure if they can take the place of ASCT or if they have curative outcomes. We know that in relapsed large cell lymphoma, ASCT does result in curative outcomes, but its benefit is diminished in the current era because we are curing more people upfront and the biology of relapse is difficult to address.

The other population in whom CAR T cells could make a big impact is in patients who have double hit lymphomas and don’t respond to initial therapy. In those patients, transplant is unsuccessful, but there are emerging data indicating that CAR T cells can work equally well whether you have a double-hit or triple-hit biology compared with alternative biologies.

Are there any other studies whose results you are especially anticipating?

Can you discuss the role of axi-cel and how that has transformed the field?

We are trying to see if CAR T-cell therapy could be an option for an older group of patients in whom transplant toxicity is significant, making it not an option for them. CRS and neurotoxicity are major concerns that may cause one to shy away from this as an option for older patients. However, those are areas with a significant unmet need that we need to address.A number of new agents are entering into the market that are inhibiting pathways like PI3K. A CUDC-907 agent that was looked at by my colleagues demonstrated provocative activity in double hit lymphomas. There are also combination approaches that take advantage of our increasing understanding of biology that are attractive. The future is incredibly bright in the world of lymphoma.We are waiting to see the magnitude of the impact and whether or not it will be a small niche market for a select group of patients—given the logistics required in CAR T cells, the price tag associated with them, and the potential toxicity—or if we can get to a place where CAR T cells are more approachable and applicable to a broader patient population.

How do patients tolerate tisagenlecleucel?

There are certainly concepts in the future that can expand the access and the availability of these agents and hopefully we can see improvements in the toxicity profile, as well. They certainly have proven to be efficacious in a proportion of patients. It is transformative in that this is a biologic and a therapeutic approach that can expand beyond lymphomas. We see activity in patients with leukemia and, if you can target an antigen specifically, you can theoretically create a CAR T cell against it, but we have a lot of work to do. This work has been ongoing for the last 2 decades. It is finally coming into fruition but there is a lot to do.The toxicity of CAR T cells [occurs early on] and does happen in a minority of patients. Fewer than 1 in 5 patients may develop CRS and the rate of neurotoxicity is below 10%. It can be reasonably well tolerated. These are patients who often have disease-related symptoms and require treatment to bridge them to the CAR T cells to control the symptoms. The biggest challenge here is the disease itself. After that initial period of potential toxicity, then it is a well-tolerated therapy. The question is, “Can it result in a durable response for the patients as they recover from the treatment?"

Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 59th Annual ASH Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 578.