Fowler Highlights Trials Accruing at MD Anderson for Relapsed/Refractory Follicular Lymphoma

Nathan H. Fowler, MD

Nathan H. Fowler, MD

For patients with relapsed/refractory follicular lymphoma (FL), the treatment options remain limited beyond the third-line setting. Often times, resistance emerges after the second- or third-line treatment that applies to multiple classes of therapeutics.

Additionally, recent data suggest that patients who relapse early on in their disease course tend to have poorer outcomes, but more research is needed to find potential predictors of these patients earlier on in their treatment.

“We need better understanding of the molecular drivers of FL. Unfortunately, little is known about the mechanisms of resistance and long-term survival,” Nathan H. Fowler, MD, said. “Hopefully, ongoing trials looking at whole genome sequencing will shed further light on this very heterogenous disease.”

Fowler is the principal investigator at The University of Texas MD Anderson Cancer Centerfor the ongoing ELARA trial (NCT03568461), a phase II, single-arm multicenter, open-label trial evaluating the efficacy and safety of tisagenlecleucel (Kymriah) in adult patients with refractory or relapsed follicular lymphoma.

“Essentially, we know this is an unmet need, we know patients with relapsed FL who are in the third- or fourth-line setting have limited treatment options, and very few of the options that are currently available will lead to long-term cares,” Fowler said.

In an interview withTargeted Oncology, Fowler, associate professor in the department of lymphoma/myeloma, at The University of Texas MD Anderson Cancer Center, discussed the current research for the treatment landscape of relapsed/refractory follicular lymphoma, including 3 clinical trials at MD Anderson that are currently accruing patients with this disease.

TARGETED ONCOLOGY: What does the treatment landscape look like currently for patients with relapsed/refractory disease?

Fowler:There’s lots of treatment options available for patients with relapsed FL. The emphasis in those options include PI3K inhibitors, monoclonal antibodies, combined chemotherapy, and stem cell transplant, as well as emerging cellular therapy approaches like CAR T cells.

TARGETED ONCOLOGY: What are some of the recent data we have seen in this setting?

Fowler:One of the most exciting presentations at ASH was the results of the AUGMENT trial. This was a trial that compared lenalidomide (Revlimid) and rituximab (Rituxan; R²) to rituximab alone in patients with relapsed FL. That study showed that there was a statistically significant benefit with R²compared to rituximab alone in terms of overall response rate, complete remission rate, and progression-free survival (PFS) in patients with relapsed FL.

This year, we also saw the approval of 2 PI3K inhibitors for treatment of patients that are in their third line of therapy, including copanlisib (Aliqopa) and duvelisib (Copiktra). These are 2 PI3K inhibitors that hit a couple different isoforms of PI3K with response rates around 50% in patients with relapsed/refractory disease.

TARGETED ONCOLOGY: What are some unmet needs in this space that should be addressed?

Fowler:There are still several unmet needs in patients with relapsed low-grade FL. Specifically, most of the options that are currently available for patients in the third-line are not curative. The PFS is often less than 1 year, which means patients who are in the third-line will often need fourth-line therapy fairly quickly after starting salvage treatment. Many times, in patients who have gone through the second- or third-line of therapy, we see emerging resistance, and sometimes that resistance applies to multiple different classes of therapeutics. I would say one of the greatest unmet needs is trying to identify agents that work in this fairly resistant subpopulation of FL.

Recent data has also suggested that patients who relapse early following first- or second-line therapy tend to have inferior outcomes long-term. We’re still looking for ways to identify those patients at diagnosis as well as following their first line of therapy. Many of the current approaches include looking at the genomic profile of patients at diagnosis and trying to determine whether molecular changes early in the disease could potentially predict inferior outcomes in patients in the first and second line of therapy. A lot of that is still ongoing, and we haven’t seen very much published.

We know that the microenvironment and a patient’s underlying immunity plays a huge role in not only the development but survival of FL cells in patients with the disease. A lot of the current efforts are looking at ways to integrate novel approaches. We are trying to modify the patient’s composition of immune cells as well as the activity in their immune cells within the lymph nodes and the bone marrow so that this microenvironment no longer supports tumor growth.

TARGETED ONCOLOGY: What new strategies are currently being looked at to treat relapsed/refractory FL?

​​​​​​​Fowler:I think some of the most exciting data may come from ongoing CAR T cell studies for relapsed FL. Very early data published by Stephen J. Schuster, MD, and colleagues showed significant prolonged responses in patients with relapsed FL who received CAR T-cell therapy. That data was in a fairly small number of patients with limited follow-up, and I think it would be very interesting to see the results of larger, ongoing phase II trials in this population. Specifically, there are large phase II trials going on with axicabtagene ciloleucel (axi-cel; Yescarta) in this population that are now reaching full accrual and may be presented at upcoming meetings. To me, that’s one of the exciting things to come out. We know that CAR T cells have significant activity in large B-cell lymphomas and acute leukemias, but they may have an even greater role in patients with relapsed FL.

I’m also looking forward to seeing longer-term data with other novel agents such as anti-CD47 antibodies and, I would say, other targeted approaches like EZH2 inhibitors in FL. There are several phase II trials ongoing with these agents in FL, and we may see that data presented at meetings in the near future.

TARGETED ONCOLOGY: Could you discuss some of the background for the ELARA trial?

​​​​​​​Fowler:As I mentioned, patients who are in the third or fourth line of therapy with FL have limited treatment options that result in prolonged PFS. We really need new agents that will truly change the course of this disease, especially when we are looking at patients in the third-line. Traditionally, those patients were often referred to autologous stem cell transplant or allogeneic stem cell transplant. However, those approaches are associated with significant morbidity and mortality. Only limited numbers of patients went on to that therapy because they required an excellent performance status.

The reason we designed the ELARA trial was to try to develop a cellular therapy in these highest-risk patients that could potentially change the long-term natural history of FL. We’ve seen excellent responses with tisagenlecleucel in patients with relapsed large cell lymphoma, and the side effect profile may be different than other existing CAR T-cell products.

Essentially, we know this is an unmet need, we know patients with relapsed FL who are in the third- or fourth-line setting have limited treatment options, and very few of the options that are currently available will lead to long-term cares. We know that this product in other B-cell malignancies is extremely effective and is associated with limited toxicity. It made sense after looking at the efficacy and toxicity data of this drug in large cell lymphoma to move this into other histologies where there is an unmet need. It’s clear that patients in the third-line of FL need better treatment options.

TARGETED ONCOLOGY: Could you also discuss the trial evaluating obinutuzumab (Gazyva) and zanubrutinib (BGB-3111) (NCT03332017)?

​​​​​​​Fowler:Zanubrutinib is a third-generation BTK inhibitor that sends significant activity in chronic lymphocytic leukemia. It may also be active in patients with FL. Other trials combining BTK inhibitors with monoclonal antibodies have shown activity in FL with response rates of 80%.

We designed this trial to look at patients who have relapsed lymphoma, and the trial was designed to use a next-generation anti-CD20 antibody, specifically obinutuzumab, with a third-generation BTK inhibitor in patients with relapsed FL. The hope was that with this approach, we could overcome resistance patterns that are often associated with relapsed low-grade disease. We are using a new antibody and a new BTK inhibitor, and the premise, again, is first-generation antibodies like rituximab and first-generation BTK inhibitors are very effective in FL, so if we then move this approach into the relapsed setting, we might be able to see responses in patients with resistant disease.

TARGETED ONCOLOGY: Are there any other FL trials that you’d like to highlight?

​​​​​​​Fowler:We are also conducting a study with lenalidomide and obinutuzumab in relapsed as well as untreated FL. Early data looks very impressive and we hope that substituting out the next-generation monoclonal antibody for rituximab may lead to improved efficacy compared to rituximab in lenalidomide combinations.

TARGETED ONCOLOGY: Is there anything else you would like to add?

​​​​​​​Fowler: