Expert Highlights Ongoing Research Efforts to Advance Treatment Paradigm in Follicular Lymphoma

Stephen Douglas Smith, MD,

Stephen Douglas Smith, MD,

The treatment paradigm in follicular lymphoma (FL) has seen a wave of advancements in terms of targeted therapies, and patients have more treatment options than ever at each stage of disease. However, available therapies still need to be improved for patients who are refractory to chemotherapy or relapse after stem cell transplantation.

“We still have patients with long histories of chemotherapy-refractory disease or patients who relapse after stem cell transplantation, and those are another set of patients that we have new options that are FDA approved, but we really need more. We need longer, more durable treatment options with longer remissions than those that are currently approved,” explained Stephen Douglas Smith, MD.

One potential non-chemotherapy approach that has investigators excited is immunotherapy, said Smith, with ongoing trials looking at treatments such as antibody drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T cells.

Smith and his fellow colleagues at the University of Washington School of Medicine are currently recruiting patients with FL and diffuse large B-cell lymphoma for a clinical trial investigating rituximab (Rituxan) plus pembrolizumab (Keytruda) (NCT03401853). The investigators are hoping that combining these 2 agents with unique mechanisms of action together may boost the chance of achieving deep remissions in a high percentage of patients.

In an interview withTargeted Oncology,Smith, clinical director, Lymphoma, Seattle Cancer Care Alliance, associate professor, UW Department of Medicine, Division of Medical Oncology, and associate member, Fred Hutchinson Cancer Research Center, Clinical Research Division, discussed recent advancements in FL, new treatments currently being evaluated in clinical trials, and the challenges that still exist within this space.

TARGETED ONCOLOGY:Can you start by discussing the current treatment landscape for FL?

Smith:In FL, there has been this rapid expansion of new targeted therapies which is a great issue, but it also confuses the treatment pathways. There have been very many options at each stage, but first, you have to remember the principle that not all patients need treatment and that there is a goal of achieving deep and durable responses. However, you can’t do that at any cost. You have to consider quality of life and toxicities for each given patient. Things like tumor burden, age, comorbidities, and preferences have to be considered when you are selecting treatments and that goes for both first-line and the relapsed setting.

In general, it’s chemotherapy plus a monoclonal antibody or lenalidomide plus a monoclonal antibody. For most patients, they are fit and have enough tumor burden or symptoms to warrant treatment. You could also consider doing a monoclonal antibody alone for the patients whose morbidities are at advanced stage.

Second-line treatment depends very, very much on the duration of the first remission. There has been a lot of attention to patient outcomes who relapse within the first 2 years of starting therapy, and that is a very different scenario from this area of patients who achieve a long remission at or are exceeding the median that is described for a given regimen. In the first situation, an early relapse within a couple of years, you have to do something to break this cycle of relapse and disease progression because those patients have inferior survival rates. That is the moment for considering a clinical trial, considering new targeted therapies as opposed to chemotherapies, or considering transplantation.

For the second group of patients who achieve long remission, they have many options. They can consider repeating the same treatment or select among 3 different FDA-approved or experimental modalities to treat the FL which would again balance their preference, age, and comorbidities, and aim for maintaining quality of life (QoL) as well.

TARGETED ONCOLOGY:What are some of the challenges with starting a patient on initial therapy? How do you decide when to start a patient and when to only watch?

Smith:The big challenge is when to consider a chemotherapy approach or nonchemotherapy approach now that we have a randomized trial which tests lenalidomide and rituximab (Rituxan) showing fairly comparable outcomes to chemotherapy and rituximab. The first question is do you consider a nonchemotherapy approach? That is a challenge. The second is if you decided to embark on chemotherapy, would you use what we consider the more modern and/or more potent regimen including the use of obinutuzumab (Gazyva) instead of rituximab, as shown in the GALLIUM trial, because this may improve outcomes, but also appears to come at increased costs in terms of toxicities, particularly infectious toxicities.

The second part of the question about deciding when to start therapy has not changed a lot over the years. Therapies have advanced quite a bit, but we still know that a large proportion of patients won’t require any treatment for a couple of years. Most patients will need therapy within the first few years of diagnosis of FL, but there is a subgroup of patients who could go 5 to 10 years where initiating therapy for very asymptomatic disease would be very inappropriate.

There are published criteria from the French group known as the GELF criteria that are prominently considered to help decide when to start therapy. There are also various risk models some would use such as the Follicular Lymphoma International Prognostic Index (FLIPI) or FLIPI 2 score. In reality, there is a high degree of nuance here, and patients who are experiencing progression of their FL, even if it’s not quite to the thresholds described in the GELF risk model, for example, or patients who have specific logistical concerns or symptoms which may be higher to attribute to lymphoma but are possibly attributable, those patients may need therapy earlier. It is still a nuance in individual decision with certain guidelines to help make that.

TARGETED ONCOLOGY:What are some of the most recent advances we have seen in FL?

Smith:We’re all seeing an array of new treatments that are FDA approved, specifically in the small molecule area of PI3-kinase inhibitors. There are now 3 drugs approved for FL treatment in the relapsed setting, and those are sort of representing a new set of options for patients, even who have failed chemotherapy and rituximab specifically. These drugs were tested in patients who failed chemotherapy and rituximab and have subsequently shown they can produce fairly good outcomes even if they have early relapses. The data requires more time to mature, and there certainly is a role of PI3-kinase inhibitors isn’t exactly defined, but this is a major set of FDA-approved therapies that have changed the landscape a lot.

There are of course other intercellular targets such as other kinases that are also increasingly being targeted by new drugs, often oral and some IV therapies, but I think the other major arm that everyone is excited about is immunotherapies. These can range from new antibodies such as antibodies targeting antigens other than CD20 or new types of antibodies, the bispecific antibodies. Those can bind 2 antigens such as CD20 and CD3, for example, which would recruit T cells onto the B cell. Finally, there is a class of ADCs which deliver a chemotherapy payload to the malignant cells. I say that the immunotherapy category involves a set of new antibodies that are very exciting.

The other arm of immunotherapies that people talk about in an increasingly focus of trials in FL is CAR T-cell therapy. There are no FDA approvals in FL for CAR T-cell therapies yet, but there are a number of clinical trials testing such therapies, and they appear to be safer and safer with lower rates of severe cytokine release syndrome and neurotoxicity in the early forms of CAR T cells.

TARGETED ONCOLOGY:What are some of the unmet treatment needs that still exist for this patient population?

Smith:For the early relapse within 2 years of therapy, there is a good consensus that these patients should be now offered a clinical trial specifically geared toward that situation or a novel nonchemotherapy approach. That is one of the greatest current unmet needs.

We still have patients with long histories of chemotherapy-refractory disease or patients who relapse after stem cell transplantation, and those are another set of patients that we have new options that are FDA approved, but we really need more. We need longer, more durable treatment options with longer remissions than those that are currently approved. I would say there is no home run for treating chemotherapy-refractory or relapse after stem cell transplantation either.

I think the last couple of unmet needs would be grade 3A FL. There’s been a lot of debate as to how to treat those patients and whether their disease is more of an indolent process or may share features of a more aggressive lymphomas and require an anthracycline. Finally, patients who transform to DLBCL, particularly after extensive prior therapies, are a major unmet need.

TARGETED ONCOLOGY:Can you discuss the trial of rituximab plus pembrolizumab (Keytruda) currently ongoing at your center?

Smith:We’ve known from early gene expression profiling data that microenvironment matters in FL quite a bit in that patients are really living with this disease for a long time. That implies that there is some sort of check and balance that may be going on with regard to immune control and eventual immune invasion by the tumor cells that lead to FL progression and potentially the transformation. We know that microenvironment matters in FL. We know that rituximab is a drug which works by stimulating immune responses, and pembrolizumab is specifically geared towards reversing the exhausted phenotype of T cells when they encounter antigens such as PD-L1. Even if there is not tumor cell PD-L1 expression, that may be that these drugs can exert a favorable effect on the microenvironment and produce remissions. So far, we would not expect a very high single-agent response rate of FL to pembrolizumab, so the combination may boost that chance for a deep remission in high percentage of patients who respond. We are relying on 2 therapies with unique mechanisms of action to provide a relatively safe and nontoxic approach for immunotherapy for FL.

I think that if we are saying these therapies are in and of themselves not likely to result in responses in high percentages of FL patients, then we have to do additional studies to determine which patients may benefit. There is a companion study here that is looking at biomarkers to predict response and resistance to immune checkpoint inhibitors such as pembrolizumab that patients also have the option of participating in.

I think we would emphasize that this combination has a good rationale on the microenvironment in FL being critical and that it is likely a relatively safe combination based on the available data so far. It is a non-intensive approach for patients. We do need to sort who will mostly respond and achieve durable benefit.

TARGETED ONCOLOGY:What type of patients are being enrolled on this trial?

Smith:It’s recruiting both arms right now. It’s recruiting for patients with DLBCL with either relapse after stem cell autologous transplantation or [who are] considered ineligible for it. For FL, you have to have relapsed/refractory disease with prior treatment including a CD20 antibody. They also must have to have an indication for treatment. In that setting, you would also want to know that because there are so many options, there is no other option for that given patient that has a better risk-benefit ratio as determined by investigators. You do want to consider all options for these patients and offer this trial for patients with FL that we think are best suited based on their age, preferences, and comorbidities.

TARGETED ONCOLOGY:Are there any other clinical trials that you would like to highlight?

Smith: