1.Bispecific antibody studies continue to show encouraging results. 

Last December, mosunetuzumab became the first bispecific antibody treatment to receive regulatory approval in the US and parts of Europe. Since then, bispecific antibody treatments (which bind to and bring together the lymphoma B cells and the lymphoma-killing T cells) have been high on the list of promising avenues in treating, and hopefully curing, FL.  

Longer-term data on mosunetuzumab being administered to relapsed/refractory FL patients in the third line setting and later, show that after two years of treatment and follow up, more than three-quarters of patients had not progressed. Other treatments on the horizon within this category include odronextamab, epcoritamab and glofitamab, all of which have shown encouraging results so far in early clinical trials. Further data is still needed however on this relatively new class of drugs, to confirm the promising results in larger numbers of patients and with longer follow-up data. 

To date, most bispecific antibodies target CD20, and most CAR T-cell therapies target CD19. Both CD19 and CD20 are biomarkers on the surface of most normal B cells and FL cells. Agents targeting the other marker are in development in each class which may be useful as, depending on a patient’s previous treatments, they may respond better to one versus the other. 

Currently, in the countries where they are available in the clinic, both CAR-T and bispecific antibody treatments are reserved for the highest-risk patients, as a third line or more option. There is still a lot of work to be done to better understand the ideal sequence of treatments and which patient sub-groups will benefit the most from these different types of therapies. Although these results are promising, we can expect to see upcoming studies looking at how we may increase the effectiveness of CAR-T and bispecific antibody treatments and reduce the cumulative toxicities from multiple rounds of treatment, by bringing CAR-T and bispecific antibody treatments to earlier lines of therapy.  

2. Broader CAR T-cell therapy options are being explored. 

CAR T-cell therapies, which involve engineering a patient’s T cells to target lymphoma B cells, have shown promising results in relapsed/refractory and other high-risk FL patients. There are two approved CAR-T cell therapies in some parts of the world (Axi-cel and Tisa-cel). A third CAR T-cell therapy (Liso-cel) and other updated formulations are also showing promising results in FL patients, including those who are in the highest risk groups – i.e. those who relapse within 24 months from their previous treatment (also known as POD24). 

Important remaining challenges in CAR T-cell therapeutics include reducing side effects and toxicities, as well as understanding better which patients will benefit the most from them. There is a potential that CAR T-cell therapies may represent a curative approach for certain high-risk FL patients. However, we need additional data from larger studies with longer follow-up. We look forward to seeing such data from studies such as TRANSCEND-FL and ZUMA-22.

3. The future of BTK inhibitors.  

Inhibitors of BTK (Bruton’s tyrosine kinase; a protein which plays a key role in controlling B-cell growth) are very active in several B cell cancers, but have shown limited activity in FL when used on their own. Despite this, several studies have investigated or are investigating combinations of each of the three BTK inhibitors currently approved for other B-cell lymphomas: ibrutinib, acalabrutinib and zanubrutinib.  

In the most interesting study in this category, investigators treated heavily pretreated relapsed/refractory FL patients with a combination of zanubrutinib and obinutuzumab (an alternative immunotherapy to rituximab). This combination has just been approved by the FDA in the US for relapsed/refractory FL patients, where there are still very few options available in the clinic.  

4. New therapeutic agents on the horizon for FL. 

There were some examples of completely new therapies in development for B-cell cancers, including FL. Though it’s very early days for these drugs, and the safety and toxicity profiles are under investigation, it’s encouraging to see the ongoing progress.  

Examples include a class of drugs called CelMod® (similar to lenalidomide), as well as an alternative inhibitor of EZH2 (an epigenetic marker that affects lymphoma cell growth) to the treatment tazemetostat – currently approved in the US for third line relapsed/refractory FL patients. As we learn more about and understand better the underlying biology and disease, these treatments and others will potentially play an important role in treating FL.