Tisa-cel Offers Durable Responses in R/R Follicular Lymphoma

Stephen J. Schuster, MD

Tisagenlecleucel (tisa-cel; Kymriah) demonstrated lasting effectiveness with a favorable safety profile among patients with relapsed/refractory (R/R) follicular lymphoma (FL), including in high-risk patients, according to updated, long-term findings from the ELARA trial (NCT03568461).

Durable responses were observed among those enrolled in the trial and treated with tisa-cel, which lasted over 3 years after treatment. A high proportion of patients with R/R FL maintained positive responses to tisa-cel, including those in the high-risk subgroup who experienced progressive disease at 24 months (POD24). At a median follow-up of 30 months, the median progression-free survival (PFS) was 37 months. The 36-month PFS rate in the overall population was 53% and 69% among those with a complete response.

The median overall survival (OS) among those treated with tisa-cel was not reached, and at 36 months, the OS rate was 82%. Duration of response (DOR) and time to the next treatment were also not reached at a median follow-up of 41 months.

There were no new safety concerns identified during long-term follow-up, and the treatment profile remains consistent with previous observations. The most common high-grade toxicities observed any time after infusion included neutropenia (43%) and anemia (19%), with frequent serious adverse effects including cytokine release syndrome (20%), pneumonia (11%), and febrile neutropenia (8%).

“The results were surprisingly great [with] high response rates, 68% complete response rates in fact, and those responses appeared durable. We are still above the median, certainly for the patients that achieved complete response, and there has been no recurrence of disease or deaths,” Stephen J. Schuster, MD, told Targeted Oncology^TM, in an interview.

Overall, tisa-cel offers a promising treatment option for patients with R/R FL, with sustained efficacy, a manageable safety profile, and potential predictive biomarkers for response.

In the interview, Schuster, professor of medicine at the University of Pennsylvania, further discussed the rationale and findings from the phase 2 ELARA study of tisa-cel among patients with follicular lymphoma.

Targeted Oncology: Can you discuss the background and known data for tisa-cel?

Schuster: For chimeric antigen receptor [CAR] T-cell therapy, most people understand the mechanism of action and how it works. It is using your body's immune system to treat the cancer, and it is genetically engineering the T cells to be directed towards the cancer cells to eliminate them. Previously, we had done work in more aggressive lymphomas, meaning those lymphomas that have a faster pace, with the same product, with excellent results. It was FDA-approved, and next moved on to follicular lymphoma, which is the second most common B-cell lymphoma after the aggressive large cell lymphoma cohort. We had excellent results, probably even better overall than we got with the aggressive lymphomas, not surprisingly, despite the fact that these were highly pretreated patients. On average, these patients had a prior number of therapies of 4, ranging up to about 12. The majority of them had been refractory or failing to respond to therapy before going on to the ELARA trial.

Lymphomas: © immimagery - stock.adobe.com

The results were surprisingly great [with] high response rates, 68% complete response rates in fact, and those responses appeared durable. We are still above the median, certainly for the patients that achieved complete response, and there has been no recurrence of disease or deaths. The progression-free survival is high, nowhere near the median, up above 70%. For all patients treated on the trial, partial responders and complete responders together, we still have not reached the median. At 3 years, it is about 53%, just above. So good therapies, single treatment, and the patients that receive it seem to have durable responses at this point.

Looking back on the outcomes of patients with aggressive lymphomas and on a pilot study I ran the University of Pennsylvania over 10 years ago in follicular lymphoma, we could expect that probably, these patients will continue to, at 5 to 10 years, still be in remission, because as we saw on the pilot studies. About two-thirds of the patients were free of disease between 5 and 10 years now. This multicenter ELARA trial, which is an international, multicenter trial with about 100 patients, confirms what we had found earlier. It is a good therapy and it is now FDA-approved for third-line therapy or later therapy for patients with relapsed/refractory follicular lymphomas.

What factors might contribute to long-term clinical outcomes with tisa-cel?

There are 2 primary factors that determine outcomes. One is the status or nature of the disease in the individual patient, and the other is the baseline immune fitness of the patient because it is a T-cell or T lymphocyte-based therapy. It is the fitness of the immune system that determines how active it is against lymphoma. We look at these 2 things. What are the factors that are bad? We call it bulky disease, meaning large volume disease. Over two-thirds of the patients on the ELARA trial had bulky disease, so they were not a good prognosis group of patients. All patients who progress, meaning relapse or recur with their disease within 24 months of ending a therapy, usually, particularly if it is a CD20 antibody and chemotherapy combination, have a bad prognosis. We call that POD24, or progression of disease within 24 months. More than two-thirds of the patients on this trial had progression of disease within 24 months and advanced stage disease as well with a median number of prior treatments of 4, but up to 12 in a couple cases. This is a group of patients for which we do not have, prior to the approval, satisfactory therapy.

Some of these patients have had 4, 5, 6, or 7 prior therapies. Their response duration, how long the responses lasted after each therapy gets shorter, until it is not working anymore. Suddenly, we have this therapy that comes along in the fourth-, fifth-, sixth-line, and now more than half the patients are in remission in 3 years. That is unusual because these patients are anticipated by that point in time to have short remission durations. Compared with historical controls, it is a very good therapy. It is now available and we [presented] the longer-term follow-up. Last year a 2-year follow-up was presented, and we published the earlier pivotal trial [results]. It is a therapy that is clinically available now. [One does not] have to enroll in a research protocol to get it, [and] it is a good therapy for a group of patients that we previously did not have a good therapy for.

Were any updates from this longer-term follow-up of tisa-cel particularly exciting or surprising?

Some of the correlates, the immune fitness correlates, we are beginning to dive into now, because early on to get a drug approved, [we were] primarily interested in safety and efficacy, how well it works, and how toxic it is. There are unique toxicities to this approach, but manageable. In any event, we started looking at some of the biological factors. Not surprisingly, the patients that had T cells with more of a capacity to survive longer and proliferate more and differentiate to killer cells for longer periods of time. Patients that had a greater proportion of those cells in their blood, from which we made the product, had better results. We have some survival curves showing the outcome based on the fitness or the phenotype of the immune cells, the T cells. We will be able to predict who is likely to do better, 1 patient vs the other, but even the patients who have the poor prognostic features, and the unfit, do much better than what we had before we had this therapy. We are studying it in greater detail because we want to make it better for everyone. Even as it stands at this point in time, it is better than what we had prior.

What are the potential implications of these findings for the future management of these patients?

Moving it up earlier. If we have a therapy that works better than everything else, how many therapies must a patient go through before you can get to the good stuff? The stuff that is a 1-time treatment? Now, the way the drug is labeled, [a patient] has to have at least 2 prior therapies. This can be used in the third-line or later, fourth-, fifth-, sixth-line, but it cannot be used like a second-line of therapy. I would not recommend it for first-line therapy because many patients with follicular lymphoma, probably 75% or 80%, do well with existing therapies. It is the 20% of patients with follicular lymphoma, particularly those that progress within 2 years of the first therapy, that we should be looking to move this up. We give the first-line therapy, their POD24 is a marker for bad outcomes down the line, progressively shorter remissions, that group is who we are looking at for second-line therapy, in my opinion. [It is] not yet done, so I cannot recommend that as treatment, but it should be done.

What should a community oncologist take away from this research of tisa-cel?

The key takeaways are that we have a therapy for patients with follicular lymphoma that is recurring, and if they have recovered after 2 lines of therapy and we want to offer them a therapy, that is capable of giving them a prolonged remission in over two-thirds of the patients, so we could consider CAR T-cell therapy, and refer patients, if you do not do it yourself, to a center that that does it.

There are new alternatives too. There is a bispecific antibody that also is based on T cells, but does not require any genetic modification. That is also good. That is recently approved as of early [in 2023]. This is now in the possibilities for these patients that are early progressors with large disease volume and a poor prognosis. For patients with follicular lymphoma, that is only approved for as third or later therapy and we will want to see earlier therapies with that too. In my opinion, when you find out that you have something that works well or better than anything else in patients with a poor prognosis, it will work better in patients with a better prognosis, and if we can, we should move it up.

REFERENCE:

Schuster SJ, Fowler N, Dickinson M, et al. Clinical outcomes of patients with relapsed/refractory follicular lymphoma treated with tisagenlecleucel: phase 2 Elara 3-year follow-up. Blood. 2023;142 (suppl 1):601. doi:10.1182/blood-2023-180936