Tisa-cel Adds a Potential New ‘Standard-of-Care’ in Third-Line Treatment of Follicular Lymphoma

Stephen J. Schuster, MD

Patients with follicular lymphoma have historically experienced diminishing efficacy when moving into the second and third lines of therapy. However, treatment with the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (tisa-cel; Kymriah) may provide a much more effective option in the third line and beyond.

On May 27, 2022, the FDA granted accelerated approval to tisa-cel for adult patients with relapsed/refractory lymphoma following at least 2 prior lines of systemic therapy.¹

Findings from the phase 2 ELARA trial (NCT03568461) supported the approval. In ELARA, patients in the primary efficacy population (n=90) achieved an overall response rate (ORR) of 86% (95% CI, 76.6%-92.1%) with a 68% (95% CI, 57.1%-77.2%) complete response (CR) rate. Notably, at a median follow-up of 9.1 months, the median duration of response (DOR) was not reached (95% CI, 15.6-not reached).²

In an interview with OncologyLive^®, Stephen J. Schuster, MD, the director of the Lymphoma Program and Lymphoma Translational Research at Penn Medicine in Philadelphia, Pennsylvania, discussed the implications of the approval on the treatment strategy for relapsed/refractory follicular lymphoma and the next steps for tisa-cel.

What did the treatment landscape look like for patients with relapsed/refractory follicular lymphoma prior to this approval?

If you look at follicular lymphoma, there are a number of factors that determine which patients are going to end up failing therapy and ultimately needing [a treatment] like tisa-cel. [With] first-line therapy, [patients] generally have a durable response of approximately 6.5 years. But once [they progress] go to the second line of therapy, it is approximately a year and a half. Once you are at the third line of therapy, remissions last approximately 10 months. So, you get these progressively shorter remissions once you need treatment.

There are 2 groups [of patients who] have a particularly poor prognosis: those who progress after their first therapy within 2 years and those who have only a 50% chance of survival at 5 years. Then there is a double-refractory group, who have failed to respond to an anti-CD20 monoclonal antibody and an alkylating agent, either together or as a part of different regimens. Those patients have a median DOR of under 2 years.

There are some patients who will fall into bad prognostic categories upfront, [such as] those who progressed within 2 years, or those, as part of their first couple therapies, who have become resistant to anti-CD20 antibodies and do not respond to alkylating agents. We have these patients who, when they needed therapy, at first about 80% of them would do well for over 5 years with their initial therapy. But then the remissions became progressively shorter and shorter.

[There are] treatment options, but none of them have reasonably long response durations. Some of the agents [such as] PI3K inhibitors were useful and patients responded for, on average, a little over 1 year with those regimens. They [also] had tremendous amount of adverse effects. We really did not have great therapies for patients with follicular lymphoma that were no longer responding to anti-CD20 antibodies or alkylating agents [prior to this approval].

What findings from the ELARA trial stood out to you and why?

We recently we did a pilot study in follicular lymphoma using tisa-cel. We observed in our trial that the response rates were great, and they were incredibly durable. For example, of our patients who had a CR we never reached the median DOR. Sixty percent of those patients were still in response, still in CR at 5 years.

In ELARA, the CR rate was 69% and we had a CR rate of 71%. A single institution, small trial, with a similar group of patients with follicular lymphoma using the same product had the same outcome as a multicenter, global trial. That is very satisfying for scientists like myself, you want people to be able to reproduce your results. Similarly, we reported a 79% ORR and ELARA reported an 86% [ORR].

What stood out to me was [that] these response rates matched ours. Even though the follow-up in ELARA was relatively short, approximately just under a year and a half, I anticipate that they are going to see the similar durable responses that we saw. I am optimistic that this will be a game changer for patients.

How does this approval shift the treatment paradigm in follicular lymphoma?

I do not believe we will be using [agents such as] PI3K inhibitors and there will be less use of EZH2 inhibitors.

I should mention that there is another CAR T-cell agent that has been approved for follicular lymphoma: axicabtagene ciloleucel [axi-cel; Yescarta]. Axi-cel has a different costimulatory domain within the chimeric receptor, so it is a more briskly proliferative cell product. It is very effective, as is tisa-cel. But it is much more toxic and requires hospitalization and patient monitoring. Tisa-cel is well tolerated. In fact, with rare exceptions that have comorbidities, I treat these patients as outpatients.

What future directions do you envision for tisa-cel in this patient population?

I hope that there is earlier application in high-risk patients. These will be the double-refractory, the [anti-]CD20 and alkylating agent refractory population. And that could be if [a patient] had the combination of an alkylating agent and [anti-]CD20 antibody upfront and progressed after that, rather than waiting for a second regimen to fail and using a third line.

[Also], the patients that have progression of disease within 24 months of their initial treatment, rather than having them fail another line of therapy to be able to make the FDA label and receive tisa-cel, I would like to see that population be able to get it as their next therapy so that they do not have to be subjected to another therapy that is likely to fail.

[Additionally], the current regimens for second line and beyond on average only achieve response durations between 1 year and 1.5 years. So, rather than going to those agents in the space where those agents are generally used, tisa-cel makes sense. It is a one-time treatment and when it is over, it is done.

If [a patient is] a responder, they have approximately two-thirds chance of being disease free at 5 years. Although the response rates are high, there still are 20% [of patients] that do not respond to CAR T-cell therapy. But, if you add all those responders and non-responders together, you are still talking about over 40% of patients who get this are going to be free of disease in 5 years, of all comers.

It is well tolerated; it is going to be more widely utilized than axi-cel simply because of the safety. Also, with tisa-cel you have the benefit of being able to use bendamustine monotherapy as a lymphodepleting agent as opposed to a relatively high dose of cyclophosphamide, which you need for axi-cel. There are a number of reasons why [tisa-cel] is a good product and should be considered [in the] third line as a standard of care.

References

1. FDA approves tisagenlecleucel for relapsed or refractory follicular lymphoma. News release. FDA. May 27, 2022. Accessed June 29, 2022. bit.ly/3ua1Ovb
2. Kymriah. Prescribing information. Novartis; 2022. Accessed June 29, 2022. bit.ly/3OO1dam