Axi-cel Elicits Durable Response in Relapsed/Refractory FL

Axicabtagene ciloleucel (Yescarta; axi-cel), a CD19directed CAR T-cell therapy, showed promising efficacy data and a favorable safety profile in adult patients with relapsed or refractory follicular lymphoma (FL), according to data from the phase 2 ZUMA-5 trial (NCT03105336).

On March 5, 2021, the FDA granted accelerated approval to axi-cel for adult patients with relapsed/refractory FL after 2 or more lines of systemic therapy. Results from ZUMA-5 showed that axi-cel elicited an objective response rate (ORR) of 91% (95% CI, 83%-96%) among 81 patients in the primary efficacy analysis, 60% (95% CI, 49%-71%) of whom had complete remission (CR). The median duration of response (DOR) was not reached and the median time to response was 1 month.^1,2

In an interview with OncLive^®, Henry Chi Hang Fung, MD, chair of the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center in Philadelphia, Pennsylvania, discussed how the durable response of axi-cel fills an unmet need for this patient population and the potentially exciting future of the therapy.

OncLive: Please provide an overview of the patient population in the ZUMA-5 trial.

Fung: [Patients in ZUMA-5 had] relapsed/refractory indolent lymphoma, including FL and marginal zone lymphoma [MZL]. Approximately three-quarters of these patients had FL and [the remaining] patients had MZL. The median age was 61 years old, so a bit of a younger population. Most had advanced disease. Approximately 50% to 70% of patients had 3 to 4 prior regimens (median of 3; range, 1-10) and a third of them had [previous] lenalidomide [Revlimid].

What was noteworthy about the efficacy data in the trial?

The response was approximately 92%, which is an amazing response, similar to if not better than [what we see in] newly diagnosed patients and not [something you usually see in] relapsed/refractory patient population. The question is now, how many of them had CR? Response is great, but to have any meaningful, durable response, you need a CR. You can’t just have a response. [The CR rate] was approximately 60% in FL, which is pretty good for a patient population that has failed multiple regimens. Very few of them can achieve complete remission with other treatments.

[Even] more important is the DOR. For a patient with first relapse, the best you can achieve is approximately 2 years. For second relapse, it’s probably 1 year at best. Median survival has not been reached yet, we need longer follow-up, but it’s at least 18 months.

Please describe the mechanism of action of axi-cel.

Axi-cel is a CAR T-cell therapy. T cells are not effective by themselves in the patient’s body due to a number of reasons. We collect the patient’s T cells and genetically modify them in a manufacturing facility; in this case, Kite Gilead.

These genetically modified cells are targeting a protein on the surface of the lymphoma cells, CD19. We modify these cells and then give it back to the patient [where] they will further expand in the patient’s body. Not only will they attack the lymphoma cells but, unlike chemotherapy, they can persist in the body for quite a while. They can stay in the body for up to 18 months or even 2 years, and they may continue working in the patient’s body. This is not the traditional cytotoxic chemotherapy that tries to kill everything. This is a targeted therapy.

What should clinicians know about axi-cel in terms of safety? 

There are 2 main adverse effects. One is cytokine release syndrome and the other is central nervous system toxicity. Both can be potentially life-threatening. Now that we have experience [using this agent], events are very manageable and the chance of that the patient will die from this treatment is very small.

You need to have an experienced group, an experienced team to utilize this treatment, which has limited the patient access. Most of the treatment centers that are certified by the company and by the FDA are major hospitals and academic centers. It will potentially be difficult to get this treated to the [wider] community.

How does this approval affect the treatment standards for relapsed/refractory FL? 

This is a great addition for these patients, especially if they have failed 2 prior regimens. As I said, most of them only have a response to other treatments for a year. This is much longer, and you just need a little more follow-up that will probably conserve it.

At the same time, as 1 treatment, it’s an intense treatment and a complicated treatment; [the administration] lasts for approximately 2 months. I think it’s very important that we consider quality of life for patients with cancer and a treatment-free period. We don’t want [the patient] to have treatment continuously. We don’t know [how long this therapy will last]. Some are very optimistic; oncologists will tell you this could last for many years, but we don’t know. We don’t have that follow-up [data]. It could be long, potentially, or even curative.

What does the future hold for axi-cel? 

[Future] studies need to examine patients with earlier disease. We need to identify a patient population that has a high risk of failed first-line treatment and for those with first relapse. We need more prospective studies to determine if this [treatment] is beneficial.

At the same time, targeted therapy is evolving. This is one of the first-generation CAR T-cell therapies and we have many others coming, which may be more effective and more convenient with less toxicity. This is a moving target and overall good for our patients.

I think this is a breakthrough of CAR T-cell therapy. The first T-cell infusions I did in clinical trial was around 1996. Now we’re in 2021, a quarter of a century [later]. There’s been a lot of work and a lot of failures. But finally, it has come to fruition and there are 4 indications now. It is exciting for our patients, [and although it is] limited to relapsed/refractory disease, we can, hopefully soon, prove its use earlier with better outcomes that could potentially be curative. This is just a step; we have to [keep moving forward].

References

1. FDA grants accelerated approval to axicabtagene ciloleucel for relapsed or refractory follicular lymphoma. FDA. March 5, 2021. Accessed June 9, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-axicabtagene-ciloleucel-relapsed-or-refractory-follicular-lymphoma
2. Yescarta. Prescribing information. Kite Pharma Inc.; 2021. Accessed June 9, 2021. https://www.fda. gov/media/108377/download