FDA Green Lights Label Update for Axi-cel to Include Prophylactic Steroid Use Spanning Approved Indications

FDA

The FDA has approved an update to the prescribing information for axicabtagene ciloleucel to include use of prophylactic corticosteroids across all approved indications.¹

The decision to update the label was based on findings from a new safety management cohort (cohort 6) of the phase 1/2 ZUMA-1 trial (NCT02348216), which was conducted to evaluate the impact of prophylactic corticosteroids and earlier treatment with corticosteroids and/or tocilizumab (Actemra) and prophylactic levetiracetam on the incidence and severity of cytokine release syndrome (CRS) and neurologic events.

Results revealed that no grade 3 or higher CRS events were observed in the 39 patients who comprised cohort 6 vs 13% of the 108 patients who comprised cohorts 1 and 2. Grade 3 or higher neurologic effects were reported in 13% of patients at the time of data cutoff vs 31% of those in cohort 1 and 2. One patient reported a late onset grade 5 effect after cutoff.

Moreover, the median time to onset of CRS in the patients who comprised cohort 6 was 5 days (range, 1-15), and the median time to neurotoxicity in was 6 days (range, 1-274).

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, global head of clinical development at Kite, stated in a press release. “Since the first approval of [axi-cel], Kite has worked closely with physicians to optimize all aspects of CAR T-cell therapy to enable as many patients as possible to have the chance to benefit from this treatment. Our responsibility includes research to expand into new diseases and earlier lines of treatment, but also continuously improving the efficacy and safety of our existing CAR T therapies.”

ZUMA-1 also included cohort 4, which was added to the FDA label in May 2021, and evaluated earlier treatment with corticosteroids and/or tocilizumab and prophylactic levetiracetam.

Cohort 6 builds on what is known about how to manage and minimize toxcities associated with the CAR T-cell product. Cohort 6 of ZUMA-1 included 39 patients with relapsed or refractory large B-cell lymphoma. Patients were allowed to receive bridging therapy following leukapheresis. Participants were administered conditioning chemotherapy for 3 days before a single infusion with axi-cel. They received oral dexamethasone at 10 mg

In Cohort 6, corticosteroids and tocilizumab were initiated earlier, at lower grades of CRS and neurologic events, than in cohorts 1 and 2 of ZUMA-1. All 39 patients received 3 prophylactic doses of corticosteroids. Participants received dexamethasone at a once-daily dose of 10 mg on days 0 through 2, and corticosteroids and/or tocilizumab for toxicity management earlier vs what was done for cohorts 1 and 2.

The primary end points of the analysis were incidence and severity of CRS and neurologic toxicities. Other end points comprised efficacy outcomes and biomarker analyses. To ensure comparability for those in cohort 6 and cohorts 1 and 2, an exploratory analysis was done after balancing for key baseline disease characteristics such as tumor burden, IPI score, number of prior lines of chemotherapy, disease stage, and lactate dehydrogenase levels.

Additional published data indicated that 68% of 40 patients did not experience CRS or neurologic events within 72 hours of infusion with the CAR T-cell product. Moreover, findings presented during the 2021 ASH Annual Meeting suggested that the toxicity management strategy leveraged for those in cohort 6 could improve select adverse effects without compromising the activity or effectiveness of axi-cel.²

Those in cohorts 4 and 6 received median cumulative steroid doses that were noted to be lower than what was used in matched cohorts 1 and 2, who received steroids to manage CRS or neurologic events when they were observed.

In October 2017, the FDA approved axi-cel for use in the treatment of adult patients with certain types of LBCL who have not responded to, or who have relapsed after, at least 2 other kinds of treatment.³

In March 2021, the agency gave the green light to the CAR T-cell product for use in adult patients with relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy.⁴ This decision was supported by findings from the phase 2 ZUMA-5 trial (NCT03105336), which demonstrated that axi-cel elicited a response rate of 91% in 81 patients with this disease, and this included a complete remission rate of 60%.

Most recently, in October 2021, a supplemental biologics license application was submitted to the FDA to expand the current indication of axi-cel to include the second-line treatment of patients with relapsed or refractory LBCL based on data from the phase 3 ZUMA-7 trial (NCT03391466).⁵ At a median follow-up of 2 years, the primary end point of event-free survival (EFS) vs standard of care (SOC) was met in this population (HR, 0.393; P < .001), which translated to a 60% reduction in the risk of EFS vs SOC.

References

1. US FDA approves new label update for CAR T-cell therapy Yescarta showing prophylactic steroid use improves management of cytokine release syndrome. News release. Kite; January 31, 2022. Accessed January 31, 2022. https://bit.ly/3HbxiFP
2. Oluwole OO, Forcade E, Muñoz J, et al. Prophylactic corticosteroid use with axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL): one-year follow-up of ZUMA-1 cohort 6 (C6). Blood. 2021;137(suppl 1):2832. doi:10.1182/blood-2021-147403
3. FDA approves CAR T-cell therapy to treat adults with certain types of large B-cell lymphoma. News release. FDA; October 18, 2017. Accessed January 31, 2022. https://bit.ly/3ufrEPe
4. US FDA approves Yescarta for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. News release. Kite. March 5, 2021. Accessed January 31, 2022. http://bit.ly/3kOyKnb
5. Kite submits supplemental biologics license application to US Food and Drug Administration for earlier use of Yescarta in large B-cell lymphoma. News release. Kite Pharma. September 30, 2021. Accessed January 31, 2022. https://bit.ly/3mkJbA7