COVID-19 Delays FDA Review of Liso-Cel for Relapsed/Refractory Large B-Cell Lymphoma

The review of the biologics license application (BLA) for the CAR T-cell product lisocabtagene maraleucel (liso-cel) for the treatment of adult patients with relapsed/refractory large B-cell lymphoma (LBCL) following at least 2 previous therapies has been delayed, according to Bristol Myers Squibb, the manufacturer of the therapy.¹

The regulatory agency was not able to conduct an inspection of a third-party manufacturing facility based in Texas during the current review cycle because of travel restrictions put in place because of the coronavirus disease 2019 pandemic. In light of this, the FDA has deferred action on the application until this task can be completed. A new action date has not been announced, but the drug remains under review.

“Bristol Myers Squibb continues to work closely with the FDA to support the ongoing review of the BLA for liso-cel,” Samit Hirawat, MD, executive vice president and chief medical officer of Global Drug Development at Bristol Myers Squibb, stated in a press release. “We are committed to bringing liso-cel to patients with relapsed or refractory large B-cell lymphoma who still have significant unmet need.”

The initial action date set for the BLA was August 17, 2020. In May 2020, the FDA added 3 months to the review period for liso-cel to allow for the review of additional information provided by the pharmaceutical company.

The BLA was based on findings from the phase 1 TRANSCEND NHL 001 study (NCT02631044), which demonstrated that the CAR T-cell product elicited an objective response rate of 73% in this patient population, with a complete response (CR) rate of 53%. Notably, the time to first CR or partial response to the agent happened at a median of 1 month.²

Moreover, at a median of 12 months, the median duration of response had not yet been reached. Approximately 60% of patients remained in response at 6 months and 54.7% remained in response at 12 months.

The median progression-free survival (PFS) reported with liso-cel was 6.8 months (95% CI, 3.3-14.1), with 44% of patients having remained free of progressive disease at the time the data were released during the 2019 ASH Annual Meeting. The median OS was 21.1 months (95% CI, 13.3–not reached); more than half, or 58%, of patients remained alive at 1 year, 86% of which were complete responders.

In the trial, a total of 344 patients with LBCL who had received 2 or more previous lines of treatment underwent leukapheresis. Of these patients, 269 received the CD19-targeted CAR T-cell product at 1 of 3 dose levels: 50 × 10⁶ (n = 51), 100 × 10⁶ (n = 177), and 150 × 10⁶ (n = 41). Notably, patients with high-risk characteristics, such as secondary central nervous system involvement and those with moderate medical comorbidities were permitted for inclusion. No lower limit of absolute lymphocyte count was established for eligibility.

Participants were able to receive bridging therapy following leukapheresis if disease control was urgently required, at the discretion of the investigator. Infusion with the CAR T-cell product was preceded by 3 days of lymphodepleting therapy with fludarabine and cyclophosphamide.

Twenty-give patients had been administered nonconforming product that was not determined to meet all specifications for liso-cel and thus, these patients were not included in the primary analysis dataset. In 2 instances, the product was unable to be manufactured.

A total of 13 patients who underwent CAR T-cell infusion were not included in the efficacy analysis because they did not have positron emission tomography (PET)–positive LBCL prior to administration of liso-cel (n = 4), no PET scan following bridging therapy (n = 6), and other reasons (n = 3). A total of 256 patients were comprised of 256 patients.

Patients had received a median of 3 previous lines of treatment. Thirty-five percent of patients previously underwent prior autologous or allogeneic hematopoietic stem cell transplant and 67% of patients had disease that was refractory to chemotherapy. Just under half, or 44%, never experienced a CR with previous therapy. Fifty-nine percent of patients received bridging therapy. All patients who received treatment were pooled for the analysis.

Moreover, the majority of patients, or 89%, had high-risk features that are known to be associated with worse overall survival. Specifically, some patients had high-grade BCL, an ECOG performance status of 2, primary refractory disease, and disease that was refractory to second line of therapy or later. Others has not undergone previous autologous stem cell transplant and they had never experienced a CR with previous treatment.

Additional results revealed that responses were comparable across all patient subgroups analyzed; this spanned several LBCL histologies and high-risk features. Notably, patients who had the highest tumor burden and those who were given bridging therapy experienced lower CR rates; however, they still responded to treatment with the CAR T-cell product. Moreover, the 25 patients who received nonconforming product had efficacy outcomes that were similar to the overall patient population.

When looking at histology, patients with double-hit lymphoma or transformed lymphoma from nonfollicular histologies had a PFS benefit that was comparable to the overall diffuse LBCL population. The median PFS for patients who experienced a CR was not reached; 65.1% of patients were free of disease progression. Moreover, 85.5% of patients remained alive at 12 months.

Liso-cel was determined to have a favorable safety profile. Sixty percent of patients reported grade 3 or higher neutropenia with the product. Other grade 3 or higher treatment-emergent toxicities included neutropenia anemia (38%) and thrombocytopenia (27%). Forty-two percent of patients experienced cytokine release syndrome (CRS) at any grade; this was observed at a median onset of 5 days. CRS that was grade 3 or greater in severity was experienced by 2% of participants.

References

1. Bristol Myers Squibb provides regulatory update on lisocabtagene maraleucel (liso-cel). News release. November 16, 2020. Accessed November 17, 2020. https://bit.ly/36KpABn.

2. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood. 2019;134(suppl 1):241. doi:10.1182/blood-2019-127508