Brexu-cel Is Effective and Tolerable in Relapsed/Refractory Mantle Cell Lymphoma Beyond ZUMA-2 Population

Yucai Wang, MD, PhD

Treatment with brexucabtagene autoleucel (brexu-cel; Tecartus) in the standard-of-care (SOC) relapsed/refractory mantle cell lymphoma (MCL) setting provided an efficacy and safety profile consistent with data reported in the phase 2 ZUMA-2 trial (NCT02601313), according to findings from a study investigating clinical outcomes with the therapy that enrolled patients with relapsed/refractory MCL with more diverse comorbidities and prior treatments than were allowed in ZUMA-2.¹

“Although the Consortium cohort included more patients with high-risk disease and comorbidities, the response, survival, and adverse event data are comparable to ZUMA-2, highlighting the efficacy, safety, and important role of brexu-cel in SOC practice,” lead study author, Yucai Wang, MD, PhD, of Mayo Clinic in Rochester, Minnesota, said to OncLive®.

Initial findings from ZUMA-2 showed that patients with relapsed/refractory MCL who received brexu-cel had an overall response rate (ORR) of 93% and a complete response (CR) rate of 67%.² The findings from this trial led to the 2020 FDA approval of brexu-cel in this population.³

To be eligible for enrollment in ZUMA-2, patients needed to have prior BTK inhibitor exposure, adequate organ function, and limited comorbidities. Patients were only allowed to receive corticosteroids and/or BTK inhibitors as bridging therapy after leukapheresis and before conditioning chemotherapy. However, the SOC indication for brexu-cel on the FDA label is for all adult patients with relapsed/refractory MCL, regardless of their comorbidities and prior treatment.

In this SOC study, at a median follow-up of 14.3 months post-infusion (95% CI, 12.7-15.9), the best ORR among all patients who received brexu-cel infusion was 90%, with a CR rate of 82% and a partial response (PR) rate of 8%.

Between August 1, 2020, and December 31, 2021, 189 patients with relapsed/refractory MCL underwent leukapheresis with the intent to manufacture commercial brexu-cel. Of these patients, 89% (n = 168) received infusion.

Patients had a median age of 67 years (range, 34-89), and 76% were male. In total, 21% had high-risk simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score, 58% had Ki-67 proliferation of at least 50%, 43% had blastoid/pleomorphic variants, 49% had TP53 aberrations, 29% had complex karyotypes, and 51% had disease progression within 2 years (POD24). Patients had a median of 3 prior lines of therapy (range, 1-10), and 77% had progressed on a BTK inhibitor.

Of the patients who received infusion, 79% would not have met ZUMA-2 eligibility criteria, the most common reasons being prior therapies (14% of patients were BTK inhibitor–naïve, 11% were anthracycline-/bendamustine-naïve, and 11% had over 5 lines of prior therapy), disease status (11% had central nervous system involvement), and comorbidities (20% had creatinine clearance of less than 60 mL/min, 14% had an ECOG performance status [PS] of 2 or higher, 10% had cardiac disease, 8% had pleural effusion, 8% had a platelet count of less than 50,000/µL, and 7% had an absolute neutrophil count of less than 1,000/µL). Overall, 14% of patients would have been ineligible for ZUMA-2 because they were naïve to BTK inhibitors, anthracyclines, or bendamustine, and 65% of patients would have been ineligible because of disease status or comorbidities.

A total of 68% of patients (n = 128) received bridging therapy, including BTK inhibitor–based (n = 31), venetoclax (Venclexta)–based (n = 10), BTK inhibitor and venetoclax combination–based (n = 17), chemotherapy-based (n = 44), radiation-based (n = 12), and lenalidomide (Revlimid)–based (n = 6) regimens, and CD20 inhibitors and/or corticosteroids (n = 8). In the 74% (n = 95) of patients (n = 128) assessed for response to bridging therapy, 33% responded, 6% with a CR and 27% with a PR. Patients received conditioning chemotherapy with cyclophosphamide and fludarabine at the same dose and schedule as in ZUMA-2.

The median times from leukapheresis to conditioning chemotherapy and conditioning chemotherapy to infusion were 28 days (range, 17-140) and 5 days (range, 5-15), respectively.

Of the patients who responded, the median time to best response was 30 days (range, 16-193). The respective CR rates for patients with TP53 aberrations, high-risk simplified MIPI, and POD24 were 72% (95% CI, 59%-83%), 65% (95% CI, 44%-83%), and 76% (95% CI, 65%-84%) vs 88% (95% CI, 77%-95%; P = .029), 82%-91% (95% CI, 72%-89%; 95% CI, 80%-97%; P = .019), and 89% (95% CI, 80%-95%; P = .028) in patients without these features.

The median duration of response was 17.2 months (95% CI, 14.4-not estimable [NE]). The 6- and 12-month continuous response rates were 75% (95% CI, 68%-82%) and 65% (95% CI, 56%-72%), respectively.

After infusion, the median progression-free survival (PFS) was 16.4 months (95% CI, 12.7-NE). The estimated 6- and 12-month PFS rates were 69% (95% CI, 61%-75%) and 59% (95% CI, 51%-66%), respectively.

The median overall survival (OS) after infusion was not reached (NR; 95% CI, 18.7-NE). The respective 6- and 12-month OS rates were 86% (95% CI, 79%-90%) and 75% (95% CI, 67%-81%).

In patients naïve to BTK inhibitors, the ORR was 96%, with a CR rate of 88%. The 12-month PFS and OS rates were 69% and 87%, respectively.

Of all patients who underwent leukapheresis, the median PFS after leukapheresis was 17.3 months (95% CI, 10.7-NE), and the median OS after leukapheresis was NR (95% CI, 17.7-NE).

The investigators observed inferior PFS in patients with high-risk simplified MIPI (HR, 3.82; 95% CI, 1.92-7.59; log-rank P < .001), Ki-67 proliferation of at least 50% (HR, 3.02; 95% CI, 1.43-6.38; log-rank P = .007), TP53aberration (HR, 1.98; 95% CI, 1.18-3.31; log-rank P = .008), complex karyotype (HR, 2.23; 95% CI, 1.25-3.98; log-rank P = .005), or blastoid/pleomorphic variant (HR, 1.61; 95% CI, 1.03-2.53; log-rank P = .036). The PFS was also numerically shorter in patients with POD24 (HR, 1.54; 95% CI, 0.97-2.43; log-rank P = .062). High-risk simplified MIPI, TP53 aberration, and complex karyotype were also associated with inferior OS.

Five patients had received prior allogeneic stem cell transplant. Three patients achieved CR after infusion, all of whom had ongoing responses at 8.0, 14.3, and 17.0 months, respectively. Two patients had early disease progression, at 0.9 months and 1.6 months post-infusion, respectively. One patient had graft-vs-host disease before CAR T-cell therapy that flared after infusion and required ruxolitinib (Jakafi) reinitiation. Three patients had received prior experimental CD19 CAR T-cell therapy. Of these patients, 1 did not respond to brexu-cel, 1 achieved a CR lasting 2.1 months, and 1 achieved a PR lasting 0.7 months.

The investigators found no statistically significant PFS differences among older patients with poorer ECOG PS, patients with higher Ki-67 proliferation, and patients with more prior lines of therapy. However, a worse OS was seen in patients who would have been ineligible for ZUMA-2 because of disease status or comorbidities.

Patients who had higher Ki-67 proliferation, more frequent blastoid/pleomorphic variant, TP53 aberration, and complex karyotype were more likely to receive bridging therapy than those without these features. However, the investigators found no statistically significant difference in PFS or OS between the 2 groups. Response to bridging therapy was not associated with PFS or OS.

Of the patients who had bendamustine exposure within 6 months prior to leukapheresis (n = 32), 41% did not receive infusion (P < .001). Of the patients who had prior bendamustine exposure within 6 months, within 6 to 24 months (n = 28), and over 24 months before infusion (n = 43), the respective ORRs were 53% (95% CI, 35%-71%), 75% (95% CI, 55%-89%), and 81% (95% CI, 67%-92%), and the respective CR rates were 47% (95% CI, 29%-65%), 64% (95% CI, 44%-81%), and 77% (95% CI, 61%-88%).

Patients with bendamustine exposure within 6 months or 6 to 24 months prior to leukapheresis had inferior PFS and OS after leukapheresis vs those with no prior bendamustine exposure. When adjusted for simplified MIPI and Ki-67 proliferation, these differences were no longer statistically significant. 

The nonrelapse mortality rates were 2.4% (95% CI, 0.8%-5.6%), 4.8% (95% CI, 2.2%-8.8%), and 9.1% (95% CI, 5.3%-14.1%) at day 30, day 90, and 1 year. Infections largely contributed to the 1-year nonrelapse mortality rate.

Overall, 90% of patients who received infusion experienced cytokine release syndrome (CRS), and 61% experienced immune effector cell–associated neurotoxicity syndrome (ICANS). In total, 7% and 32% of patients experienced grade 3 or higher CRS and neurotoxicity, respectively. One patient had grade 5 CRS. The median time to CRS onset was 4 days (range, 0-13). The median duration of CRS was 5 days (range, 1-33). The median time to ICANS onset was 6 days (range, 1-18). The median duration of ICANS was 6 days (range, 1-144+). Age 65 years or older, an ECOG PS of 2 or higher, high-risk simplified MIPI, blastoid/pleomorphic variant, bridging therapy, and bulky disease were associated with higher rates of grade 3 or higher ICANS. CNS involvement was not associated with higher rates of severe ICANS.

To manage CRS and/or ICANS, patients received tocilizumab (Actemra; 77%), corticosteroids (69%), anakinra (Kineret; 17%), and siltuximab (Sylvant; 3%). Additionally, 20% of patients required intensive care unit admission with a median stay of 3 days (range, 1-12). Of those patients, 11%, 3%, and 2% required vasopressors, mechanical ventilation, and dialysis, respectively. At day 90, 5%, 11%, and 18% of patients had prolonged significant anemia, thrombocytopenia, and neutropenia, respectively. In addition, 21% and 12% of patients had infections requiring antimicrobial treatment before day 30 and between day 31 and day 90, respectively.

“Traditional high-risk factors in MCL remain prognostic in patients treated with brexu-cel. Patients with disease-intrinsic high-risk factors remain a population with unmet clinical needs even in the CAR T era,” Yucai concluded.

Editor’s Note: Dr Yucai has an immediate family member who is employed by Merck and has stock and other ownership interests with Merck. Dr Yucai has received honoraria from Kite (Inst); has a consulting or advisory role with Loxo (Inst), Incyte (Inst), InnoCare (Inst), TG Therapeutics (Inst), Kite (Inst), and Lilly (Inst); and has received research funding from InnoCare (Inst), Incyte (Inst), Novartis (Inst), Genentech (Inst), Loxo (Inst), MorphoSys (Inst), and Genmab (Inst).

References

1. Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: results from the US Lymphoma CAR T Consortium. J Clin Oncol. Published online February 8, 2023. doi:10.1200/JCO.22.01797
2. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347
3. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. News release. FDA. July 24, 2020. Accessed February 13, 2023. https://www.fda.gov/drugs