Folding CAR T-cell Therapy Into Relapsed/Refractory MCL Treatment

Treatment with the CD19-directed CAR T-cell therapy brexucabtagene autoleucel (Tecartus) demonstrated significant activity, marked by high response rates and prolonged survival, in patients with relapsed mantle cell lymphoma (MCL) in the pivotal phase 2 ZUMA-2 trial (NCT02601313), which despite the eligibility criteria of the study is showing equally impressive activity in real-world populations.

Results of the ZUMA-2 trial made a case for the use of CAR T-cell therapy for patients with MCL.¹ Investigators assessed the use of brexucabtagene autoleucel in patients with relapsed disease. The FDA approved the cellular therapy in July 2020 for the treatment of patients with relapsed or refractory disease.²

Among the 60 patients with at least 7 months follow-up enrolled in the ZUMA-2 trial, the objective response rate (ORR) was 93% (95% CI, 84%-98%), with 67% (95% CI, 53%-78%) of responders having a complete response (CR). Further, among the 54 patients with a response, 27% had a partial response (PR). The median duration of response was not reached (95% CI, 8.6-NE) and median time to initial response was 1 month (range, 0.8-3.1) with a median time to CR of 3.0 months (range, 0.9-9.3).

In terms of survival data, the median progression-free survival (PFS) was not reached (95% CI, 9.2-NE) and the median overall survival (OS) was also not reached (95% CI, 24.0-NE). The 12-month estimated PFS, and OS rates were 61% and 83%, respectively.

Of note, patients enrolled in ZUMA-2 were required to have disease that was refractory to BTK inhibitor therapy or had disease that had progressed during or after receipt of a BTK inhibitor. Contrary to this eligibility criteria, the FDA did not include this stipulation in the label for the cellular therapy, Caron Jacobson, MD, MMSC, noted, as part of a panel discussion with other hematologic experts.

“The FDA actually approved a much broader label, so it’s any [patient with] relapsed or refractory MCL,” Jacobson said, adding that it was a very forward-thinking decision by the agency. “The vast majority of patients in the real world, as we’ve seen from [results of] 2 different series— 1 from Europe and 1 from the United States—have received a BTK inhibitor. But what’s very interesting is that approximately 18% of patients in the US series had not received a prior BTK inhibitor and their results following brexucabtagene autoleucel were nearly identical to patients who had.”

Jacobson was an investigator involved in a multicenter, retrospective analysis of patients treated with brexucabtagene autoleucel in a nontrial setting across 14 centers in the US Lymphoma CAR T Consortium. In results presented at the 63rd American Society of Hematology Annual Meeting and Exposition, data for 93 patients with MCL who received brexucabtagene autoleucel were available.3 Baseline patient characteristics of the real-world population showed 72% of patients would not have met the criteria for enrollment in ZUMA-2 and included such factors as ECOG performance status, central nervous system involvement, prior therapies, and more (Table 1³).

With a median follow-up of 3 months (range, 0.1-9.6), the ORR was 86% among 81 patients for whom day 30 response was evaluable. The CR rate was 64%. For patients who achieved a response at day 30, the rate of continued response was 83.7% (95% CI, 68.3%92.0%). Twenty patients who achieved a PR went on to CR at a median of 64 days (range, 22-135); the median time to best response was 30 days (range, 16-168).

Investigators reported that among patients who would not have been eligible for enrollment in ZUMA-2 (n = 74), the objective response rate was 91% (95% CI, 81%-96%) with a CR rate of 80% (95% CI, 69%-88%). In terms of prior BTK inhibitor exposure, the ORR and CR rates were 88% (95% CI, 79%-95%) and 79% (95% CI, 69%-88%), respectively, for those who received prior BTK therapy (n = 78) vs 94% (95% CI, 71%-100%) and 88% (95% CI, 64%-99%), respectively, for those who were BTK naïve (n = 17).

“I think the big question is, is prior exposure to a BTK inhibitor important for T-cell fitness and the T-cell product?” Jacobson said. “At least from this very small cohort, it suggests that maybe it is not as important as we might have thought.”

Survival data were also comparable with the data reported for ZUMA-2. The median PFS was not reached, with a 6-month rate of 66% and a 12-month rate of 51%. The median OS was also not reached, with the 6-month and 12-month OS rates of 81% and 72%, respectively.

National Comprehensive Cancer Network guidelines recommend that brexucabtagene autoleucel be administered following chemoimmunotherapy and a BTK inhibitor⁴ (Figure⁵); however, Jacobson remains optimistic about the role of cellular therapy for all patients with MCL.

“I think the data from ZUMA-2 have been replicated in these real-world series,” Jacobson said. “Just like we’ve seen in large cell lymphoma, it’s very consistent—response rates are consistent, the CR rates of nearly 70% are consistent, and so far, 1-year [PFS and OS] are very consistent. [Approximately] 70% of patients would not have been eligible for the pivotal clinical trials, so we can now apply these therapies to a broader population of patients—patients with renal failure, patients with heart failure, patients with lower blood cell counts and bone marrow dysfunction—and still see the same excellent results. They continue to be really transformative for our patients.”

References

1. 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
2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. Updated July 27, 2020. Accessed January 19, 2022. https://bit.ly/3444TCK
3. Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: real world experience from the US Lymphoma CAR T Consortium. Blood. 2021:138(suppl 1):744. doi:10.1182/blood-2021-147563
4. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 5.2021. Accessed January 21, 2022. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
5. Bond DA, Martin P, Maddocks KJ. Relapsed mantle cell lymphoma: current management, recent progress, and future directions. J Clin Med. 2021;10(6):1207. doi:10.3390/jcm10061207