Positive Efficacy and Safety Outcomes Result from Second-line Liso-cel in LBCL

For patients with relapsed/refractory large B-cell lymphoma, PFS and OS data from CD-19-directed, 4-1BB CAR T-cell Liso-cel therapy were consistent with prior results.

According to real world findings presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH), in patients with relapsed or refractory large B-cell lymphoma (LBCL), treatment in the second-line with CD19-directed, 4-1BB CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) yielded comporable safety and efficacy end points to the 2 pivotal trials that informed the FDA’s approval.¹

Results from the observational, post marketing study using data collected from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry were compared again the pivotal, phase 3 TRANSFORM (NCT03575351) and phase 2 PILOT (NCT03483103) trials.

At a median follow-up of 6.4 months (95% CI, 6.1-6.5; range, 0.2-14.8) the median progression-free survival (PFS) and overall survival (OS) in the overall second-line cohort (n = 156) was not reached (NR; 95% CI, NR-NR). In the TRANSFORM-ineligible cohort the median PFS and OS was NR (95% CI, 5.8-NR) and NR (95% CI, NR-NR), respectively. For the cohort of patients whose eligibility for TRANSFORM was unknown or eligible, the median PFS was NR (95% CI, 6.0-NR) and the median OS was NR (95% CI, NR-NR).

The 6-month PFS rates in the overall, TRANSFORM-ineligible, and TRANSFORM-unknown/eligible cohorts were 61% (95% CI, 52%-69%), 58.5% (95% CI, 48%-68%), and 65% (95% CI, 49%-77%), respectively. The 6-month OS rates in these respective populations were 87% (95% CI, 80%-92%), 85% (95% CI, 76%-91%), and 90% (95% CI, 76%-96%).

Additional efficacy findings illustrated that the objective response rate (ORR) in the second-line cohort was 84% (95% CI, 77%-89%), with a complete response (CR) rate of 70% (95% CI, 62%-77%). The ORRs in the TRANSFORM-ineligible and TRANSFORM-unknown/eligible cohorts were 84% (95% CI, 75%-90%) and 84% (95% CI, 71%-93%), respectively. The respective CRs in these populations were 68% (95% CI, 58%-76%) and 75% (95% CI, 60%-86%). The median duration of response (DOR) was NR in all 3 cohorts, with 6-month DOR rates of 73% (95% CI, 62%-81%), 70% (95% CI, 57%-80%), and 78% (95% CI, 59%-89%) in the second-line, TRANSFORM-ineligible, and TRANSFORM-unknown/eligible cohorts, respectively.

“Liso-cel continued to demonstrate consistently deep responses in this broad, real-world patient cohort. Median DOR, PFS, and OS were NR for the overall population, or the subgroups analyzed. While longer follow-up in a larger cohort is needed, these results support the use of liso-cel as [a] second-line standard-of-care treatment for patients with relapsed/refractory LBCL regardless of age,” lead study author María Silvina Odstrcil Bobillo, MD, a hematology fellow at the University of Utah School of Medicine in Salt Lake City, said in a presentation of the results.

In June 2022, the FDA approved liso-cel for adult patients with LBCL who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation due to comorbidities or age.²

The approval was based on data from the randomized TRANSFORM and single-arm PILOT trials in patients with transplant-eligible and -ineligible disease, respectively. In the former, treatment with liso-cel led to a median PFS that was NR vs 6.2 months with standard-of-care therapy (HR, 0.422) and respective CR rates of 74% and 43%. In the latter, liso-cel led to a CR rate of 54% (95% CI, 41%-67%).¹

Study Eligibility and Baseline Characteristics

To be eligible for inclusion in the analysis presented at the 2024 ASH Annual Meeting, patients needed to have relapsed/refractory LBCL and received commercial liso-cel infusion in the second line.¹ At least 1 evaluation for safety and response following infusion was also required.

Efficacy end points included ORR, CR rate, DOR, PFS, and OS. Safety end points included adverse effects (AEs) of special interest, non–relapse mortality (NRM), and deaths. ORR, CR rate, DOR, PFS, and OS by TRANSFORM eligibility criteria, refractory or relapsed disease status, and age were also evaluated in subgroup analyses.

Data for 1,067 patients who had received commercial liso-cel were pooled from the CIBMTR registry. A total of 911 patients were excluded from the analysis because they didn’t receive liso-cel in the second line (n = 867), had no post infusion assessment (n = 43), or had no response data available (n = 1), leaving 156 eligible patients. A total of 105 of the 157 patients who received liso-cel in the second line were evaluated separately because they would have been ineligible for inclusion in TRANSFORM.

Within the second-line cohort (n = 157) the median age was 72 years (range, 27-85) and most patients were male (57%). Diffuse large B-cell lymphoma represented the most common histology (84%), followed by high-grade B-cell lymphoma (11%) and other, including primary mediastinal large B-cell lymphoma (4%). Most patients had active disease at the time of infusion (88%); 50% had primary refractory disease and 48% had early relapse. Central nervous system involvement was documented in 3% of patients. Most patients had an ECOG performance status of 0 or 1 (95%) although 60% had at least 1 comorbidity. Additionally, 72% of patients received bridging therapy, and R-CHOP was the most common regimen patients had received (87%) prior to liso-cel.

Subgroup Analyses According to Disease Status and Age

Among the patients with refractory disease (n = 78) the median PFS and OS were NR (95% CI, 3.9-NR) and NR (95% CI, NR-NR). Patients with primary refractory disease had a median PFS and OS that were both NR (95% CI, NR-NR). The 6-month PFS rates were 53% (95% CI, 40%-64%) and 69% (95% CI, 57%-79%) in the refractory and early relapse cohorts, respectively. The respective 6-month OS rates were 85% (95% CI, 74%-91%) and 91% (95% CI, 81%-96%).

The ORR in the refractory cohort was 83% (95% CI, 73%-91%), with a CR rate of 63% (95% CI, 51%-74%). In the early relapse cohort, the ORR was 84% (95% CI, 74%-92%), with a CR rate of 78% (95% CI, 67%-86%). The median DOR was NR in either cohort; the 6-month DOR rates were 60% (95% CI, 44%-73%) and 86% (95% CI, 72%-93%) in the refractory and early relapse cohorts, respectively.

With respect to age, patients 70 years of age or younger achieved an ORR of 85% (95% CI, 74%-92%), with a CR rate of 77% (95% CI, 65%-87%). Patients over the age of 70 achieved an ORR of 84% (95% CI, 74%-91%), with a CR rate of 65% (95% CI, 54%-75%). The median DOR was NR in either age group; the 6-month DOR rates were 81% (95% CI, 66%-90%) and 65% (95% CI, 49%-77%) in the less than 70 and over the age of 70 cohorts, respectively.

The median PFS and OS in both age groups were NR. The 6-month PFS rates in the younger and older cohorts were 68% (95% CI, 55%-79%) and 55% (95% CI, 43%-65%), respectively. The respective 6-month OS rates were 91% (95% CI, 79%-96%) and 84% (95% CI, 74%-91%).

CRS, ICANS, and Other Adverse Effects of Special Interest

Cytokine release syndrome (CRS) occurred in 45% of patients (grade 1, 31%; grade 2, 12%; grade 3, <1%; grade 4, <1%; grade 5, <1%). Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 20% of patients (grade 1, 8%; grade 2, 4%; grade 3, 5%; grade 4, 1%); 2 cases had yet to be determined by the time of data cutoff. The median time to onset of CRS and ICANS was 4 (IQR, 3-7) and 8 (IQR, 5-9) days, respectively. The median duration of each event was 3 (IQR, 2-5) and 10 (IQR, 4-378) days, respectively. Most patients received treatment for either CRS (82%) or ICANS (91%), the most common being tocilizumab (Actemra; 59%) for CRS and corticosteroids (48%) for ICANS.

“The safety profile was consistent with previous reports; most patients did not experience, or had low-grade CRS, ICANS, prolonged cytopenia, or infections,” Bobillo said. Bobillo also noted that despite a higher incidence of CRS and ICANS for the TRANSFORM-ineligible, refractory, and older patient cohorts, the differences were not statistically significant, with the exception of ICANS for older patients.

Regarding other AEs of special interest, 11% of patients experienced prolonged cytopenia, 33% experienced clinically significant infections, 4% developed second primary malignancies––all of which were solid tumors apart from 1 case of myelodysplastic syndrome, 5% had grade 3/4 organ toxicity, and 0.6% developed tumor lysis syndrome.

Within the overall second-line cohort 78% of patients remained alive. The most common reason for death was progressive disease (n = 14%), followed by other and unknown causes (3% each), infections (1%), and CRS (≤1%).

The 6-month cumulative incidence of NRM was 1.3 (95% CI, 0.3-4.3), and the 6-month cumulative incidence of relapse/progression or death due to primary disease was 37.9 (95% CI, 29.6-46.0).

“These results continue to highlight that liso-cel is utilized in the second-line setting in a broad population of patients with relapsed/refractory LBCL with efficacy and safety outcomes consistent with pivotal clinical trials,” Bobillo concluded.

References

1. Bobillo MSO, Thiruvengadam SK, et al. Lee D, et al. Real-world (rw) outcomes of lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (lbcl): first results from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry. Blood. 2024;144(suppl 1):470. doi:10.1182/blood-2024.199723
2. FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma. FDA. Updated June 27, 2022. Accessed December 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-second-line-treatment-large-b-cell-lymphoma