Exploring CAR T-Cell Therapies in the Context of Indolent Lymphoma
Caron A. Jacobson MD, MMSC, Medical Director, Immune Effector Cell Therapy Program and Senior Physician at Dana-Farber Cancer Institute in Boston, Massachusetts, discussed the results of the ZUMA-5 trial (NCT03105336), provided a comparison between ZUMA-5 and the SCHOLAR-5 trials,2 and the interim results of the ELARA study (NCT03568461) in a presentation at the 2021 Annual Meeting of the Society of Hematological Oncology on September 10, 2021.
ZUMA-5 evaluated axicabtagene ciloleucel (axi-cel; Yescarta) in 124 patients with follicular lymphoma (FL) and 22 patients with marginal zone lymphoma (MZL) who had undergone 3 prior lines of treatment. The primary endpoint was the overall response rate (ORR) and the primary secondary endpoints were the complete response rate (CR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse reactions. events (AE).
“This was a high-risk group of patients, the majority [46.5%] having FLIPI scores greater than 3, ”said Jacobson, assistant professor of medicine at Harvard Medical School. In addition, many patients (54.1%) were classified as POD24, meaning whose disease progressed within 24 months of receiving their first treatment containing anti-CD20 monoclonal antibodies.
In ZUMA-5, the ORR was 92% with a CR rate of 76%. For patients with FL, after 12 months of follow-up, the ORR was 94% (n = 84) with an OR of 80%. For patients with MZL, the ORR was 85% (n = 20) with a CR rate of 60% (n = 12). “Of note, 52% of patients who had an initial partial response during the first tumor restaging had CR after a median of 2.2 months of follow-up,” Jacobson said in his presentation.
In patients with FL, the median MSS, PFS, and OS were not achieved; among patients who responded to a median follow-up of 18 months, 78% maintained their response. Jacobson said the MZL survival curves were quite immature because patients only needed one month of follow-up to be included in the efficacy analysis. “We are awaiting longer-term follow-up for this cohort,” noted Jacobson.
When POD24 results were examined, patients with FL and MZL with POD24 had a lower CR rate and shorter ROR and PFS than those without POD24. “This was most noticeable in the MZL cohort, where only 58% of patients had CR in the POD24 group versus 75% and the median DOR was 11.1 months. The median PFS was 9.2 months for patients with POD24 versus not reached for both endpoints for patients with MZL without POD24, ”explained Jacobson.
The safety profile appeared to be more favorable than that observed with axi-cel in patients with diffuse large B-cell lymphoma (DLBCL) with only 7% of patients presenting with grade 3 cytokine release syndrome (CRS) or above and 19% of patients with grade 3 or greater neurological events. In addition, the median time to onset of CRS was later in LF and MZL at 4 days, compared with DLBCL at 2 days, according to the results of study ZUMA-1 (NCT02348216).
The results of the SCHOLAR-5 study were presented at the 2021 meeting of the European Hematology Association (EHA2021).2 This was a retrospective meta-analysis comparing clinical results from the updated 18-month ZUMA-5 study to a matched sample from the SCHOLAR-5 study. Data from the pivotal DELTA trial (NCT01282424) evaluating idelalisib (Zydelig) were included in the SCHOLAR-5 cohort. Eighty-five patients in the SCHOLAR-5 study and 86 patients in ZUMA-5 were evaluable after propensity score weighting was applied to the cohorts.
In the third line or more, the ORR was 49.9% in SCHOLAR-5 versus 94.2% for an OR of 16.2 (95% CI, 5.6-46.9). The median PFS and OS were not achieved in ZUMA-5 and SCHOLAR-5, being 12.7 months and 59.8 months, respectively. “The analysis revealed a statistically significant improvement in both the overall response rate from 49.9% to 94.2% and a complete response rate from 29.9% to 79.2%,” said Jacobson (TABLE). “This translates into an improvement in PFS, time to next treatment and a statistically significant improvement in overall survival that was observed even within the first 3 years of follow-up. “
Another study that evaluates CAR T cell therapy directed against CD19 in follicular treatment is the ELARA study.3 The study evaluated tisagenlecleucel (Kymriah) in relapsed FA in third-line patients and beyond. Investigators reported a complete response rate of 66%, with an ORR of 86% and a median follow-up of 11 months. Jacobson noted that a high proportion of patients maintained their response and that the PFS and OS curves were similar to those shown in ZUMA-5.
Regarding safety, Jacobson stated that the toxicity profile of tisagenlecleucel in LF was improved compared to the toxicity of the agent in patients with DLBCL and was better than the safety profile of axicabtagene ciloleucel. . Investigators reported that 48.5% of patients had grade 3 or greater CRS. In terms of immune cell-associated neurological syndrome (ICANS), 9.3% of patients had ICANS of any grade and 1% of patients had ICANS grade 3 or above.3
According to Jacobson, other ongoing studies include ZUMA-5, exploring axi-cel in patients with marginal zone lymphoma, the ongoing ELARA study and the TRANSCEND study (NCT02631044), which is evaluating lisocabtagene maraleucel (Breyanzi) in follicular lymphoma. In addition, Phase 1/2 studies that explore new agents include both allogeneic and natural CAR T cells, as well as dual antigen targeting CARs that involve patients with indolent lymphoma.
“We hope that these emerging therapies will change the course of these cancers and provide a cure for our patients,” Jacobson concluded.
1. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed / refractory (R / R) indolent non-Hodgkin lymphoma (iNHL). Presented at the 62nd Annual Meeting and Exhibition of the American Society of Hematology, December 5-8, 2020. Abstract 700. Accessed September 8, 2021. https://ash.confex.com/ash/2020/webprogram/Paper136834. html
2. Ghione P, Patel A, Bobillo S, et al. A comparison of the clinical results of ZUMA-5 (axicabtagene ciloleucel) and the Scholar-5 external control international cohort in relapsed / refractory follicular lymphoma (R / R FL). Presented at: Virtual Congress 2021 of the European Hematology Association. Abstract LB1904. Accessed September 8, 2021. https://bit.ly/3n8LfgG
3. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed / refractory follicular lymphoma (r / r FL): primary analysis of the phase 2 Elara trial. J Clin Oncol. 2021; 39 (suppl 15): abstr 7508. doi: 10.1200 / JCO.2021.39.15_suppl.7508