medwireNews: Zamtocabtagene-autoleucel (zamto-cel) has demonstrated superior event-free survival (EFS) over rituximab, gemcitabine and oxaliplatin (R-GEMOx) in a study of transplant-ineligible patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL).
Patients receiving zamto-cel were a significant 61% less likely than those receiving R-GEMOx to meet the composite primary endpoint for EFS of objective disease progression, failure to achieve partial or complete response at or beyond week 8 resulting in the need for new anti-lymphoma therapy, or death from any cause.
The findings from the pivotal DALY 2-EU study were presented by Peter Borchmann (University of Cologne, Germany) at the 67th ASH Annual Meeting and Exposition in Orlando, Florida, USA.
The presenter explained that zamto-cel is a CD19–CD20 directed therapy that is produced using CliniMACS Prodigy© (Miltenyi Biotec, Bergisch Gladbach, Germany), a fully automated system that administers a fresh, non-cryopreserved, formulation of the product, which shortens the manufacturing time to 12 days, with a vein-to-vein time of 13–15 days.
He observed that while anti-CD19 chimeric antigen receptor (CAR)-T therapies have shown second-line efficacy for high-risk R/R LBCL in transplant-eligible patients, “the level of evidence for CAR-T cell therapies should and could be strengthened for transplant-ineligible patients.”
Treatment criteria and patient characteristics
Borchmann and colleagues therefore compared zamto-cel with R-GEMOx in 160 patients with LBCL who had R/R disease within 24 months of receiving frontline chemotherapy and an ECOG performance status (ECOG PS) of 2 points or below out of a possible 5 points. Of these patients, 76 in each group received treatment.
Participants were ineligible for transplantation due to prior autologous stem cell transplantation or a hematopoietic cell transplantation-specific comorbidity index above 3 points; being older than 65 years and having impaired cardiac, renal, or pulmonary function, or an ECOG PS above 1 point; or being 70 years of age or older.
Most patients in both treatment groups had diffuse LBCL not otherwise specified (69%), with other histologic diagnoses including high-grade BCL. The median age of the patients was 74 years, with 42–50% of patients aged 75 years and older.
A lactase dehydrogenase (LDH) level 1 times above the upper limit of normal was seen in just over half (52%) of the patients, and 58% had an International Prognostic Index (IPI) score of 3–5 points.
The zamto-cel group received a single intravenous infusion of fresh CAR-T product after lymphodepletion, at a target dose of 2.5 × 106 cells/kg. Corticosteroid bridging therapy was permitted for high disease burden for up to 4 days. The presenter highlighted that “all patients received the [CAR-T] product on time and there were no delays in manufacturing.”
The R-GEMOx group received treatment on cycles1 to 4 of a 14-day cycle for 8 weeks, at which point they were allowed to crossover to zamto-cel if they had not achieved a partial or complete response (CR), or to continue R-GEMOx treatment, with a second option to crossover if they progressed or relapsed within the first year. In all, 28 patients crossed over.
Significant EFS benefit with zamto-cel
At a median follow-up of 17 months, the median duration of EFS was significantly longer in the zamto-cel group than the R-GEMOx group, at 6.21 versus 2.53 months. The rate of events was a respective 63.4% versus 80.8%.
This “highly statistically significant and clinically relevant superiority [of zamto-cel] over R-GemOx for EFS,” was “highly consistent” across the majority of subgroups, including for LDH, IPI, and ECOG PS risk status, noted Borchmann.
Zamto-cel was also associated with a significant 3.8-fold higher rate of CR in the modified intention-to-treat analysis of patients, at 60% versus 15%, with respective objective response rates of 81% and 48%. Zamto-cel also achieved significantly longer median progression-free survival, at 8.51 versus 3.35 months, with a hazard ratio for progression or death of 0.43.
“[A]ntigen loss does not appear to be a driver of progression,” the researcher said, nothing that 84% of patients had no antigen loss, with loss of CD20 and CD19 occurring in one (8%) patient each, and none of the patients experienced dual antigen loss.
The safety profile of zamto-cel was “manageable” and “well tolerated in this elderly population,” said the investigator. There were “low rates” of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) with zamto-cel, at a respective 5.3% and 1.3% for grades 3 or above, and a median time to onset of events of any grade of 2 days and 10 days, respectively, lasting for a median of 6 and 5 days.
He concluded: “The favorable risk/benefit profile of zamto-cel supports its use as a preferred second-line treatment option for patients with relapsed or refractory de novo or transformed large B-cell lymphomas.”
