Tisagenlecleucel-T Highly Active, With Durable Responses in DLBCL

Stephen J. Schuster, MD

Tisagenlecleucel-T (CTL019) met its primary endpoint for best objective response rate (ORR) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to findings presented at the 2017 International Conference on Malignant Lymphoma (ICML) biennial meeting in Lugano, Switzerland.¹

In the pivotal phase II JULIET study, best ORR was 59% (95% CI, 44.2%-72.4%; P<.0001) in 51 patients with DLBCL at a median follow-up of 3.7 months. Nearly half (43%) of patients had complete response (CR) and 16% achieved partial response (PR). About one-quarter of patients experienced disease progression.

Investigators found that the response was durable, with 79% of patients who demonstrated CR or PR at 3 months remaining relapse-free at 6 months. As of the data cutoff of December 2016, the median duration of response and overall were not reached.

Tisagenlecleucel-T was detectable in peripheral blood by quantitative PCR for up to 355 days in responding patients.

“The overall response rate seen in this early analysis is impressive for these heavily pretreated patients with relapsed/refractory DLBCL who have limited treatment options,” said lead investigator Stephen Schuster, MD, professor of hematology/oncology at the University of Pennsylvania Abramson Cancer Center. “Patients failing second-line salvage therapy have a poor prognosis with a median overall survival of just 4.4 months. The goal for these patients is durable response; the most promising aspect of these data is that, at the time of this interim analysis, all patients with complete response at three months have remained in complete response.

“This analysis of CTL019 in adults with relapsed or refractory DLBCL confirms the high response rates and durable responses seen in the previous single center trial,2” he added.

This analysis included data from 51 of the 141 enrolled adult patients with DLBCL who had ≥3 months of follow-up. The final primary analysis is expected to include data from all 81 treated patients who completed follow-up or discontinued early.

All patients underwent restaging and lymphodepleting chemotherapy with 25 mg/m2 of fludarabine and 250 mg/m2 of cyclophosphamide daily for 3 days or 90 mg/m2 of bendamustine daily for 2 days. Thereafter, 81 patients received a single dose of median 3.1 × 108 CTL019 transduced cells.

Patients had received a median of 3 (range, 2-7) prior lines of antineoplastic therapy, including 51% who received autologous stem cell transplant. Seventy-six patients received bridging chemotherapy.

The safety cohort included 85 treated patients, 57% of whom experienced any grade of cytokine release syndrome (CRS) 17% of patients had grade 3 CRS and 9% experienced grade 4. CRS was managed by a protocol-specific algorithm and 16% of patients received tocilizumab.

Grade 3/4 neurologic adverse events occurred in 13% patients and were managed with supportive care. Grade 3/4 cytopenia lasting >28 days occurred in 21% of patients, and 14% experienced grade 3/4 febrile neutropenia. Grade 3 tumor lysis syndrome was reported in 1% of patients.

“Adverse events were reversible and effectively managed by study site personnel,” Schuster said. “Of the patients who discontinued the trial before infusion, the majority were due to rapid progression of their disease or deterioration in their clinical status.”

Although 3 patients died from disease progression within 30 days of infusion, there were no treatment-related deaths reported. There were no deaths due to CRS, and no incidents of cerebral edema.

In April 2017, the FDA granted a breakthrough therapy designation to tisagenlecleucel-T for use as a treatment for adult patients with relapsed/refractory DLBCL after the failure of at least 2 prior therapies.

The FDA granted a priority review designation to a biologics license application (BLA) for tisagenlecleucel-T in March 2017 as a treatment for pediatric and young adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia. Subsequently, the FDA’s Oncologic Drugs Advisory Committee scheduled a meeting for July 12 to review the BLA.

References

1. Schuster SJ, Bishop MR, Tam, et al. Global pivotal phase 2 trial of the cd19-targeted therapy ctl019 in adult patients with relapsed or refractory (r/r) diffuse large b-cell lymphoma (DLBCL)—an interim analysis. Hematol Oncol. [published online June 7, 2017] 35, 2017 (suppl S2).
2. Schuster SJ et al. Blood; 128(22): abstract 3026.