Azer-Cel Produces CRs in R/R DLBCL After Prior Autologous CAR T-Cell Therapy

Treatment with the allogeneic CD19-directed CAR T-cell therapy azercabtagene zapreleucel (azer-cel; PBCAR0191) led to complete responses (CRs) in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had received prior autologous CAR T-cell therapy, according to data from a phase 1b trial (NCT03666000).¹

Findings announced by Imugene showed that 2 CRs were reported in evaluable patients enrolled in cohort B (n = 3), who all received azer-cel, lymphodepleting chemotherapy, and interleukin 2 (IL-2). The third patient in this cohort had stable disease. The 2 patients in cohort B who experienced a CR had ongoing responses of more than 120 days and more than 90 days, respectively. Evaluation is pending for 1 patient in cohort B, and additional patients will be enrolled to this group.

Among patients in cohort A (n = 6) who received azer-cel and lymphodepletion, 1 patient achieved a CR, and another had a partial response. The overall response rate (ORR) for evaluable patients in cohorts A and B (n = 9) was 44%.

Thus far, safety data have shown that azer-cel is safe and tolerable.

“We are delighted that the first 2 patients in cohort B in our azer-cel phase 1b trial achieved a CR and continue to maintain their CRs," Paul Woodard, MD, chief medical officer of Imugene, stated in a news release. “All 4 patients enrolled in cohort B have [progressed on] 4 to 5 prior treatments, including autologous CAR [T-cell] therapy. All 4 patients remain on the study, and given the robust response rates and durability seen to date, we will continue to enroll patients in the azer-cel plus IL-2 cohort and will closely follow all patients for further responses and durability.”

The multicenter, nonrandomized, open-label, dose-escalation and -expansion phase 1 study is evaluating azer-cel in patients with relapsed/refractory acute lymphoblastic leukemia or relapsed/refractory non-Hodgkin lymphoma (NHL). Patients with B-cell NHL are required to have CD19-positive relapsed/refractory disease. During dose escalation, patients are required to have DLBCL, including Richter transformation; follicular lymphoma (FL), including grade III or transformed FL; high-grade B-cell lymphoma (HBCL); or primary mediastinal lymphoma. In dose expansion, patients need to have DLBCL not otherwise specified; HBCL; or DLBCL transformed from FL, marginal zone lymphoma, or Waldenström macroglobulinemia.²

Other key inclusion criteria for those with relapsed/refractory NHL include measurable or detectable disease per Lugano criteria; at least 2 prior lines of anticancer therapy, including at least 1 chemoimmunotherapy regimen; and no more than 7 prior lines of therapy. For patients who received prior treatment with a CD19-directed autologous CAR T-cell therapy, no more than 2 lines of therapy following the CAR T-cell product are allowed.

All patients must have an ECOG performance status of 0 or 1; a life expectancy of at least 12 weeks; and adequate bone marrow, renal, hepatic, pulmonary, and cardiac function.

Patients with relapsed/refractory NHL are being excluded if they require urgent therapy for tumor mass effects, such as bowel obstruction or blood vessel compression, or if they have active hemolytic anemia. For all patients, active central nervous system metastases are not permitted.

All enrolled patients are receiving lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide prior to CAR T-cell therapy. In the first 3 arms, patients received azer-cel as a single infusion at escalating doses of 3 x 10⁵ CAR T cells, 1 x 10⁶ CAR T cells, or 3 x 10⁶ CAR T cells. At dose level 4, azer-cel is being given as 2 infusions at 3 x 10⁶ CAR T cells for a target total of 6 x 10⁶ CAR T cells. Patients being treated at dose level 4b are receiving a single infusion of the CAR T-cell therapy at 500 x 10⁶ CAR T cells plus IL-2, and those being treated at dose level 4c are being administered 2 infusions of azer-cel at 500 x 10⁶ CAR T cells on days 0 and 5.

The primary end point for dose escalation is the incidence of dose-limiting toxicities, and the primary end point for dose expansion is ORR. Secondary end points included CR rate, duration of response, progression-free survival, overall survival, time to next treatment, and safety.

“I am proud of our clinical development team who assessed ways to enhance azer-cel’s durability of response, as one of the biggest challenges in CAR [T-cell] therapy is ensuring that the modified T cells stay in the body long enough to kill cancer cells,” Leslie Chong, managing director and chief executive officer of Imugene, added in the news release.¹ “To maximize the response rates and durability further, we added a very low dose of IL-2 to the regimen in cohort B. We are pleased with the results, which suggest improved outcomes in patients, and we look forward to amassing more data using this dosing regimen. We will continue to seek biomarker evidence from cohort B patients that suggest our strategy is improving the performance of azer-cel.”

References

1. Three complete responses in azer-cel allogeneic CD19 CAR T phase 1b trial in blood cancer (diffuse large B-cell lymphoma). News release. Imugene. September 2, 2024. Accessed September 3, 2024. https://app.sharelinktechnologies.com/announcement/asx/9ec9d95529ab3adb318296ee5b344164
2. Dose-escalation, dose-expansion study of safety of azer-cel (PBCAR0191) in patients with R/R NHL and R/R B-cell ALL. ClinicalTrials.gov. Updated July 3, 2024. Accessed September 3, 2024. https://clinicaltrials.gov/study/NCT03666000