ASH 2016 | ZUMA-1: KTE-C19 CAR-T cells show significant clinical benefit

On 3–6 December 2016, the Annual Meeting & Exposition of the American Society of Hematology (ASH) took place in San Diego, CA. On Tuesday 6^th December, a Late-Breaking Abstracts session was held between 7:30am and 9:00am and was co-chaired by Jorge Di Paola, MD, of the University of Colorado, and Selina Luger, MD, of the University of Pennsylvania.

Late-Breaking Abstract 6 (LBA-6) was the last abstract presented during this session, titled “KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from Pivotal Phase II ZUMA-1” by Sattva S. Neelapu, MD, from The University of Texas MD Anderson Cancer Center, Houston, TX, and colleagues.

ZUMA-1 is the first multicenter trial of anti-CD19 CAR-T cells in refractory, aggressive NHL (NCT02348216). Two cohorts of patients are included in the Phase II portion of the ZUMA-1 study: DLBCL (cohort 1), and transformed FL (TFL) or PMBL (cohort 2). Results of a prespecified interim analysis were presented during this talk.

Overall, 111 patients from 22 different centers were enrolled and leukapheresed. Of these, 101 were administered KTE-C19. The study design is shown below:

Highlights:

• Successful manufacture of KTE-C19 was achieved in nearly all (99%) patients who enrolled
• Average turnaround time from apheresis to administration of KTE-C19 at the clinical site = 17.4 days
• 1 month follow-up (n=93): ORR = 71% (DLBCL 68%, PMBCL/TFL 80%), CR = 38% (DLBCL 33%, PMBCL/TFL 55%)
• Estimated 1-month PFS = 92%; estimated 3-month PFS = 56%

• Final interim analysis results: ORR = 76%; CRs = 47% (p<0.0001)
• Responses in patients refractory to chemo = 76%; Responses in patients who relapsed post-ASCT = 80%

• The most frequently reported ≥grade 3 treatment-emergent AEs = neutropenia (67%), anemia (39%), thrombocytopenia (29%), febrile neutropenia (27%), and encephalopathy (24%)
• Grade ≥3 neurologic events and CRS were reported in 29% and 20% of patients, respectively

• Patients who experienced grade ≥3 neurological events had increased serum levels of IL-15, IL-6, IL-10, and IP-10 (P=0.0002, 0.003, 0.009, 0.0003, respectively)

Importantly, the data shown was stated as being consistent with earlier studies into KTE-C19 in aggressive NHL. Finally, this talk concluded by stating that KTE-C19 CAR-T cell therapy showed significant clinical benefit in patients with DLBCL and no other curative treatment options. Indeed, Sattva Neelapu stated that there was a 6-fold higher CR rate, with 39% durable CR after 3 months. The manufacture, logistics, and management of AEs were successfully carried out across 22 different institutions; the majority having no previous experience implementing CAR-T cell therapy. This pivotal, multicenter study provides exciting data for the field of CAR-T cell technology.

Abstract

Background: Patients (pts) with refractory aggressive non-Hodgkin lymphoma (NHL) have poor outcomes with currently available therapies, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months (mo) as demonstrated in the 635 pt SCHOLAR-1 meta-analysis (Crump, ASCO 2016; abstract 7516). ZUMA-1 is the first multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells in refractory, aggressive NHL (NCT02348216). The phase 1 portion of ZUMA-1 showed ongoing CRs at 12+ mos in 43% of pts (Locke, ESMO 2016; abstract 1048O). The pivotal phase 2 portion of ZUMA-1 comprises 2 cohorts based on tumor type: DLBCL (cohort 1) and primary mediastinal B-cell lymphoma or transformed follicular lymphoma (cohort 2). Here, we present results of a prespecified interim analysis from cohort 1.

Methods: Pts received a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg after a low-dose conditioning regimen of cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) daily for 3 days. The primary endpoint is objective response rate (ORR) per 2007 IWG criteria. Key secondary endpoints include duration of response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. Key inclusion criteria include age ≥18 years, ECOG performance status (PS) 0-1, and refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 mos after autologous stem cell transplant (ASCT). Pts must have received a prior anti-CD20 antibody and an anthracycline-containing regimen. A prespecified interim analysis was to be conducted to determine early efficacy with a nominal alpha level of 0.017 in 50 treated pts in cohort 1 with a minimum follow-up of 3 mos.

Results: In total, 111 pts from 22 institutions were enrolled and leukapheresed, and 101 pts received KTE-C19. As of August 24, 2016, 51 pts in cohort 1 were eligible for analysis. Median age was 58 years (range, 25-76), 73% were male, 71% had ECOG PS 1, 78% were refractory to ≥2 lines of therapy, 20% relapsed ≤12 mos of ASCT, and 61% were treated with ≥3 lines of prior therapy. KTE-C19 was successfully manufactured in 99% of pts enrolled. Average turnaround time from apheresis to receipt of KTE-C19 at the clinical site was 17.4 days. With an ORR of 76%, the study met the primary endpoint (P<0.0001; exact binomial test comparing observed ORR to a historical control assumption of 20%), with 47% CRs and 29% PRs. 92% of responses occurred within the 1st mo, and 39% of pts had ongoing responses (CR in 33%) at 3 mos. Responses were seen across key covariates, including refractory subgroup (refractory to chemotherapy=76%, relapse post ASCT=80%). Kaplan-Meier estimates of progression-free survival at 1 and 3 mos were 92% and 56%, respectively. The most common grade ≥3 treatment-emergent AEs were neutropenia (67%), anemia (39%), thrombocytopenia (29%), febrile neutropenia (27%), and encephalopathy (24%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 20% and 29% of pts, respectively. There was 1 grade 5 KTE-C19–related event of hemophagocytic lymphohistiocytosis. CAR T cells expanded within 14 days of KTE-C19 infusion, and peak expansion was associated with ongoing response at mo 3 (P=0.008). Pts who developed grade ≥3 neurological events had increased serum levels of IL-15 (P=0.0002), IL-6 (P=0.003); IL-10 (P=0.009) and IP-10 (P=0.0003). Cytokines/chemokines returned to baseline levels in most pts by day 28. Data from 93 pts with at least 1 mo of follow-up at the data cutoff will be presented.

Conclusions: ZUMA-1 is the first reported multicenter trial of CAR T cell therapy in pts with refractory aggressive NHL. KTE-C19 induced a nearly 6-fold higher CR rate compared to historical outcomes in SCHOLAR-1. Efficacy strongly associated with peak CAR T levels. Central manufacturing, logistics, and AE management were successfully implemented across 22 sites, most with no prior CAR T therapy experience. Results from cohort 2 of ZUMA-1 are also presented (Abstract #998). KTE-C19 demonstrated significant clinical benefit in pts with no curative treatment options.

Supported in part by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program®. Drs Neelapu and Locke contributed equally to this study.