Advertisement

Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Sattva S. Neelapu, Frederick L. Locke, Nancy L. Bartlett, Lazaros J. Lekakis, David B. Miklos, Eric D. Jacobsen, Ira Braunschweig, Olalekan O. Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick M. Reagan, Adrian Bot, John M. Rossi, Lynn Navale, Yizhou Jiang, Jeff S. Aycock, Meg Elias, Jeffrey S. Wiezorek and William Y. Go

Abstract

Embedded Image

Background: Patients with refractory NHL experience poor outcomes to currently available therapies. In the SCHOLAR-1 pooled analysis of patients with refractory aggressive NHL, the objective response rate (ORR) was 26% (complete response [CR] rate was 7%), and the median overall survival (OS) was 6.3 months (Crump et al. Blood . In press). The primary analysis of ZUMA-1 demonstrated positive results with an ORR of 82% and a CR rate of 54% after a single infusion of axi-cel. The safety profile was manageable: grade ≥ 3 cytokine release syndrome and neurologic events were generally reversible and reported for 13% and 28%, respectively (Locke et al. AACR 2017. #9986). With a median follow-up of 8.7 months, 44% of patients in ZUMA-1 were in ongoing response. We plan to present the 1-year follow-up of ZUMA-1 to confirm the stability of response following anti-CD19 CAR T cell therapy as previously suggested (Locke et al. Mol Ther . 2016; Kochenderfer et al. Mol Ther . 2017). Additionally, exploratory biomarker analyses were conducted to understand the mechanisms of resistance to anti-CD19 CAR T cell treatment.

Methods: Patients with refractory diffuse large B cell lymphoma, transformed follicular lymphoma, or primary mediastinal large B cell lymphoma were enrolled and dosed per Locke et al. (AACR 2017. #9986). Refractory disease was defined as progressive disease or stable disease as best response to last line of therapy, or relapse ≤ 12 months after autologous stem cell transplant. Patients must have had a prior anti-CD20 antibody and an anthracycline-containing regimen.The primary endpoint was ORR per 2007 International Working Group criteria. Key secondary endpoints included duration of response (DOR), OS, and incidence of adverse events (AEs). A key exploratory endpoint was to investigate the mechanisms of resistance using post-treatment tumor biopsies obtained at time of relapse or progression.

Results: A long-term follow-up analysis will be performed with a data cut-off of August 11, 2017. To date, no patients have been lost to follow-up, and all patients who are alive remain in disease and survival follow-up. Updated DOR and OS will be presented with a minimum follow-up of 1 year and a median follow-up of 15 months. Updated subgroups and associative analyses of efficacy outcomes will be presented. Baseline and post-progression biopsies were evaluable by central review from 12 patients. CD19 and PD-L1 immunohistochemistry results are tabulated. Three of 11 (27%) patients with CD19-positive status at baseline developed CD19-negative disease at time of disease progression. Eight of 10 (80%) patients evaluable for PD-L1 at time of disease progression had PD-L1-positive disease. Of the 8 patients with CD19-positive samples at progression, 5 (63%) demonstrated PD-L1-positive tumor cells. Of the 3 patients with CD19-negative samples at progression, 2 had PD-L1-positive tumor cells.

In addition, post-progression biopsies from 6 separate patients were evaluable by local review, of which 3 (50%) had ≤ 1% CD19 staining. Cumulatively, 17 patients were evaluable for CD19 expression at time of progression by either central or local review, and 6 (35%) had ≤ 1% CD19 expression. Updated results will be presented.

Conclusions: In the ZUMA-1 study, axi-cel demonstrated significant clinical benefit with manageable AEs in patients with no curative treatment options. Additional long-term efficacy, safety, subgroup, and biomarker associative analyses with a median of 15 months of follow-up will be presented. Loss of CD19 and gain of PD-L1 expression in tumors are identified as possible mechanisms of resistance following axi-cel treatment. These results provide insights into development of novel therapeutic strategies to overcome CD19 CAR T resistance and further improve outcomes in these patients.

Drs. Neelapu and Locke contributed equally to this work.

Disclosures Neelapu: BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Locke: Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Miklos: Genentech: Research Funding; Roche: Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria; Novartis: Research Funding. Jacobsen: Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Braunschweig: Kite Pharma: Equity Ownership. Oluwole: Kite Pharma: Consultancy. Siddiqi: Juno: Other: Steering committee for JCAR017; Seattle Genetics: Speakers Bureau; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman: ImmuneGene: Research Funding; Kite Pharma: Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan: Seattle Genetics: Research Funding. Bot: Kite Pharma: Employment, Equity Ownership. Rossi: Kite Pharma: Employment, Equity Ownership. Navale: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Elias: Kite Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Go: Kite Pharma: Employment, Equity Ownership.

  • * Asterisk with author names denotes non-ASH members.

  • Embedded Image This icon denotes a clinically relevant abstract