Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity

Abstract

Purpose: Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately 40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting.

Patients and methods: One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance.

Results: Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1-eligible and ZUMA-1-ineligible groups (70% v 68%), there was a statistically significant improvement in CR rate (63% v 42%, P = .016), DOR (median, NR v 5.0 months; P = .014), PFS (median, NR v 3.3 months; P = .020), and OS (1-year OS, 89% v 54%; P < .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively.

Conclusion: Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.

FIG 1.

Efficacy outcomes of axicabtagene ciloleucel (axi-cel) overall and by ZUMA-1 eligibility. (A) Duration of response (DOR) curves for patients with overall response at first restage after chimeric antigen receptor (CAR) T-cell therapy. (B) Progression-free survival (PFS) curves for all patients. (C) Overall survival (OS) curves for all patients who underwent infusion of axi-cel. (D) DOR curves for patients who would have been eligible for ZUMA-1 (blue) and those who were ineligible for ZUMA-1 (orange). (E) PFS curves for patients who would have been eligible for ZUMA-1 (blue) and those who were ineligible for ZUMA-1 (orange). (F) OS curves for patients who would have been eligible for ZUMA-1 (blue) and those who were ineligible for ZUMA-1 (orange). All, all patients who underwent infusion of axi-cel; CR, complete response at first restage; NR, not reached; PR, partial response at first restage.

FIG 2.

Univariate analysis of response and toxicity. (A) Presence of grade ≥ 3 cytokine release syndrome (CRS) stratified by multiple covariates. (B) Presence of grade ≥ 3 neurotoxicity (NT) stratified by multiple covariates. (C) Overall response rate stratified by levels of key cytokines and absolute lymphocyte count (ALC). (D) Presence of grade ≥ 3 CRS or NT stratified by multiple covariates. CR, complete response; CRP, C-reactive protein; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, International Prognostic Index; n/a, not applicable; NR, no response; PR, partial response.

FIG 3.

Relationship between day 0 C-reactive protein (CRP) and peak ferritin and outcome with axi-cel. (A) Duration of response (DOR) stratified by CRP (units, milligrams per liter) at day 0. (B) Progression-free survival (PFS) stratified by CRP at day 0. (C) Overall survival (OS) stratified by CRP at day 0. (D) DOR stratified by peak ferritin (units, micrograms per liter). (E) PFS stratified by peak ferritin. (F) OS stratified by peak ferritin. NR, not reached.

FIG 4.

Correlative studies of tumor tissue and of blood from patients treated with axi-cel demonstrate potential mechanisms of resistance. (A and B) Two post-treatment tumor biopsy specimens stained for cluster of differentiation (CD) 19 and programmed death ligand 1 (PD-L1) by immunohistochemistry, as well as for paired box 5 (PAX5), kinesin-like protein 1 (KIP-1), CD3, and 4′,6-diamidino-2-phenylindole (DAPI) by multiplex immunofluorescence. Biopsy specimens were obtained on day 37 (A) and on day 58 (B). (C) CyTOF analysis of expression of CD4, CD8, Ki67, and iducible T cell costimulator (ICOS) of chimeric antigen receptor (CAR) T+ and CAR T− cells from 4 responding (R) and 4 nonresponding (nR) patients. (D) CyTOF comparison of intensity of expression of Ki67 and ICOS among CAR+ (KIP+) and CAR− (KIP−) CD4 as well as CD8 cells from 4 R and 4 nR patients. (E) Differences in expression of multiple cell markers between CAR+ and CAR− T cells from blood samples taken on day 7 of axicabtagene ciloleucel therapy. (F) Differences in expression of multiple cell markers stratified by CAR positivity and CD4/8 expression from serial blood samples.

FIG A1.

Disposition of all patients, including those leuakapheresed and not treated (intent-to-treat population). (A) Consort diagram of patient disposition throughout the course of the study. (B) Overall survival of the intent-to-treat population from the day of leuakapheresis. CR, complete response; CRS, cytokine release syndrome; NR, not reached; NT, neurotoxicity; PD, progressive disease; PR, partial response; SD, stable disease.

FIG A2.

Key variates and efficacy outcomes of axicabtagene ciloleucel. (A) Overall response rate (ORR) stratified by multiple covariates. (B) Duration of response curves stratified by ZUMA-1 eligibility and use of bridging therapy. (C) Progression-free survival (PFS) stratified by ZUMA-1 eligibility and use of bridging therapy. (D) Overall survival (OS) stratified by ZUMA-1 eligibility and use of bridging therapy. CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B cell lymphoma; ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; GCB, germinal center B cell; HGBL, high-grade B-cell lymphoma; MZL, marginal zone lymphoma; NR, not reached; NT, neurotoxicity; PMBCL, primary mediastinal large B-cell lymphoma; ZE, ZUMA-1 eligible; ZI, ZUMA-1 ineligible for reasons other than bridging therapy; ZI-BR, ZUMA-1 ineligible solely because of the use of bridging therapy.