Clinical: CAR T-Cell Therapy

Real-World Evidence With Axicabtagene Ciloleucel CAR T-Cell Treatment Similar to ZUMA-1 Trial Findings

Surabhi Dangi-Garimella, PhD

A multicenter retrospective study that evaluated the efficacy and safety of chimeric antigen receptor (CAR) T-cell treatment, axicabtagene ciloleucel (axi-cel; Yescarta), in a real-world setting produced a similar response as well as toxicity compared with the ZUMA-1 clinical trial results. Predictors of response included low day 0 C-reactive protein (CRP) and high absolute lymphocyte count at leukapheresis. The results were presented December 1, 2018, during the 60th American Society of Hematology (ASH) Annual Meeting & Exposition, held in San Diego, California.¹

The FDA approved axi-cel in October 2017,² and long-term results for the treatment were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in June 2018.³ The results presented at ASCO showed the objective response rate (ORR) was 82% at 8.7 months, which had been maintained by the long-term 15.4-months follow-up time. The complete response (CR) rate was 58% at the long-term follow-up.

Caron A. Jacobson, MD, instructor in medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, and first author of the study presented at ASH, said that in a real-world setting, eligibility criteria and patient management factors may be very distinct from a clinical trial setting. Therefore, bridging therapy may be needed between leukapheresis and treatment with the CAR T product.

Thus, the study examined patient and disease characteristics and biomarkers of response or toxicity following axi-cel treatment in a real-world setting. In this case, the settings were 6 US academic medical centers that used commercial axi-cel.

Among the 104 patients with lymphoma who were part of this retrospective study (median age was 63.8 years; range, 21-80), 94 (90%) had an European Cooperative Oncology Group (ECOG) performance status of 0-1 and 48 (46%) had a prelymphodepletion International Prognostic Index (IPI) score of ≥3. Twenty-eight (27%) patients had a prior autologous transplant and 3 (3%) had received a prior allogenic stem cell transplant. Forty-two patients (40%) each had bulky disease (tumor bulk >5 cm) and received bridging therapy following leukapheresis.

At a median follow-up of 5.6 months, 13 patients had their T cells collected but they did not receive CAR T-cell infusion: 6 patients had progressive disease, 2 patients had infections, 3 patients had technical issues with cell production, 1 patient had a CR to bridging therapy, and 1 patient had another malignancy diagnosed.

When evaluated in 95 patients, an overall response (OR) was observed in 67 (62%) patients. A CR was observed in 42 (44%) patients and a partial response (PR) in 25 (26%). Among 51 patients with a 6-month follow-up, an OR was observed in 22 (43%).

Half of the patients who had an initial PR and who were not being followed went on to have a CR, Jacobson said. The median duration of response was 4.9 months.

According to Jacobson, univariate analysis showed that ECOG performance status (P = .009), tumor bulk (P = .016), baseline CRP (P = .029), and prior ibrutinib (Imbruvica) treatment (P = .002) had a significant association with lack of response to treatment with axi-cel.

Toxicity

A majority (96%) of the treated patients experienced cytokine-release syndrome (CRS), a flare-up that is characterized by low/high fever and low blood pressure and can sometimes lead to capillary leak syndrome, according to Stephen J. Schuster, MD, of the Perelman School of Medicine.⁴

In 17 (16%) patients, CRS was grade 3 or higher; 2 patients (2%) died. A median time to onset was 1 day (range, 0-14), symptoms associated with the flare-up lasted a median of 6 days (range, 1-27). Fifty-eight (55.7%) patients experienced neurotoxicity following treatment with axi-cel, 29 (50%) of whom had grade 3 or higher neurotoxicity. There was 1 fatality associated with this toxic effect. Neurotoxic effects had a median onset time of 5 days (range, 0-34) and lasted for a median of 8 days (range, 1-52 days). Patients received tocilizumab (Actemra; n = 70) and steroids (n = 66) to counter the toxicity, and 30% required a stay in an intensive care unit. Six patients died following disease progression, and 5 died from toxicity. Univariate analysis that the researchers conducted for toxicity, mainly grade 3 or higher CRS or neurotoxicity, found no association with performance status, tumor bulk, IPI, prior treatment, bridging therapy, or eligibility for ZUMA-1.

Cytogenetic and immunohistochemistry staining found that 3 patients with programmed death ligand -1 postive (PD-L1) tumors were refractory to CAR T-cell therapy. Based on the staining results, a positive response could be associated with increased expression of PD-1, 41BB, ICOS, and Ki67, as well as CC3 indicating apoptosis, when CAR T-cell levels peaked by day 7. Subsequently, CAR T cells fell by day 14.

Jacobson said that the deviation from the observations in the ZUMA-1 trial may be due to the inclusion of sicker patients with a poorer performance status and possible different histologies in this patient population. Although rates of CRS and neurotoxicity were similar to ZUMA-1, toxicity was not associated with tumor bulk or response, but with higher peak inflammatory markers and absolute lymphocyte count, indicative of peak CAR T-cell levels.

“Unique combination approaches are necessary for specific patients/tumors,” she noted, adding that their trial results support the use of axi-cel outside of strict clinical trial criteria, although the outcomes may be slightly inferior.

REFERENCES:

1. Jacobson CA, Hunter B, Armand P, et al. Axicabtagene ciloleucel in the real world: outcomes and predictors of response, resistance and toxicity. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 92. ash.confex.com/ ash/2018/webprogram/Paper117199.html.
2. FDA approves CAR T-cell therapy to treat adults with certain types of large B-cell lymphoma [press release]. Silver Spring, MD: FDA; October 17, 2018. www.fda.gov/newsevents/newsroom/pressannouncements/ucm581216.htm. Accessed December 1, 2018.
3. Dangi-Garimella S. ZUMA-1: response to axi-cel at 3 months prognostic for remission in B-cell lymphoma. Am J Manag Care. 2018;24(SP9):SP367.
4. Dr Stephen Schuster: unique CAR T toxicities require provider education. The American Journal of Managed Care^® website. ajmc.com/conferences/ash-2017/dr-stephen-schus- ter-unique-car-t-toxicities-require-provider-education. Published April 17, 2018. Accessed December 1, 2018.