Real-world experience with the chimeric antigen receptor (CAR) T-cell agent axicabtagene ciloleucel (axi-cel, Yescarta) mimicked the results of the pivotal clinical trial that led to FDA approval for relapsed/refractory large B-cell lymphoma, members of a national clinical consortium reported.
The treatment led to an overall response rate (ORR) of 82% and complete responses in 64% of 275 treated patients. That compared with an ORR of 83% and complete response rate of 58% in the ZUMA-1 trial. Results with standard-of-care (SOC) axi-cel were consistent despite the fact that more than 40% of patients would not have met eligibility criteria for the pivotal trial.
No excessive or unexpected toxicities were reported from the SOC experience, reported Loretta J. Nastoupil, MD, of MD Anderson Cancer Center in Houston, and colleagues online in the Journal of Clinical Oncology.
“What was striking about our findings is that we felt like the outcomes were comparable to the ZUMA-1, which had much more strict eligibility criteria,” Nastoupil told MedPage Today. “We found that the safety and efficacy look quite similar despite most of the patients not really being reflective of the study population in ZUMA-1. You might imagine when you’re outside of the confines of eligibility criteria, you’re going to have sicker patients with more morbidities, and that’s exactly what we found.”
CAR T-cell therapy has had a transformative impact on the treatment of relapsed/refractory leukemia and lymphoma. Patients with chemotherapy-refractory diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma, have a poor prognosis associated with high mortality. Anthracycline-based chemotherapy remained SOC for years, despite leading to a 2-year overall survival (OS) of about 20%, the authors noted.
After a median follow-up of 27.1 months in the ZUMA-1 trial, the median duration of response was 11.1 months, 39% of patients remained in remission, and the median OS had yet to be reached. Given that clinical trial experience often does not represent real-world clinical practice, members of the U.S. Lymphoma CAR T Consortium evaluated data on the safety and efficacy of SOC axi-cel at their 17 participating centers.
The analysis comprised 298 patients who underwent leukapheresis as of Sept. 30, 2018, 275 of whom actually received axi-cel therapy. The cohort had a median follow-up of 13.8 months from leukapheresis.
As compared with patients enrolled in ZUMA-1, 129 (43%) patients in the SOC analysis had comorbidities that made them ineligible for the clinical trial, including 53 patients with two or more comorbid conditions. Chief among the comorbidities were ECOG performance status >1 (58 patients), platelets <75,000/µL (34), and a recent venous thromboembolic event (31).
Additionally, 158 patients received bridging therapy, which was not allowed in ZUMA-1. Bridging therapy included chemotherapy along or with other therapy in 54% of cases, corticosteroids in 23%, radiation therapy with or without corticosteroids in 12%, and targeted therapies in 10%.
Real-World Safety, Efficacy
The authors reported that 91% of patients in the SOC cohort developed cytokine release syndrome, which was grade ≥3 severity in 7% of patients. One patient died of hemophagocytic lymphohistiocytosis (HLH). Neurotoxicity occurred in 69% of patients, grade ≥3 in 31%. One patient died of cerebral edema, but all other neurologic adverse events resolved.
Among patients who received axi-cel, 97 died, including 84 lymphoma-related deaths. One patient died of graft-versus-host disease after allogeneic transplantation, and an additional 12 patients died of non-relapse causes, including infection (eight patients), the fatal case of HLH, the fatal cerebral edema, and two of unknown causes.
Responding patients had a median time to response of 30 days and no patient had a first response beyond 90 days. Of 121 patients who achieved a complete response at day 30, 90 (78%) maintained the response at day 90. Of 93 patients who had a partial response at day 30, a third improved to complete response by day 90. Only one of 14 patients with stable disease at day 30 improved to complete response by day 90.
“We’re all trying to define who is a CAR T-cell therapy candidate,” said Nastoupil. “What we shared in this study is that there are a number of eligibility criteria that were outlined for the ZUMA-1 study that probably didn’t have an impact on efficacy and safety. The major exception was performance status (PS >1), which universally did poorly across all of our outcomes. Also, elevated LDH [lactate dehydrogenase] at the time of conditioning therapy was also associated with inferior survival.”
“As this technology has been transformative for patients with chemorefractory disease, the uptake has been quite low,” she added. “I think partly there’s a healthy fear surrounding the toxicity associated with this therapy, but also the healthcare resource utilization that’s involved. In the absence of having a poor performance status and an elevated LDH, which is likely a measure of highly aggressive tumor burden, patients should be considered for this therapy. I think referral to treating centers sooner rather than later should also be considered.”
The study was supported by the NIH.
Nastoupil disclosed relevant relationships with Celgene, Gilead Sciences, Novartis, Spectrum Pharmaceuticals, Bayer AG, Janssen Oncology, Juno Therapeutics, Pfizer, Gamida Cell, TG Therapeutics, Janssen Biotech, Genentech/Roche, Karus Therapeutics, and LAM Therapeutics.