Patients

Table 1. Table 1. Treatment Disposition and Baseline Characteristics of the Patients.

A total of 111 patients were enrolled in the study. Axi-cel was manufactured for 110 patients (99%) and administered to 101 patients (91%); the latter population was included in the modified intention-to-treat analysis. Patients included 77 with diffuse large B-cell lymphoma and 24 with primary mediastinal B-cell lymphoma or transformed follicular lymphoma (Table 1, and Fig. S1 in the Supplementary Appendix). The date of data cutoff for the primary analysis was January 27, 2017; the median follow-up was 8.7 months. The cutoff date for the updated analysis was August 11, 2017, which resulted in a median follow-up of 15.4 months.

The median time from leukapheresis to delivery of axi-cel to the treatment facility was 17 days. Of the 10 patients who did not receive axi-cel, 1 had unsuccessful manufacture of the CAR T-cell product, 4 had adverse events, 1 died from disease progression, and 2 had nonmeasurable disease before conditioning chemotherapy. After conditioning chemotherapy but before axi-cel infusion, 1 patient had sepsis and 1 died from multiple factors with laboratory abnormalities suggestive of the tumor lysis syndrome, gastrointestinal bleeding and perforation, and disease progression.

Among the patients who were treated with axi-cel, the median age was 58 years (range, 23 to 76). Most of the patients (85%) had stage III or IV disease; 77% had disease that was resistant to second-line or later therapies, 21% had disease relapse after transplantation, 69% had received at least three previous therapies, and 26% had a history of primary refractory disease (Table 1).

Efficacy

Primary Analysis

Figure 1. Figure 1. Objective Response Rate among the 101 Treated Patients. Panel A shows the objective response rate (ORR; calculated as complete response [CR] plus partial response [PR]) among the patients who received axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor T-cell therapy, as well as the response among the patients with stable disease (SD), disease progression (PD), and those who could not be evaluated (NE). The patients in the modified intention-to-treat population were evaluated according to the two main disease cohorts: diffuse large B-cell lymphoma (DLBCL) and either primary mediastinal large B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TLF). The numbers in parentheses indicate the number of patients who had the specified response. On independent central review, the objective response rate was 71%, including a complete response rate of 51% and a partial response rate of 20%. Panel B shows the subgroup analysis of the objective response rate for key baseline and clinical covariates. Scores on the International Prognostic Index (IPI) include low risk (0 or 1 point), low-intermediate risk (2 points), high-intermediate risk (3 points), and high risk (4 or 5 points). The 95% confidence interval (CI) was calculated with the use of the Clopper–Pearson method. ASCT denotes autologous stem-cell transplantation.

At a minimum of 6 months of follow-up, the objective response rate among the protocol-specified 92 patients was 82% (95% confidence interval [CI], 72 to 89; P<0.001 for the comparison with a 20% historical control rate); among these patients, the complete response rate was 52% (Table S1 in the Supplementary Appendix). An additional 9 patients were enrolled and awaiting treatment at the time that the 92nd patient received the axi-cel infusion. Among the 101 patients who received axi-cel, the objective response rate was 82% (95% CI, 73 to 89), with a 54% complete response rate (Figure 1A, and Fig. S2 in the Supplementary Appendix).

The median time to response was rapid (1.0 month; range, 0.8 to 6.0). The median duration of response was 8.1 months (95% CI, 3.3 to could not be estimated). Response rates were consistent across key covariates, including age, disease stage, International Prognostic Index score at enrollment, presence or absence of bulky disease, cell-of-origin subtype, and use of tocilizumab or glucocorticoids. Responses were also consistent in 26 patients who had a history of primary refractory disease (response rate, 88%) and in 21 patients who had a history of autologous stem-cell transplantation (response rate, 76%). The response rates did not appear to be influenced by biologic covariates, such as the prevalence and intensity of CD19 expression, or by product characteristics, such as the ratio of CD4 cells to CD8 cells and T-cell phenotypes (Figure 1B, and Tables S2, S3, and S4 in the Supplementary Appendix).

At the time of the primary analysis, 52 patients had disease progression, 3 patients had died from adverse events during treatment, 1 patient started an alternative therapy before disease progression, 44 remained in remission (of whom 39 had a complete response), and 1 had stable disease. Of the patients who had disease progression after an initial response, 9 were retreated with axi-cel, according to the protocol. Of these patients, 5 had a response (2 complete and 3 partial), and 2 of these patients had an ongoing response.

Updated Analysis

To evaluate the durability of response with axi-cel, we performed an updated analysis when the 108 patients in the phase 1 and 2 portions of ZUMA-1 had been followed for a minimum of 1 year. The objective response rate was 82%, including a complete response rate of 58%. Of the patients who did not have a complete response at the time of the first tumor assessment (1 month after the infusion of axi-cel), 23 patients (11 of 35 with a partial response and 12 of 25 with stable disease) subsequently had a complete response in the absence of additional therapies as late as 15 months after treatment. At the data cutoff, 42% remained in response, including 40% with a complete response. Of the 7 patients in phase 1 of the study, 3 had an ongoing complete response at 24 months.

Preliminary analysis of CD19 expression at baseline and at the time of disease progression was ongoing. Of the 11 patients with disease progression who were included in the analysis, 3 (27%) with CD19-positive status at baseline had CD19-negative disease at time of disease progression.

Figure 2. Figure 2. Kaplan–Meier Estimates of the Duration of Response, Progression-free Survival, and Overall Survival. Panel A shows the duration of response, according to investigator assessment, in the 89 study patients who had an objective response, including those with a complete response and those with a partial response. Patients who had a complete response had a longer duration of response than those with an objective or partial response. According to independent central review, the median duration of response was 8.1 months (range, 3.5 to could not be estimated [NE]). Panel B shows the rate of progression-free survival, and Panel C the rate of overall survival in the 108 patients who were treated in the phase 1 and phase 2 studies. Tick marks indicate the time of data censoring at the last follow-up. NR denotes not reached.

Ongoing response rates were consistent across key covariates, including the use of tocilizumab or glucocorticoids (Fig. S3 in the Supplementary Appendix). The median duration of response was 11.1 months (95% CI, 3.9 to could not be estimated) (Figure 2A). The median duration of progression-free survival was 5.8 months (95% CI, 3.3 to could not be estimated) (Figure 2B), with progression-free survival rates of 49% (95% CI, 39 to 58) at 6 months, 44% (95% CI, 34 to 53) at 12 months, and 41% (95% CI, 31 to 50) at 15 months. The median overall survival was not yet reached (95% CI, 12.0 months to could not be estimated) (Figure 2C), with overall survival rates of 78% (95% CI, 69 to 85) at 6 months, 59% (95% CI, 49 to 68) at 12 months, and 52% (95% CI, 41 to 62) at 18 months. A total of 56% of patients remained alive at the time of the data cutoff. Two patients who had a response underwent allogeneic stem-cell transplantation.

Safety

Primary Analysis

Table 2. Table 2. Adverse Events, the Cytokine Release Syndrome, and Neurologic Events Associated with Treatment.

During treatment, all 101 patients who had received axi-cel had adverse events, which were grade 3 or higher in 95% (Table 2). The most common adverse events of any grade were pyrexia (in 85% of the patients), neutropenia (in 84%), and anemia (in 66%). The most common adverse events of grade 3 or higher were neutropenia (in 78%), anemia (in 43%), and thrombocytopenia (in 38%). The cytokine release syndrome occurred in 94 patients (93%). Most cases were of low grade (37% of grade 1 and 44% of grade 2), with 13% of grade 3 or higher (9% of grade 3, 3% of grade 4, and 1% of grade 5).

The most common symptoms of the cytokine release syndrome of grade 3 or higher were pyrexia (in 11% of the patients), hypoxia (in 9%), and hypotension (in 9%). Vasopressors were used in 17% of the patients. The median time after infusion until the onset of the cytokine release syndrome was 2 days (range, 1 to 12), and the median time until resolution was 8 days. All the events associated with the cytokine release syndrome resolved except for one event of grade 5 hemophagocytic lymphohistiocytosis. Another event of grade 5 cardiac arrest occurred in a patient with the cytokine release syndrome.

Neurologic events occurred in 65 patients (64%); 28% were grade 3 or higher. The most common neurologic events of grade 3 or higher were encephalopathy (in 21% of the patients), confusional state (in 9%), aphasia (in 7%), and somnolence (in 7%). Early neurologic signs included word-finding difficulties (dysphasia), attention or calculation defects (counting backward by serial 7s), and difficulty executing complex commands (handwriting).27 The median onset of neurologic events occurred on day 5 (range, 1 to 17), with median resolution on day 17 after infusion. One patient had ongoing grade 1 memory impairment that resolved after the data cutoff for the primary analysis. All the other neurologic events resolved except for four events, which were ongoing at the time of death (two deaths from progressive disease and two from adverse events unrelated to neurologic events). Rates of the cytokine release syndrome and neurologic events decreased over the course of the study (Table S5 in the Supplementary Appendix). Forty-three percent of patients received tocilizumab and 27% received glucocorticoids for the management of the cytokine release syndrome, neurologic events, or both,24 with no apparent effect on overall or ongoing response rates (Figure 1B, and Fig. S3 in the Supplementary Appendix).

Updated Analysis

Ten patients had serious adverse events (including nine infections in 8 patients) after the data cutoff for the primary analysis (Table S6 in the Supplementary Appendix). There were no new events associated with the cytokine release syndrome or neurologic events related to axi-cel treatment. Forty-four patients (44%) died from causes that included disease progression (in 37 patients), adverse events (in 3 patients, including 2 with the above-mentioned axi-cel–related events associated with the cytokine release syndrome and 1 with pulmonary embolism that was not related to axi-cel), and other causes after disease progression and subsequent therapies that were not related to axi-cel (in 4). One death that was not associated with axi-cel was previously reported in phase 1 of ZUMA-1.21 There were no new deaths from adverse events after the primary analysis. No cases of replication-competent retrovirus or axi-cel treatment-related secondary cancers were reported.

Biomarkers

Figure 3. Figure 3. CAR T-Cell Expansion and Correlations with Response and Adverse Events. Serial blood samples were analyzed for chimeric antigen receptor (CAR) T-cell levels and serum biomarkers in all 101 patients who were treated with axi-cel, as described previously.21 Panel A shows CAR T-cell expansion and persistence with median values and interquartile ranges (Q1 and Q3). Panel B shows the association between CAR T-cell expansion, which was measured as peak levels of CAR cells per microliter of blood, and the objective response rate, neurologic events, and the cytokine release syndrome. The peak factor change is shown for patients with a response as compared with those without a response, for those with neurologic events of grade 3 or higher, and for those with the cytokine release syndrome of grade 3 or higher. P values were calculated by means of the Wilcoxon rank-sum test. Panel C shows serum biomarkers (interleukin-2, granulocyte–macrophage colony-stimulating factor [GM-CSF], and ferritin) that were associated only with neurologic events and not with the cytokine release syndrome. The peak value is defined as the maximum level of the cytokine after baseline. The peak factor is the value in patients with neurologic events of grade 3 or higher versus those with events of grade 0 to 2. Adjusted P values were calculated with the use of Holm’s procedure after multiple testing by means of the Wilcoxon rank-sum test. In Panels B and C, the horizontal line within each box represents the median, and the lower and upper borders of each box represent the 25th and the 75th percentiles, respectively, and the I bars represent the minimum and maximum range.

CAR T levels peaked in the peripheral blood within 14 days after infusion of axi-cel and were detectable in most patients at 180 days after infusion (Figure 3A). Three patients with ongoing complete remission at 24 months still had detectable CAR T levels in the blood. Expansion was significantly associated with response (P<0.001), with an area under the curve within the first 28 days after treatment that was 5.4 times as high among the patients who had a response as among those who did not have a response. Peak expansion and area under the curve were significantly associated with neurologic events of grade 3 or higher but not with the cytokine release syndrome (Figure 3B, and Table S7 and Fig. S4 in the Supplementary Appendix). Of 44 serum biomarkers that were examined, several biomarkers, including interleukin-6, -10, -15, and -2Rα and granzyme B, were significantly associated with neurologic events and the cytokine release syndrome of grade 3 or higher (Table S8 in the Supplementary Appendix). Several biomarkers, including interleukin-2, granulocyte–macrophage colony-stimulating factor (GM-CSF), and ferritin, were significantly associated only with neurologic events of grade 3 or higher (Figure 3C). The induction of anti-CAR antibodies was not observed in any patient.