Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma.

BACKGROUND: In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. METHODS: In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. RESULTS: A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. CONCLUSIONS: At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume.

ABSTRACT: Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [median or less] vs high [greater than median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem cell transplantation in patients who had a response). All P values are descriptive. Within high- and low-MTV subgroups, event-free survival (EFS) and progression-free survival (PFS) were superior with axi-cel vs standard care. EFS in patients with high MTV (vs low MTV) was numerically shorter with axi-cel and was significantly shorter with standard care. PFS was shorter in patients with high MTV vs low MTV in both the axi-cel and standard-care arms, and median MTV was lower in patients in ongoing response at data cutoff vs others. Median MTV was higher in patients treated with axi-cel who experienced grade ≥3 neurologic events or cytokine release syndrome (CRS) than in patients with grade 1/2 or no neurologic events or CRS, respectively. Baseline MTV less than or equal to median was associated with better clinical outcomes in patients receiving axi-cel or standard care for second-line LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.

Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma.

BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor. METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed. RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred. CONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7).

Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products. SIGNIFICANCE: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4.

Outcomes of subsequent antilymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7.

ABSTRACT: The optimal management of patients with relapsed/refractory large B-cell lymphoma (LBCL) after disease progression or lack of response to second-line (2L) therapy remains unclear. Here, we report outcomes among patients who received subsequent antilymphoma therapy per investigator discretion separately by their randomized 2L arm in ZUMA-7, namely axicabtagene ciloleucel (axi-cel) vs standard of care (SOC). Progression-free survival (PFS) and overall survival (OS) were calculated from 3L therapy initiation. In the SOC arm, 127 of 179 randomized patients (71%) received 3L therapy. Median PFS among those who received 3L cellular immunotherapy (n = 68) vs those who did not (n = 59) was 6.3 vs 1.9 months, respectively; median OS was 16.3 vs 9.5 months, respectively. In the axi-cel arm, 84 of 180 randomized patients (47%) received 3L therapy. Median PFS among those who received 3L chemotherapy (n = 60) vs cellular immunotherapy (n = 8) was 1.7 vs 3.5 months, respectively; median OS was 8.1 months vs not reached, respectively. Of the 60 patients who received 3L chemotherapy, 10 underwent stem cell transplantation (SCT) after salvage chemotherapy. Median PFS was 11.5 vs 1.6 months, and median OS was 17.5 vs 7.2 months for those who did vs did not reach SCT, respectively. Eight patients received 3L cellular immunotherapy after 2L axi-cel. Of these, 6 patients received subsequent SCT in any line; all 6 were alive at data cutoff. These findings help inform subsequent treatment choices after 2L therapy failure for relapsed/refractory LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.

Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10-9 for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10-9 for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.

A Multicenter Phase II Study of AMG 337 in Patients with MET-Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma and Other MET-Amplified Solid Tumors.

PURPOSE: MET gene amplification is associated with poor prognosis in gastric/gastroesophageal junction/esophageal (G/GEJ/E) cancers. We determined antitumor activity, safety, and pharmacokinetics of the small-molecule MET inhibitor AMG 337 in MET-amplified G/GEJ/E adenocarcinoma or other solid tumors.Patients and Methods: In this phase II, single-arm study, adults with MET-amplified G/GEJ/E adenocarcinoma (cohort 1) or other MET-amplified solid tumors (cohort 2) received AMG 337 300 mg/day orally in 28-day cycles. The primary endpoint was objective response rate (ORR; cohort 1). Secondary endpoints included ORR (cohort 2), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 2101 patients screened for MET amplification, 132 were MET-amplified and 60 were enrolled: 45 in cohort 1, and 15 in cohort 2. Fifty-six patients (97%) had metastatic disease; 57 had prior lines of therapy (1 prior line, 29%; ≥2 prior lines, 69%). A protocol-permitted review showed efficacy that was lower-than-expected based on preliminary data from a first-in-human study, and enrollment was stopped. Fifty-eight patients received ≥1 AMG 337 dose. ORR in cohort 1 was 18% (8 partial responses). No responses were observed in cohort 2. Of 54 evaluable patients, median (95% CI) PFS and OS were 3.4 (2.2-5.0) and 7.9 (4.8-10.9) months, respectively. The most frequent adverse events (AEs) were headache (60%), nausea (38%), vomiting (38%), and abdominal pain, decreased appetite, and peripheral edema (33% each); 71% had grade ≥3 AEs and 59% had serious AEs. CONCLUSIONS: AMG 337 showed antitumor activity in MET-amplified G/GEJ/E adenocarcinoma but not in MET-amplified non-small-cell lung cancer.See related commentary by Ma, p. 2375.

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study.

BACKGROUND: Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function. METHODS: Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56 mg/m2 doses. RESULTS: The majority of patients enrolled in this study had solid tumors (n = 44) vs. MM (n = 2) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC0-last, respectively (27 mg/m2 dose); increases at the 56 mg/m2 dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities. CONCLUSIONS: In this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20-50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure-response relationship of carfilzomib. Trial registration http://clinicaltrials.gov NCT01949545; date of registration: September 6, 2013.

A Randomized, Placebo-Controlled, Phase 1b/2 Study of Rilotumumab or Ganitumab in Combination With Platinum-Based Chemotherapy as First-Line Treatment for Extensive-Stage Small-Cell Lung Cancer.

INTRODUCTION/BACKGROUND: In this randomized, double-blind, placebo-controlled phase 1b/2 study we assessed the efficacy/safety of rilotumumab or ganitumab combined with etoposide and carboplatin or cisplatin as first-line treatment in patients with extensive stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: In the phase 1b study, patients received rilotumumab 15 mg/kg or ganitumab 18 mg/kg with etoposide and carboplatin or cisplatin. In the phase 2 study, patients were randomly assigned 1:1:1 to receive placebo, rilotumumab, or ganitumab with etoposide and carboplatin or cisplatin. Chemotherapy was administered for ≤ 6 cycles; rilotumumab, ganitumab, or placebo was then continued as maintenance therapy. The primary end points were incidence of dose-limiting toxicities (DLTs; phase 1b) and overall survival (OS; phase 2). Secondary end points included progression-free survival (PFS) and safety. RESULTS: In the phase 1b study (n = 28), 1 patient treated with ganitumab experienced a DLT (Grade 4 neutropenia/thrombocytopenia lasting ≥ 7 days). In the phase 2 study, 185 patients were enrolled (placebo, n = 61; rilotumumab, n = 62; ganitumab, n = 62). Median OS was 10.8, 12.2 (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.56-1.25; P = .384), and 10.7 (HR, 0.95; 95% CI, 0.63-1.41; P = .787) months, in placebo, rilotumumab, or ganitumumab arms, respectively. Median PFS was 5.4, 5.4 (HR, 1.05; 95% CI, 0.71-1.54; P = .797), and 5.5 (HR, 1.05; 95% CI, 0.72-1.55; P = .780) months, respectively. Adverse events resulting in treatment discontinuation occurred in 11 (19%), 10 (16%), and 7 (12%) patients, respectively. Serum biomarker analysis showed improved survival for patients with baseline hepatocyte growth factor levels below the median in the rilotumumab arm. CONCLUSION: Although the combination of rilotumumab or ganitumab with chemotherapy was tolerable, overall outcomes were not improved in patients with ES-SCLC.