Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

Summary Background Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number . Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment r...

ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

Purpose: To investigate whether EGF receptor (EGFR) pathway mutations predicted response to monotherapy with panitumumab, an anti-EGFR monoclonal antibody, in a randomized phase III study of metastatic colorectal cancer.Experimental Design: Using massively parallel multigene sequencing, we analyzed 320 samples for 9 genes, with multigene sequence data from 288 (90%) samples.Results: Mutation rates were:, and CTNNB1 (2%). In the randomized study and open-label extension, 22 of 138 (16%) wild-type KRAS (codons 12/13/61) patients versus 0 of 103 mutant KRAS (codons 12/13) patients had objective responses. Of 6 mutant KRAS (codon 61) patients, 1 with a Q61H mutation achieved partial response during the extension. Among wild-type KRAS (codons 12/13/61) patients, 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. No patients responded to best supportive care alone. Panitumumab treatment was associated with longer progression-free survival (PFS) among wild-type KRAS (codons 12/13/61) patients [HR, 0.39; 95% confidence interval (CI), 0.28-0.56]. Among wild-type KRAS patients, a treatment effect for PFS favoring panitumumab occurred in patients with wild-type NRAS (HR, 0.39; 95% CI, 0.27-0.56) and wild-type BRAF (HR, 0.37; 95% CI, 0.24-0.55) but not mutant NRAS (HR, 1.94; 95% CI, 0.44-8.44).Conclusions: These results show the feasibility and potential clinical use of next-generation sequencing for evaluating predictive biomarkers.