BackgroundPatients with advanced cutaneous melanoma and persistent disease after checkpoint inhibitor therapy have poor outcomes and limited treatment options, highlighting a significant unmet ...medical need.1 Autologous TIL cell therapies have shown promise in this population attributable, in part, to their intrinsic and patient-specific antitumor activity2; however, no such therapies are approved. Made from each patient‘s digested and cryopreserved tumor, ITIL-168 is an autologous TIL cell therapy manufactured to offer an unrestricted T-cell receptor repertoire. A single-center compassionate use clinical series demonstrated the feasibility and clinical utility of an earlier version of ITIL-168.3 DELTA-1 is a global, multicenter phase 2 study to evaluate efficacy and safety of ITIL-168. DELTA-1 will enroll patients with melanoma relapsed after or refractory to PD-1 inhibitors (PD-1i), patients intolerant to PD-1i, and patients whose best response to PD-1i was stable disease.MethodsPatients aged ≥18 years with histologically confirmed advanced cutaneous melanoma, ECOG performance status 0–1, and adequate organ function will be enrolled in 1 of 3 cohorts. Cohort 1 (n≈80) will include patients who relapsed after or were refractory to ≥1 prior line of systemic therapy, including a PD-1i and, if BRAF-mutated, a BRAFi ± MEKi. Cohorts 2 and 3 (n≈25 each) will include patients intolerant to PD-1i and those with stable disease after ≥4 doses of PD-1i, respectively. After tumor resection for TIL harvest, patients must have ≥1 remaining measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients with uveal, acral, or mucosal melanoma, prior allogeneic transplant or cell therapy, and with central nervous system (CNS) disorder or symptomatic and/or untreated CNS metastases are ineligible. Patients will receive 5 days of lymphodepleting chemotherapy (cyclophosphamide ×2 days overlapping with fludarabine ×5 days) followed by a single ITIL-168 infusion (≥5×109 cells) and supportive short course high-dose IL-2. The primary endpoint is objective response rate (ORR) per central review. Key secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, TIL persistence, and safety. Hypothesis testing of ORR will be performed for cohort 1. Two interim analyses will occur after 20 patients in cohort 1 have been followed for ≥28 days (safety) and evaluated for response ≥3 months after ITIL-168 infusion (futility). The primary analysis will occur when all patients in the cohort 1 modified intent-to-treat population have been followed for ≥6 months after the first posttreatment disease assessment.AcknowledgementsMedical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc, and Phylicia Aaron, PhD, of Nexus GG Science, with funding from Instil Bio, Inc.ReferencesSchadendorf D, van Akkoi ACJ, Berking C, et al. Melanoma. Lancet 2018;392(10151):971–984.Borch TH, Anderson R, Ellebaek E, et al. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer 2020;8(2):e000668.Hawkins RE, Jiang Y, Lorigan PC, et al. Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Cancer Res 2021;81(13):LB150.Ethics ApprovalAll patients will provide written informed consent. The study will be approved by the Institutional Review Board/Independent Ethics Committee at each site and conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation.ConsentN/A; the abstract does not contain sensitive or identifiable patient information.
In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after ...the failure of conventional therapy.
In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10
anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen ...receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.
In a multicenter phase 1 study, Locke, Neelapu, et al. report tolerability and safety of KTE-C19, a CD19 chimeric antigen receptor technology, in patients with chemorefractory DLBCL. More importantly, KTE-C19 could provide durable clinical benefit in this difficult-to-treat patient population, demonstrating broad clinical applicability of KTE-C19.
BackgroundDespite the benefits of immune checkpoint inhibitors (ICIs) in solid tumors, additional treatment options are needed for patients with primary or acquired resistance.1 TILs are present in ...various solid tumors, and TIL therapy has demonstrated efficacy and durable responses in some advanced solid tumors due to its antitumor reactivity and broad T-cell repertoire.2-4 Additionally, preclinical data suggest ICIs may further support the persistence of TILs in immunogenic tumors.5 Here, we describe a study that will explore the safety, feasibility, and preliminary efficacy of an autologous TIL therapy, ITIL-168, in combination with pembrolizumab in patients with cervical cancer (CC), head and neck squamous-cell carcinoma (HNSCC), or non-small cell lung cancer (NSCLC).MethodsDELTA-2 (NCT05393635) is an ongoing phase 1, multicenter, multicohort, open-label trial evaluating ITIL-168 with pembrolizumab in previously treated patients with advanced solid tumors. Patients will be enrolled in 1 of 3 cohorts (n≈9-15 patients per cohort): advanced CC (Cohort 1), HNSCC (Cohort 2), or NSCLC (Cohort 3). Eligible patients must have progressed during or following ≥1 prior line of chemotherapy along with an ICI. EGFR mutations or ALK translocations in NSCLC are included in Cohort 3, and patients are required to have progressed on targeted therapy but not ICI. Eligibility criteria across all cohorts include ECOG PS ≤1, adequate organ function, resectable tumor lesion(s), and ≥1 remaining measurable lesion per RECIST v1.1 post-tumor resection. Bridging therapy is allowed but must be discontinued at least 2 weeks or 5 half-lives before baseline imaging. Patients with prior cell therapy treatment, symptomatic and/or untreated central nervous system metastases, or requiring chronic steroids are ineligible. Treatment will include lymphodepleting chemotherapy (the dosage of cyclophosphamide and fludarabine will be adjusted based on cohort and patient comorbidities) followed by a single infusion of ITIL-168 and up to 8 doses of high-dose IL-2 (figure 1). Patients will receive pembrolizumab at baseline before ITIL-168 infusion, day 21 postinfusion, and then every 6 weeks for ≤48 weeks or until disease progression or intolerable toxicity. An interim and a primary analysis for each cohort will be conducted. The primary endpoint is the frequency and severity of ITIL-168 treatment-emergent adverse events (AEs) per Common Terminology Criteria for AEs version 5.0. Secondary endpoints include manufacturing success rate, objective response rate per modified RECIST v1.1, duration of response, progression-free survival, and overall survival. The study opened in July 2022 and is currently recruiting patients.AcknowledgementsMedical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc. and Lauryn Samelko, PhD, and Phylicia Aaron, PhD, of Nexus Global Group Science, with funding from Instil Bio, Inc.ReferencesNordstrom BL, Hamilton M, Collins JM, et al. Treatment patterns and outcomes following disease progression on anti-PD-1 therapies for advanced melanoma. Future Oncol. 2022;18:1343–1355.Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105(1):93–103.van den Berg JH, Heemskerk B, van Rooij N, et al. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up. J Immunother Cancer. 2020;8:e000848.Borch TH, Andersen R, Ellebaek E, et al. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. JITC. 2020;8:e000668.Donia M, Kjeldsen JW, Andersen R, et al. PD-1+ polyfunctional T cells dominate the periphery after tumor-infiltrating lymphocyte therapy for cancer. Clin Cancer Res. 2017;23:5779–5788.Ethics ApprovalAll patients will provide written informed consent. The study will be approved by the Institutional Review Board/Independent Ethics Committee at each site and conducted in accordance with the Good Clinical Practice Guidelines of the International Council for Harmonisation.Abstract 781 Figure 1DELTA-2 Treatment SchemaDELTA-2 is a phase 1 trial evaluating the safety, feasibility, and preliminary efficacy of ITIL-168 in combination with pembrolizumab in patients with select advanced solid tumors with progressive disease during or after 1 prior line of treatment.*Tumor resection occurs within 30 days after patient consent, followed by optional bridging therapy.†Baseline visit occurs within 14 days prior to lymphodepleting chemotherapy, followed by pembrolizumab (200 mg).‡Cohorts 1/3 will receive lymphodepleting chemotherapy on days –7 to –3; Cohort 2 will receive lymphodepleting chemotherapy on days –5 to –3.§Pembrolizumab is administered once on day 21 (200 mg), followed by every 6 weeks from weeks 6 to 48 (400 mg).D, day; HD, high-dose; IL-2, interleukin-2; Q6W, every six weeks; W, week.Figure omitted. 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Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, has shown promising efficacy in refractory aggressive non-Hodgkin lymphoma in the ZUMA-1 trial with an ...objective response rate (ORR) of 82%, including 54% complete responses (CRs; Locke et al. AACR 2017. #9986). Checkpoint expression within the tumor environment, at baseline and post-CAR T cell infusion, suggests that checkpoint blockade could augment axi-cel activity (Galon et al. ASCO 2017. #3025; Vranic et al. PLOS One. 2016). ZUMA-6 is a phase 1/2 study evaluating the safety and efficacy of combination treatment with axi-cel and the anti-PD-L1 antibody, atezolizumab (atezo), in patients with refractory DLBCL (NCT02926833).
Methods: Eligible patients (≥ 18 years) had received ≥ 1 prior CD20-targeting and anthracycline-containing regimen with stable or progressive disease to last line of therapy or early relapse after autologous stem cell transplant, had an ECOG ≤ 1, and had adequate bone marrow and organ function. Patients received low-dose conditioning with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day × 3 days, followed by axi-cel infusion at a target dose of 2 × 106 cells/kg. In the phase 1 portion of the study, in cohorts 1, 2, and 3, atezo 1200 mg was administered every 21 days for 4 doses starting on day 21, 14, and 1 post-axi-cel infusion, respectively. This report describes phase 1 results from the first 2 dosing cohorts. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs) within 21 days from the first atezo dose. Secondary endpoints included frequency of adverse events (AEs), ORR, and biomarkers.
Results: As of the June 23, 2017 data cut-off, there were 6 patients dosed with axi-cel and atezo (3 in cohort 1; 3 in cohort 2). Median age was 52 years (range, 29-66). Patients had a median of 3 prior therapies (range, 2-4), 4 had disease progression as best response to last prior treatment before study entry, and 3 had an International Prognostic Index score of 3 or 4. No DLTs were observed in either cohort and there was no evidence of worsening or recurrent AEs consistent with cytokine release syndrome (CRS), neurologic events (NE), or other CAR T cell-related toxicities following atezo administration in either dosing schedule. All patients experienced at least 1 AE, the majority of which were cytopenias attributed to conditioning chemotherapy. The most common grade ≥ 3 AEs were anemia (67%), encephalopathy (67%), and hyponatremia (50%). Incidences of grade ≥ 3 CRS and NE were 33% and 67%, respectively. Five patients were evaluable for response; ORR was 100% (5/5) with 1 CR observed. One CR and 2 partial responses are ongoing. All 6 ZUMA-6 patients demonstrated a CAR T cell area under the curve in the first 28 days (AUC28) that was over 2-fold higher than the median observed in patients with DLBCL enrolled in ZUMA-1 (ZUMA-6 range, 816-2301 days × cells/uL; ZUMA-1 median, 374 days × cells/uL). A second peak of > 2-fold over the pre-atezo level in serum concentrations of the immune-modulating cytokine interferon gamma was also observed 1 week after the first atezo infusion in 4/5 evaluable patients. Cohort 3 is currently enrolling and updated results, including those from cohort 3, will be presented.
Conclusions: In this ongoing phase 1 study, PD-L1 blockade with atezo following axi-cel infusion appeared to have a manageable safety profile, and translational evidence suggested an enhancing pharmacodynamic action on CAR T cells. Results collected thus far support further evaluation of the combination in the phase 2 portion of the study.
Locke:Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Miklos:Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses; Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding. Herrara:BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Immune Design: Research Funding. Jacobson:Kite Pharma: Consultancy; Pharmacyclics, LLC: Consultancy. Lee:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Bot:Kite Pharma: Employment, Equity Ownership. Xue:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Roberts:Kite Pharma: Employment, Equity Ownership.
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Background: Approximately 45% of new ALL cases occur in adults ≥ 20 years of age (Howlader et al. SEER Cancer Statistics. 2015), and approximately 50% of adult patients relapse with poor subsequent ...outcomes (Oriol et al. Haematologica. 2010; Basson et al. JCO. 2011). Promising early efficacy and manageable safety were previously reported with anti-CD19 CAR T cells (KTE-C19) in adult patients with R/R ALL (Shah et al. ASCO 2017. #3024). Here we report updated results of the ZUMA-3 trial.
Methods: Adult patients (≥ 18 years of age) with R/R ALL (Philadelphia+ eligible), > 5% bone marrow (BM) lymphoblasts; Eastern Cooperative Oncology Group performance status (ECOG) 0-1; and adequate renal, hepatic, and cardiac function were eligible. Patients with active graft-versus-host disease or clinically significant infection were not eligible. Patients received a target dose of 1 × 106 CAR T cells/kg or 2 × 106 CAR T cells/kg after lymphodepletion with 25 mg/m2/day fludarabine for 3 days and 900 mg/m2/day cyclophosphamide given on the last day. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence of adverse events (AEs), incidence of minimal residual disease-negative (MRD-) responses, duration of remission (DOR), relapse-free survival (RFS), and overall survival (OS). Exploratory endpoints included levels of anti-CD19 CAR T cells in blood and levels of cytokines in serum.
Results: As of the data cut-off date (DCO; April 26, 2017), 22 patients have been enrolled, and 16 patients received KTE-C19 on study. Four patients had not received treatment by the DCO, 1 patient did not receive KTE-C19 due to an AE after conditioning, and 1 patient received KTE-C19 under compassionate use. All 16 patients who received KTE-C19 prior to the DCO were included in the safety analysis, and all patients who had the opportunity to be followed for 8 weeks prior to the DCO were included in the efficacy analysis (n = 11). Of the 16 patients dosed with KTE-C19, 63% were male, 56% had ECOG 1, and 50% had received ≥ 2 previous lines of treatment, including 3 patients with prior blinatumomab. Nineteen percent of patients had undergone prior allogeneic stem cell transplant, 31% had R/R to ≥ second-line therapy, 31% had primary refractory disease, and 19% experienced first relapse within 12 months of first remission. Most patients (81%) had baseline BM blasts ≥ 60%.
Six patients received the 2 × 106 cells/kg dose and 10 received the 1 × 106 cells/kg dose. No DLTs were observed. One patient experienced a grade 5 event of cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose, and no other KTE-C19-related grade 5 AEs were observed. In the 16 patients who received KTE-C19, all of whom were followed for at least 4 weeks, the most common grade ≥ 3 AEs were hypotension (56%), anemia (50%), pyrexia (50%), and decreased platelet counts (44%). Grade ≥ 3 CRS and neurologic events (NE) were reported in 25% and 63% of patients, respectively. Tocilizumab (toci) or steroids were given for AE management in 94% and 75% of patients, respectively. In the 11 patients eligible for the efficacy analysis, objective response rate was 82%, including 8 (73%) patients with a complete remission (CR or CR with partial hematopoietic recovery), and 1 (9%) with blast-free BM. All remissions were MRD- as determined by flow cytometry. All 5 (100%) of the other patients who were too early for inclusion in the efficacy analysis had MRD- bone marrow with varying degrees of count recovery at the time of the DCO. Median follow-up was 6.8 months; 4 patients relapsed 63 - 168 days after treatment with KTE-C19. Efficacy was comparable between patients who recieved KTE-C19 doses of 1 × 106 and 2 × 106 CAR T cells/kg. Data from additional patients, including those treated with a lower dose of 0.5 × 106 CAR T cells/kg, as well as updated safety, efficacy, biomarker, and product characteristic analyses across dosing groups will be presented.
Conclusions: In this ongoing phase 1 study, KTE-C19 has shown promising efficacy in adult patients with R/R ALL. The safety profile was generally manageable and additional approaches to improve the benefit:risk profile are being explored. ZUMA-3 continues to enroll additional patients at the 0.5 × 106 CAR T cells/kg dose level.
Wierda:AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Juno: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding. Oluwole:Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Schiller:Kite Pharma: Research Funding. Topp:Regeneron: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Celgene: Other: Travel; Macrogenics: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Research Funding. Kersten:Kite Pharma: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millenium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Mojadidi:Kite Pharma: Employment, Equity Ownership. Xue:Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Stout:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Jain:Kite Pharma: Employment, Equity Ownership.
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Background: Patients with refractory NHL experience poor outcomes to currently available therapies. In the SCHOLAR-1 pooled analysis of patients with refractory aggressive NHL, the objective ...response rate (ORR) was 26% (complete response CR rate was 7%), and the median overall survival (OS) was 6.3 months (Crump et al. Blood . In press). The primary analysis of ZUMA-1 demonstrated positive results with an ORR of 82% and a CR rate of 54% after a single infusion of axi-cel. The safety profile was manageable: grade ≥ 3 cytokine release syndrome and neurologic events were generally reversible and reported for 13% and 28%, respectively (Locke et al. AACR 2017. #9986). With a median follow-up of 8.7 months, 44% of patients in ZUMA-1 were in ongoing response. We plan to present the 1-year follow-up of ZUMA-1 to confirm the stability of response following anti-CD19 CAR T cell therapy as previously suggested (Locke et al. Mol Ther . 2016; Kochenderfer et al. Mol Ther . 2017). Additionally, exploratory biomarker analyses were conducted to understand the mechanisms of resistance to anti-CD19 CAR T cell treatment.
Methods: Patients with refractory diffuse large B cell lymphoma, transformed follicular lymphoma, or primary mediastinal large B cell lymphoma were enrolled and dosed per Locke et al. (AACR 2017. #9986). Refractory disease was defined as progressive disease or stable disease as best response to last line of therapy, or relapse ≤ 12 months after autologous stem cell transplant. Patients must have had a prior anti-CD20 antibody and an anthracycline-containing regimen.The primary endpoint was ORR per 2007 International Working Group criteria. Key secondary endpoints included duration of response (DOR), OS, and incidence of adverse events (AEs). A key exploratory endpoint was to investigate the mechanisms of resistance using post-treatment tumor biopsies obtained at time of relapse or progression.
Results: A long-term follow-up analysis will be performed with a data cut-off of August 11, 2017. To date, no patients have been lost to follow-up, and all patients who are alive remain in disease and survival follow-up. Updated DOR and OS will be presented with a minimum follow-up of 1 year and a median follow-up of 15 months. Updated subgroups and associative analyses of efficacy outcomes will be presented. Baseline and post-progression biopsies were evaluable by central review from 12 patients. CD19 and PD-L1 immunohistochemistry results are tabulated. Three of 11 (27%) patients with CD19-positive status at baseline developed CD19-negative disease at time of disease progression. Eight of 10 (80%) patients evaluable for PD-L1 at time of disease progression had PD-L1-positive disease. Of the 8 patients with CD19-positive samples at progression, 5 (63%) demonstrated PD-L1-positive tumor cells. Of the 3 patients with CD19-negative samples at progression, 2 had PD-L1-positive tumor cells.
In addition, post-progression biopsies from 6 separate patients were evaluable by local review, of which 3 (50%) had ≤ 1% CD19 staining. Cumulatively, 17 patients were evaluable for CD19 expression at time of progression by either central or local review, and 6 (35%) had ≤ 1% CD19 expression. Updated results will be presented.
Conclusions: In the ZUMA-1 study, axi-cel demonstrated significant clinical benefit with manageable AEs in patients with no curative treatment options. Additional long-term efficacy, safety, subgroup, and biomarker associative analyses with a median of 15 months of follow-up will be presented. Loss of CD19 and gain of PD-L1 expression in tumors are identified as possible mechanisms of resistance following axi-cel treatment. These results provide insights into development of novel therapeutic strategies to overcome CD19 CAR T resistance and further improve outcomes in these patients.
Drs. Neelapu and Locke contributed equally to this work.
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Neelapu:BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Locke:Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Miklos:Genentech: Research Funding; Roche: Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria; Novartis: Research Funding. Jacobsen:Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Braunschweig:Kite Pharma: Equity Ownership. Oluwole:Kite Pharma: Consultancy. Siddiqi:Juno: Other: Steering committee for JCAR017; Seattle Genetics: Speakers Bureau; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman:ImmuneGene: Research Funding; Kite Pharma: Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan:Seattle Genetics: Research Funding. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.
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Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, for the treatment of patients with refractory, aggressive NHL. ...The objective response rate (ORR) was 82% with a 54% rate of complete response and 44% of responses were ongoing at the time of the primary analysis (Locke et al. AACR 2017. #9986). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of patients, respectively. A safety expansion cohort was added to further characterize mechanisms underlying CRS and NE associated with CAR T cell therapy and to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs).
Methods: Patients (≥ 18 years) must have had an Eastern Cooperative Oncology Group performance status of 0-1 and refractory or relapsed transplant ineligible disease. Patients received low-dose conditioning of 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days followed by axi-cel at a target dose of 2 × 106 CAR T cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice a day on day 0 and 8 mg/kg of tocilizumab on day 2 post axi-cel infusion. To evaluate the mechanisms of NE, paired serum and cerebrospinal fluid (CSF) were obtained for all patients prior to conditioning chemotherapy and after axi-cel infusion (day 5).
Results: As of April 26, 2017, 31 patients received axi-cel. Median age was 51 years (range, 21-74), 52% were male, 65% had stage III-IV disease, 74% were refractory to ≥ second-line therapy, and 19% relapsed ≤ 12 months after autologous stem cell transplant. Most patients (97%) experienced at least 1 grade ≥ 3 AE. The most common grade ≥ 3 AEs were neutropenia/neutrophil count decreased (71%), anemia (55%), thrombocytopenia/platelet count decreased (52%), leukopenia/white blood cell count decreased (35%), febrile neutropenia (29%), encephalopathy (23%), and hypotension (23%). One patient (3%) experienced a grade ≥ 3 (grade 4) CRS. Grade 3 and 4 NE occurred in 29% and 6% of patients, respectively. One patient died of cerebral edema; there were no other deaths due to AE.
Updated efficacy, safety, subgroups, and paired blood/serum/CSF biomarker associative analyses will be presented.
Conclusions: Early use of tocilizumab may reduce the incidence of severe CRS but not NE in patients treated with CAR T cell therapy. These data provide evidence that the underlying pathophysiology of NE may differ from that of CRS. Understanding the mechanisms of NE may help to further improve the benefit:risk profile for CAR T cell therapy.
Drs Locke and Neelapu contributed equally to this work.
Locke:Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Neelapu:Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobson:Pharmacyclics, LLC: Consultancy; Kite Pharma: Consultancy. Braunschweig:Kite Pharma: Equity Ownership. Oluwole:Kite Pharma: Consultancy. Siddiqi:Seattle Genetics: Speakers Bureau; Juno: Other: Steering committee for JCAR017; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman:Celgene: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Research Funding; ImmuneGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan:Seattle Genetics: Research Funding. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Sherman:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership. Miklos:Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria.
This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program®
Introduction: A single institution study conducted at the National Cancer Institute ...(NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) (Kochenderfer et al. Blood 2012, J Clin Onc 2014, ASH 2014). KTE-C19 utilizes the same anti-CD19 CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better et al. ASCO 2014). The ZUMA-1 trial is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in subjects with refractory aggressive B-cell NHL. Preliminary phase 1 results presented.
Methods: Subjects received KTE-C19 at a target dose of 2 x 106 (minimum 1 x 106) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 is to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Cytokine release syndrome (CRS) was graded per revised criteria (Lee et al. Blood 2014). Key secondary objectives include evaluating the overall response rate (ORR=CR+PR) per Cheson 2007, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as stable disease or progressive disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Subjects must have received at least prior anti-CD20 therapy and an anthracycline containing regimen.
Results: As of 28 July 2015, 6 subjects were dosed in the phase 1 portion of the study. All subjects are evaluable for safety with a median follow up time of 4.8 weeks post KTE-C19 infusion and 3 subjects have had 1 month tumor assessments. Two subjects experienced only grade (gr) 1-2 KTE-C19 related events. Three subjects had gr 3 KTE-C19 related events as highest gr toxicities; all these events were reversible within 3 days. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. One subject experienced a DLT of gr 4 encephalopathy and gr 4 CRS. This subject died within 30 days of KTE-C19 cell infusion; the death was due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Of the 3 subjects assessed for response at one month, 2 achieved a complete response and one achieved a partial response. Key safety and efficacy findings are summarized in the table. Biomarker and translational endpoints are included in a separate abstract. Enrollment is ongoing and updated trial results will be presented.
Conclusions: Preliminary phase I results ofthe ZUMA-1 study demonstrate that KTE-C19 can be centrally manufactured and administered in a multicenter trial. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease at 1 month after KTE-C19 administration. This potentially pivotal study is the first enrolling multicenter anti-CD19 CAR T cell trial in refractory aggressive NHL. Clinical trial: NCT02348216.
Table 1SubjectSex/Age/ECOGDisease TypeTreatment HistoryGr 3 or Higher KTE-C19-Related Adverse EventsResponse at 1 Month101-002-001M/59/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 encephalopathy (resolved)Partial Response101-002-003M/69/1DLBCLRefractory to 2nd line chemotherapyGr 3 tremor (resolved) Gr 3 delirium (resolved) Gr 3 agitation (resolved) Gr 3 restlessness (resolved) Gr 3 somnolence (resolved)Complete Response101-009-001F/29/1PMBCLRefractory to 1st, 2nd, 3rd line chemotherapyGr 4 CRS Gr 4 encephalopathyN/A101-003-001M/67/1DLBCLRelapse ≤ 12 mo after ASCTNoneComplete Response101-002-004M/69/0DLBCLRefractory to 4th line chemotherapyGr 3 encephalopathy (resolved)Assessment not yet reached101-003-002F/34/0DLBCLRelapse ≤ 12 mo after ASCTNoneAssessment not yet reached
mo - months
M - male, F - female
N/A - not applicable
Locke:Kite Pharma: Other: Scientific Advisory Boards. Off Label Use: Tocilizumab for CRS per Blood et al. 2014. Bartlett:Kite: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Colgene: Research Funding; Millennium: Research Funding; MERC: Research Funding; Gilead: Consultancy, Research Funding; Insight: Research Funding; Medimmune: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Pharmacyclics/Jannsen: Speakers Bureau. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership.
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Background: ZUMA-1 is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in patients with refractory aggressive B-cell non-Hodgkin lymphoma. In phase 1, KTE-C19 ...demonstrated ongoing complete remissions with a tolerable safety profile (Neelapu, ASCO 2016). The phase 2 portion of the study has 2 cohorts based on tumor type: diffuse large B-cell lymphoma (cohort 1) or PMBCL/TFL (cohort 2). Results from cohort 2 at the time of the first pre-specified interim analysis of ZUMA-1 are presented here.
Methods: Patients received KTE-C19 at a target dose of 2 × 106 (minimum 1 × 106) anti-CD19 chimeric antigen receptor (CAR) T cells/kg after a low-dose conditioning chemotherapy regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint was overall remission rate per International Working Group criteria (Cheson, J Clin Oncol2007). Key secondary endpoints include duration of response, incidence of adverse events (AEs), levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and chemorefractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 months after autologous stem cell transplant. Patients must have received prior anti-CD20 therapy and an anthracycline-containing regimen.
Results: As of June 16, 2016, six patients in cohort 2 were treated with KTE-C19 and had at least 30 days of follow up. The median follow up time was 3.2 months. Fifty percent of patients had PMBCL and 50% had TFL. Median age was 55 years (range, 28-60), 67% were male, 67% ECOG performance status 0, and 50% were refractory to second or greater line of chemotherapy while 50% relapsed after autologous stem cell transplant. The objective response rate was 100%. All patients have ongoing complete remissions. Worst grades 3 and 4 treatment-emergent AEs occurred in 17% and 67% of patients, respectively. There were no grade 5 events. All grade 4 treatment-emergent AEs were cytopenias. KTE-C19-related worst grade 3 and 4 AEs occurred in 50% and 17% of patients, respectively. Patient incidence of any grade/grade 3/grade 4 CRS and neurotoxicity were 100%/0%/0% and 67%/33%/0%, respectively. All KTE-C19-related AEs have resolved. Biomarker endpoints will be presented.
Conclusions: KTE-C19 demonstrated early promising activity in patients with refractory PMBCL and TFL. The predominant toxicities of CRS and neurotoxicity were generally reversible. Updated trial results from 11 patients at interim analysis 2 will be presented. Clinical trial: NCT02348216.
This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program®
Locke:Kite: Membership on an entity's Board of Directors or advisory committees. Bartlett:Gilead: Consultancy. Siddiqi:Pharmacyclics, LLC, an AbbVie Company: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite pharma: Other: Funded travel, 1 day registration, and 1 night hotel stay for EHA2016 so I could present trial data there. . Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Westin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Forty Seven: Consultancy; Forty Seven: Consultancy. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.
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