A Review of Selected Presentations From the 2018 American Society of Clinical Oncology Annual Meeting • June 1-5, 2018 • Chicago, Illinois
Special Reporting on:
• Durability of Response in ZUMA-1, the Pivotal Phase 2 Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
• Updated Safety and Long-Term Clinical Outcomes in TRANSCEND NHL 001, Pivotal Trial of Lisocabtagene Maraleucel (JCAR017) in R/R Aggressive NHL
• Outcomes by Prior Lines of Therapy in ZUMA-1, the Pivotal Phase 2 Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
• Factors Associated With Duration of Response After CD-Specific CAR-T Cell Therapy for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma
• Randomized Phase 2 Trial of Polatuzumab Vedotin With Bendamustine and Rituximab in Relapsed/Refractory FL and DLBCL
• Radiotherapy to Bulky and Extralymphatic Disease in Combination With 6×R-CHOP-14 or R-CHOP-21 in Young Good-Prognosis DLBCL Patients: Results of the 2×2 Randomized UNFOLDER Trial of the DSHNHL/GLA
• Phase I/II Clinical Trial of Ibrutinib and Buparlisib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, and Follicular Lymphoma
• Dose-Adjusted-EPOCH-R With High-Dose Methotrexate for Newly Diagnosed Stage II-IV CD5-Positive Diffuse Large B-Cell Lymphoma: Primary Analysis of the PEARL5 Study
Durability of Response in ZUMA-1, the Pivotal Phase 2 Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
Axicabtagene ciloleucel is an autologous chimeric antigen receptor (CAR) therapy that is designed to reinstate T-cell activation by allowing a patient’s genetically engineered T cells to recognize CD19, a cell surface marker that is expressed on the vast majority of B-cell malignancies.1 The axicabtagene ciloleucel CAR molecule consists of an antibody variable domain, a transmembrane region, and the CD28 and CD3ζ domains, which signal T-cell activation. The construct enables recognition of CD19 that induces T-cell activation and proliferation, as well as activation of inflammatory pathways that result in tumor cell lysis.
The phase 1/2 ZUMA-1 trial (A Phase 1-2 Multi-Center Study Evaluating Axicabtagene Ciloleucel in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma) evaluated axicabtagene ciloleucel therapy in patients with refractory, aggressive B-cell non-Hodgkin lymphoma (NHL).2 The trial met its primary endpoint after the primary analysis, which led to the approval of axicabtagene ciloleucel by the US Food and Drug Administration for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.3 The trial enrolled patients with refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma. Patients had not responded to their most recent line of chemotherapy or had relapsed within 12 months after autologous hematopoietic stem cell transplant (SCT). After leukapheresis and manufacture of axicabtagene ciloleucel, patients received treatment with a low-dose conditioning chemotherapy regimen that consisted of fludarabine (30 mg/m2 daily) and cyclophosphamide (500 mg/m2 daily) on days –5, –4, and –3 before administration of axicabtagene ciloleucel. Axicabtagene ciloleucel was administered via a single intravenous infusion at a target dose of 2 × 106 CAR T cells/kg on day 0. Patients who demonstrated an initial response followed by disease progression at least 3 months after the initial dose of axicabtagene ciloleucel were re-treated. The primary endpoint was the investigator-assessed objective response rate (ORR) according to the International Working Group Response Criteria for Malignant Lymphoma.4 Cytokine release syndrome was graded according to published recommendations.5 Adverse events (AEs), including symptoms of cytokine release syndrome, were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
The overall analysis of ZUMA-1 showed an ORR of 82%, with a complete response (CR) rate of 54%. At a median follow-up of 15.4 months, the ORR was 42%, and the CR was 40%. The overall rate of survival was 52% at 18 months.2
Dr Frederick Locke presented results of long-term follow-up, which was available for 108 patients, including 7 patients from phase 1 and 101 patients from phase 2.6 In the phase 1 portion, the 7 patients had refractory DLBCL, PMBCL, or transformed follicular lymphoma. In the phase 2 trial, 77 patients with DLBCL and 24 patients with PMBCL or transformed follicular lymphoma were enrolled into separate cohorts. The data cutoff was August 11, 2017. The median follow-up was 15.4 months, and the minimum was 12 months. Axicabtagene ciloleucel manufacture was successful in 99% of enrolled patients, and 91% of patients received an infusion of genetically engineered CAR T cells.
With long-term follow-up, the ORR was 82%, and included a CR rate of 58%. Ongoing responses were observed in 42% of patients, and most consisted of CRs. Median overall survival (OS) was not reached, and 12-month OS was 60%. These results compare favorably with data from historical controls in a similar patient population, which show that the ORR reaches 25% after another line of salvage therapy. Twelve percent of patients in the phase 1/2 population experienced cytokine release syndrome of grade 3 or higher, and 31% had a neurologic AE of at least grade 3. The median duration of response was 11.1 months overall (95% CI, 3.9 months to not reached), not reached among patients with a CR (95% CI, not reached to not reached), and 1.9 months (1.4-2.1 months) among those with a partial response (PR).
Among the patients who achieved a CR, one-third initially exhibited a PR, and that response deepened over time. Among patients who progressed, more than half progressed by 3 months after treatment, underscoring month 3 as a clinically important time to evaluate the potential need for any further treatment. As a result, a main objective of the long-term analysis was to evaluate the time to response, including CRs, and to assess PR and CR at month 3 posttreatment as a prognostic factor for progression-free survival (PFS; Figure 1). Among the 44 patients who initially experienced a PR, 18 patients (41%) eventually exhibited a CR (Figure 2). The median time to response was 1 month (range, 0.8-14.8 months) in the overall population and 1 month (range, 0.8-12.3 months) among patients with a CR. Kaplan-Meier analysis of ORR and CR over time showed an inflection point at month 3, reflecting the deepening response in some patients with a PR as they transitioned to a CR. Although many conversions from a PR to a CR were seen at 3 months after the axicabtagene ciloleucel treatment, some patients with an initial PR did not develop a CR until as late as 12 months after the single infusion of CAR T-cell therapy.
Baseline characteristics were generally similar in patients who achieved a PR vs a CR at 3 months, as well as in the overall phase 2 population of 101 patients. In the overall population, the median age was 58 years (range, 23-76 years), and 85% had stage III/IV disease. Forty-six percent of patients had an International Prognostic Index (IPI) score of 3 to 4, and 69% had received 3 or more prior therapies. PFS at month 3 was not reached in patients who achieved a CR (95% CI, not reached to not reached) or PR (95% CI, 4.4 months to not reached). The Kaplan-Meier curves for the 2 response cohorts were similar and crossed over after approximately 9 months. For the small number of patients with stable disease at month 3, 44% remained in response at 12 months after the axicabtagene ciloleucel infusion.
Patients with a response at month 3 were likely to remain in response at month 12. For the 9 patients with a PR at month 3, 78% (95% CI,
36%-94%) remained in PR at month 12. Similarly, among the 42 patients with a CR at month 3 after treatment, 79% (95% CI, 63%-88%) maintained the response at month 12. Based on this analysis, watchful waiting is the preferred approach for patients who exhibit a CR or PR at 3 months.
Similar rates of cytokine release syndrome and neurologic events were observed across all response groups and in the overall study population. In the phase 2 population of 101 patients, 100% of patients with a PR and 93% of those with a CR experienced an AE of grade 3 or higher. Cytokine release syndrome of grade 3 or higher was observed in no patients with a PR vs 12% of those with a CR. Neurologic events of grade 3 or higher occurred in 33% vs 36%, respectively. Based on the ZUMA-1 experience, a multidisciplinary app-roach has been recommended for monitoring, grading, and managing the acute toxicities that may occur in patients who received CAR T-cell therapy.7 Management of toxicities may include aggressive supportive care, anti-interleukin (IL) 6 therapy, and/or corticosteroids for severe cases. Intervening when toxicities are at grade 2 may forestall advancement to higher-grade AEs.
References
1. Jain MD, Bachmeier CA, Phuoc VH, Chavez JC. Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma. Ther Clin Risk Manag. 2018;14:1007-1017.
2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
3. Yescarta [package insert]. Santa Monica, CA: Kite Pharma, Inc; 2017.
4. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
5. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.
6. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma [ASCO abstract 3003]. J Clin Oncol. 2018;36(15 suppl).
7. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
Updated Safety and Long-Term Clinical Outcomes in TRANSCEND NHL 001, Pivotal Trial of Lisocabtagene Maraleucel (JCAR017) in
R/R Aggressive NHL
The international, multicohort SCHOLAR-1 study (Ret-ro-spective Non-Hodgkin Lym-ph–oma Research) retrospectively analy-zed data from 636 patients with refractory DLBCL.1,2 Salvage therapy yielded an ORR of 26% and a CR rate of 7%. Poor survival was more common in patients who had never achieved a CR, had never received autologous SCT, had chemorefractory disease, or had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Lisocabtagene maraleucel (also known as JCAR017) is a CD19-directed CAR T-cell therapy that provides a known ratio of CD4-positive and CD8-positive cells.3,4 In addition to having an anti-CD19 single-chain antibody variable domain, the CAR construct uses the 4-1BB co-stimulatory domain and provides intracellular T-cell signaling through CD3ζ. After leukapheresis, the patient’s CD4-positive cells are separated from CD8-positive cells. These T-cell populations then undergo transduction with a lentivirus vector that expresses the CAR construct, followed by expansion.
The TRANSCEND NHL 001 trial (Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-Cell Non-Hodgkin Lymphoma) investigated 3 dose levels of lisocabtagene maraleucel in NHL patients who had received at least 2 prior lines of therapy.5 In the dose-finding cohorts, patients received 5 × 107 CAR T cells in a single dose (DL1S); the same total number of CAR T cells divided into 2 half-doses (DL1D); or a single dose of 1 × 108 engineered cells (DL2S). This initial study was followed by evaluation of 2 dose-expansion cohorts. The analysis included 102 patients in the full cohort and 73 in the core cohort. Patients in the core cohort had DLBCL or high-grade B-cell lymphoma. Patients in the full cohort included those in the core cohort, but patients could also have PMBCL or stage 3B follicular lymphoma. Patients in the initial cohorts had an ECOG performance status of 0 to 2, but the status was limited to 0 or 1 among patients in the pivotal cohort. There was no minimum absolute lymphocyte count required for leukapheresis. Prior SCT and central nervous system involvement were allowed. After apheresis, patients underwent 3 days of treatment for lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2). Lisocabtagene maraleucel treatment was administered 2 to 7 days later.
The trial enrolled 134 patients with DLBCL, and a CAR T-cell product was successfully manufactured for 132 of them (99%). Among these patients, 5 withdrew and 13 developed progressive disease or died. Lisocabtagene maraleucel was administered to 114 patients; however, 12 of these patients received a nonconforming lisocabtagene maraleucel product. Among 102 evaluable patients, 45 were from cohort DL1S, 6 from DL1D, and 51 from DL2S. Patient characteristics were similar in the full and core cohorts. In the full cohort of 102 patients, the median age was 61 years (range, 20-82 years) and 36% were age 65 years or older. The most common NHL subtype was de novo DLBCL not otherwise specified (62%), and 19% of patients had double-hit or triple-hit genetic mutations. Key characteristics were well-balanced between the cohorts, including chemorefractory disease (70% in the full cohort vs 67% in the core cohort), never achieved a CR (48% vs 49%), and central nervous system involvement (2% vs 1%). Both cohorts had received a median of 3 prior lines of therapy, and patients in both cohorts had received as many as 8 prior lines of therapy.
In the full cohort, the ORR was 75% (95% CI, 65%-83%), with a CR rate of 55% (95% CI, 45%-65%). Based on imaging conducted at 6 months after CAR T-cell treatment, the ongoing ORR was 40% (95% CI, 31%-50%), with CRs in 34% (95% CI, 25%-44%; Figure 3). For all dose levels in the core cohort, the ORR was 80% (95% CI, 68%-88%), with a CR rate of 59% (95% CI, 47%-70%). A higher CR rate was observed with the higher dose level of CAR T cells (DL2S), with 6-month CR rates of 33% (95% CI, 18%-52%) in cohort DL1S vs 46% (95% CI, 30%-63%) in cohort DL2S. Therefore, the dose of 1 × 108 CAR T cells was chosen for the pivotal cohort.
In a subgroup analysis, the lowest ORR, 26.9%, was observed among patients with an IPI score of 3 to 5 (95% CI, 11.6%-47.8%). The highest ORR was 62.5%, and was seen in patients with double-hit or triple-hit mutations. Among patients with stable or progressive disease after prior therapy, the ORR was 41.2%. The median duration of response and OS were not reached for the full or the core cohort. In the core cohort, 88% of patients with a CR at 3 months remained in CR at 6 months.
As anticipated, after lymphodepleting treatment, most grade 3/4 AEs consisted of cytopenias. The most common nonhematologic AE was fatigue. In the core DLBCL population, no increase was observed in the incidence of cytokine release syndrome or neurotoxicity at the highest dose level (DL2S), and no deaths from these AEs occurred. In the full cohort, any-grade cytokine release syndrome was observed in 37% of patients, including grade 3/4 syndrome in 1%. The median time to onset of cytokine release syndrome was 5 days (range, 2-12 days). Neurotoxicity of any grade was observed in 23% of patients in the full cohort, and included grade 3/4 events in 13%. The median time to onset of neurotoxicity was 10 days (range, 3-23 days). Serious cytokine release syndrome or neurotoxicity was observed in 13% of patients in the full cohort.
References
1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808.
2. Van Den Neste E, Schmitz N, Mounier N, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the international CORAL study. Bone Marrow Transplant. 2016;51(1):51-57.
3. Ramsborg CG, Guptill P, Weber C, et al. JCAR017 is a defined composition CAR T cell product with product and process controls that deliver precise doses of CD4 and CD8 CAR T cell to patients with NHL [ASH abstract 4771]. Blood. 2017;130(suppl 1).
4. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492-500.
5. Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long-term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL [ASCO abstract 7505]. J Clin Oncol. 2018;36(15 suppl).
Outcomes by Prior Lines of Therapy in ZUMA-1, the Pivotal Phase 2 Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
To further understand the efficacy associated with axicabtagene ciloleucel in patients with refractory large B-cell lymphoma, outcomes in patients included in phases 1 and 2 of the ZUMA-1 trial were assessed by prior lines of therapy.1-3 (Autologous SCT was considered a prior line of therapy.) Tumor burden was estimated by calculating the sum of the product of the diameters (SPD) of index lesions.4 Analyses were conducted on patient cohorts that were defined according to the number of prior lines of therapy: 1 to 2 (cohort 1; n=32); 3 (cohort 2; n=33); 4 (cohort 3; n=30); or 5 or more (cohort 4; n=13). The proportion of patients with an IPI score of 3 to 4 increased with more lines of therapy, from one-third in patients who received 1 to 3 lines of therapy to 69% in patients treated with 5 or more. The median SPD increased as well, from 2993 mm2 (range, 180-12,795 mm2) in patients treated with 1 or 2 lines to 5106 mm2 (range, 310-14,354 mm2) in those treated with 5 or more. Patients treated with 5 or more lines of therapy were also more likely to have relapsed after autologous SCT (46% vs 0%-33% in cohorts 1-3). Among the 4 cohorts, the CAR T-cell product parameters were similar, with doubling times of 1.4 days to 1.7 days, transduction rates ranging from 50% to 60%, and a CD4-to-CD8 ratio ranging from 0.7 to 1.1.
ORRs ranged from 94% in patients treated with 3 lines to 38% in patients treated with 5 or more. Across the 4 cohorts, rates of serious AEs ranged from 23% in patients treated with 3 lines to 54% in those treated with 5 or more. Rates of cytokine release syndrome of grade 3 or higher were similar across the 4 cohorts. There was, however, a trend toward higher rates of serious AEs of grade 3 or higher and neurologic events among patients treated with 5 or more lines. Patients treated with 1 to 3 lines of therapy showed similar outcomes in terms of CAR T-cell production. The median peak number of cells/µL ranged from 31 cells/µL to 44 cells/µL, and the median area under the curve ranged from 462 cells/µL × days to 502 cells/µL × days. These numbers were lower among patients treated with 5 or more lines, in whom the median peak was 20 cells/µL and the median area under the curve was 273 cells/µL × days.
Patients were also divided into quartiles according to tumor burden. The median SPD was 840 mm2 in quartile 1, 2823 mm2 in quartile 2, 5106 mm2 in quartile 3, and 9340 mm2 in quartile 4 (Figure 4). The ORRs ranged from 74% in quartile 3 to 89% in quartile 1 (Figure 5). However, the proportion of patients with an ongoing response at 1 year after treatment decreased with increasing SPD, from 67% in quartile 1 to 27% in quartile 4. The proportion of patients with an IPI score of 3 to 4 was 30% in SPD quartiles 1 and 2, 63% in quartile 3, and 54% in quartile 4.
References
1. Locke FL, Ghobadi A, Lekakis LJ, et al. Outcomes by prior lines of therapy in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with refractory large B-cell lymphoma [ASCO abstract 3039]. J Clin Oncol. 2018;36(15 suppl).
2. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma [ASCO abstract 3003]. J Clin Oncol. 2018;36(15 suppl).
3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
4. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
Factors Associated With Duration of Response After CD-Specific CAR-T Cell Therapy for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma
A phase 1/2 study investigated the factors that affect disease response and related outcomes among lymphoma patients treated with CAR T-cell therapy.1-3 The study included adults with relapsed or refractory, CD19-positive B-cell malignancies. As of April 20, 2017, 166 patients had been treated, including 57 with acute lymphoblastic leukemia (ALL), 30 with chronic lymphocytic leukemia, and 79 with NHL. Dr Jordan Gauthier reported results from 57 patients included in the trial, all of whom underwent lymphodepletion followed by infusion of 2 × 106 CAR
T cells at a 1-to-1 ratio of CD4-positive and CD8-positive engineered cells.4 Disease histology was indolent in 9 patients and aggressive in 48. The patients had a median age of 56.5 years (range, 27-71 years), and 95% had stage III/IV disease. Among the patients with indolent histology, 44% had extranodal disease, 12% had an IPI score of 3 or 4, and none had bulky disease. Among the patients with aggressive histology, 92% had extranodal disease, 52% had an IPI score of 3 or 4, and 17% had bulky disease. For the entire study population, the median number of prior lines of therapy was 4 (range, 1-11), and the median SPD was 3343 mm2 (range, 124-16,765 mm2).
The ORR was 89% in patients with indolent NHL, and all responses were complete. In patients with aggressive NHL, the ORR was 53%, which included a CR rate of 38%. In the mixed population of 57 patients, those who achieved a CR had a dramatically improved median PFS compared with those who did not (24-month PFS, 57.2%; 95% CI, 39%-83%; P<.0001; Figure 6). Median OS was also significantly prolonged in patients who achieved a CR (24-month OS, 78%; 95% CI, 63%-97%; P<.0001). In a multivariate analysis, lower serum levels of lactate dehydrogenase prior to lymphodepletion were associated with an increased probability of a CR (odds ratio, 0.51; 95% CI, 0.26-0.90; P=.03). A higher peak level of CD8-positive CAR T cells was also associated with an improved PFS, OS, and likelihood of CR. In patients with aggressive NHL, landmark multivariable analysis identified factors associated with a superior response. At baseline, a higher peak level of IL-7 and a lower level of IL-18 were each associated with a 24-month PFS rate of 100% (P=.002) among patients with aggressive NHL who achieved a CR.
References
1. Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123-2138.
2. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116.
3. Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010-3020.
4. Gauthier J, Hirayama AV, Hay KA, et al. Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma [ASCO abstract 7567]. J Clin Oncol. 2018;36(15 suppl).
Randomized Phase 2 Trial of Polatuzumab Vedotin With Bendamustine and Rituximab in Relapsed/Refractory FL and DLBCL
Polatuzumab vedotin is an antibody-drug conjugate dir-ected at CD79b, a marker that is universally expressed on follicular lymphoma and DLBCL cells. After bind-ing, polatuzumab vedotin is inter-nalized and the cytotoxic moiety, monomethyl auristatin E (MMAE), is released. In the safety run-in phase of a phase 1b/2 trial, polatuzumab vedotin combined with bendamustine and rituximab yielded promising response rates in heavily pretreated patients with follicular lymphoma and DLBCL.1 Dr Laurie Sehn presented safety and efficacy findings from the phase 2 portion of the trial.2 The trial randomly assigned 80 patients with follicular lymphoma and 80 with DLBCL in separate cohorts to receive 6 cycles of bendamustine plus rituximab, with or without polatuzumab vedotin. Treatment cycles were 28 days for the follicular lymphoma patients and 21 days for those with DLBCL. The primary endpoint was CR confirmed by 18F-fluorodeoxyglucose positron emission tomography (PET-CR), as evaluated by an independent review committee (using modified Lugano criteria) at 6 to 8 weeks after the end of treatment.3 Patients who had undergone prior allogeneic SCT were excluded from the analysis.
The baseline characteristics were generally well-balanced between the 2 treatment arms for both sets of patients. However, in the follicular lymphoma cohort, more patients in the polatuzumab vedotin arm had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 or higher (64% vs 37%). In the DLBCL cohort, more patients treated with bendamustine plus rituximab alone had an IPI of 3 or higher (73% vs 55%). Patients in all 4 arms had received a median of 2 prior lines of therapy.
Among patients with follicular lymphoma, the use of polatuzumab vedotin did not improve outcome. The PET-CR rates were 63% with bendamustine and rituximab alone vs 69% with the addition of polatuzumab vedotin. ORR was 73% vs 77%, respectively. The median PFS was 17.3 months vs 17.0 months (P=.58).
In contrast, in DLBCL patients, the polatuzumab vedotin combination yielded a significantly improved ORR (45% vs 18%; P=.008) and CR rate (40% vs 15%; P=.012). DLBCL patients in the polatuzumab combination arm also demonstrated a prolonged PFS (6.7 months vs 2.0 months; P<.0001; Figure 7) and OS (11.8 months vs 4.7 months; P=.0008). In a subgroup analysis, the polatuzumab vedotin combination was superior to bendamustine plus rituximab alone regardless of the patient’s number of prior lines of therapy or refractory status.
In the follicular lymphoma cohort, 74% to 76% of patients in each arm completed 6 cycles of treatment. In the DLBCL cohort, 23% treated with bendamustine plus rituximab alone and 49% of those treated with the polatuzumab vedotin combination completed all 6 treatment cycles. Among all patients, serious AEs were more common in those treated with polatuzumab vedotin plus bendamustine and rituximab (55% vs 33%). Serious AEs included infections (23% vs 18%) and febrile neutropenia (12% vs 3%). The 2 treatment regimens yielded similar rates of grade 3 to 5 infections (16% vs 19%) and peripheral neuropathy (0% vs 1%).
References
1. Matasar M, Herrera AF, Kamdar M, et al. Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma: updated results of a phase 1b/2 study. Paper presented at: the European Hematology Meeting; June 22-25, 2017; Madrid, Spain. Abstract S468.
2. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL [ASCO abstract 7507]. J Clin Oncol. 2018;36(15 suppl).
3. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Radiotherapy to Bulky and Extralymphatic Disease in Combination With 6×R-CHOP-14 or R-CHOP-21 in Young Good-Prognosis DLBCL Patients: Results of the 2×2 Randomized UNFOLDER Trial of the DSHNHL/GLA
There is keen interest in defining the best use of radiation therapy in young patients with DLBCL.1 The phase 3 UNFOLDER study (Rituximab and Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With B-Cell Non-Hodgkin’s Lymphoma) evaluated rituximab plus cyclophosphamide, doxorubicin, prednisone, and vincristine (R-CHOP) with or without radiation therapy in young patients with DLBCL. The trial was conducted by the German High-Grade Non-Hodgkin’s Lymphoma Study Group. R-CHOP therapy was administered in 14-day or 21-day cycles. Eligible patients were ages 18 to 60 years and qualified to receive radiotherapy to bulky or extralymphatic tumor sites. Patients were randomly assigned to treatment in a 2 × 2 factorial design, and the primary endpoint was event-free survival (EFS). The study included 467 patients in the 4 arms. Patients had a median age of 44 years (range, 18-60 years). Thirty-five percent of patients had stage III/IV disease, 52% had extralymphatic involvement, and 76% had bulky disease. The most common B-cell lymphoma subtype was DLBCL (89%). A planned interim analysis of the first 285 patients showed a significant improvement in EFS among patients who received radiotherapy (P=.004), and led to the protocol-defined closure of the 2 arms that did not include radiotherapy.
The final analysis of data from the UNFOLDER trial included 305 patients assigned to radiotherapy plus R-CHOP and 162 assigned to R-CHOP alone.2 Protocol adherence and toxicity findings were similar for R-CHOP-14 and R-CHOP-21, as were EFS (P=.591), PFS (P=.304), and OS (P=.575). The CR/unconfirmed CR rate was 79% in patients who did not receive radiotherapy vs 90% in those who did. After a median of 66 months of observation, 3-year EFS was superior in patients who received radiotherapy (84% vs 68%; P=.001; Figure 8). The reduced EFS in patients who did not receive radiotherapy was linked to a higher rate of PRs (11% vs 2%) that triggered additional treatment that qualified as an EFS event. However, 3-year PFS was not significantly better among patients treated with radiotherapy vs those treated with R-CHOP alone (89% vs 81%; P=.221). Three-year OS was 93% for patients treated with or without radiotherapy (P=.506). The findings were confirmed by multivariate analysis that adjusted for elevated lactate dehydrogenase levels, disease stage, and presence of bulky disease or extranodal involvement. Similar results were produced by restricting the analysis to patients with bulky disease only.
References
1. Mendes F, Domingues C, Teixo R, et al. The importance of radiotherapy on diffuse large B cell lymphoma treatment: a current review. Cancer Metastasis Rev. 2015;34(3):511-525.
2. Pfreundschuh M, Murawski N, Ziepert M, et al. Radiotherapy to bulky and extralymphatic disease in combination with 6×R-CHOP-14 or R-CHOP-21 in young good-prognosis DLBCL patients: results of the 2×2 randomized UNFOLDER trial of the DSHNHL/GLA [ASCO abstract 7574]. J Clin Oncol. 2018;36(15 suppl).
Phase I/II Clinical Trial of Ibrutinib and Buparlisib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, and Follicular Lymphoma
Preclinical studies have shown synergistic activity between Bruton tyrosine kinase and inhi-bitors of phosphoinositide 3-kinase in models of B-cell NHL.1,2 A phase 1/2 clinical trial evaluated the efficacy and safety of ibrutinib plus buparlisib, a pan-phosphoinositide 3-kinase inhibitor, in patients with relapsed or refractory DLBCL, follicular lymphoma, or mantle cell lymphoma.3 The trial used a standard 3 + 3 dose-escalation design with 4 dose levels. Ibrutinib and buparlisib were administered daily in 28-day cycles. The trial enrolled 14 patients with DLBCL, 5 with follicular lymphoma, and 18 with mantle cell lymphoma. Patients had a median age of 70 years (range, 48-84 years), and 73% were male. The median number of prior lines of treatment was 3 for patients with DLBCL, 2 for those with follicular lymphoma, and 1 for those with mantle cell lymphoma.
Based on Lugano criteria, the ORR was 51%, including a CR rate of 43%. In the B-cell NHL subtypes, ORRs were 29% for DLBCL (CR of 21%), 20% for follicular lymphoma (CR of 20%), and 76% for mantle cell lymphoma (CR of 71%). The median time to response was 1.7 months (range, 1.6-2.0 months) in mantle cell lymphoma patients and 2.1 months in those with DLBCL (range, 1.6-11.8 months). The best percent change in SPD is shown in Figure 9. Targeted next-generation sequencing of circulating cell-free DNA is being conducted to explore tumor evolution. Targeted sequencing showed a decrease in mutation number and variant allele frequency in a patient who achieved an initial PR that subsequently converted to a CR.
The most common AEs of any grade were hyperglycemia, bilirubin elevation, diarrhea, and thrombocytopenia. Treatment-related AEs of grade 3 or higher were observed in 61% of patients; the most common of these events were rash (22%), hyperglycemia (16%), diarrhea (11%), and hypertension (11%). At dose level 1 (ibrutinib [420 mg daily] plus buparlisib [80 mg daily]), a single dose-limiting toxicity of grade 3 anorexia was observed in 6 patients. Several dose-limiting toxicities were observed at dose level 3 (ibrutinib [560 mg daily] plus buparlisib [100 mg daily]), including grade 2 stroke (in a patient with preexisting pituitary adenoma) and grade 2 hyperbilirubinemia. Grade 3 events included rash, anorexia, diarrhea, pain, mucositis, and gastroesophageal reflux. A dose reduction of buparlisib was required by 41% of patients, and 81% required a dose interruption.
References
1. Erdmann T, Klener P, Lynch JT, et al. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017;130(3):310-322.
2. Mathews Griner LA, Guha R, Shinn P, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci U S A. 2014;111(6):2349-2354.
3. Batlevi CL, De Frank S, Stewart C, et al. Phase I/II clinical trial of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma [ASCO abstract 7520]. J Clin Oncol. 2018;36(15 suppl).
Dose-Adjusted-EPOCH-R With High-Dose Methotrexate for Newly Diagnosed Stage II-IV CD5-Positive Diffuse Large B-Cell Lymphoma: Primary Analysis of the PEARL5 Study
In the 5% to 10% of DLBCL cases that express CD5, the disease is characterized by an aggressive course, with relapse commonly observed in the central nervous system.1 A retrospective study showed that adding rituximab to CHOP improved OS (P=.002) and yielded a 2-year PFS of 51%. However, this strategy did not reduce the incidence of central nervous system relapse (P=.89) in patients with newly diagnosed DLBCL.2 The single-arm, multicenter, phase 2 PEARL 5 study investigated dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) followed by high-dose methotrexate in patients with newly diagnosed DLBCL.3 Treatment was administered in 4 cycles of DA-EPOCH-R, followed by 2 cycles of high-dose methotrexate, followed by 4 more cycles of DA-EPOCH-R. Eligible patients had stage II to IV disease, were ages 20 to 75 years, and had an ECOG performance status of 0 to 3. The primary endpoint was 2-year PFS. An interim analysis showed a CR rate of 91%, with manageable toxicity.
Dr Kana Miyazaki presented results of the primary analysis of the PEARL 5 study.4 The 47 patients had a median age of 62 years, and 60% were older than 60 years. Fifty-three percent had stage III/IV disease, 34% had more than 1 extranodal disease site, and 85% had activated B-cell DLBCL. After a median follow-up of 3.1 years, primary endpoint analysis revealed a 2-year PFS of 79% (95% CI, 64%-88%; Figure 10), which compared favorably with the historical control of 51% seen with R-CHOP. Two-year OS was 89% (95% CI, 76%-95%), and the 2-year rate of central nervous system relapse was 9% (95% CI, 3%-21%). Three of these patients experienced central nervous system relapse prior to administration of high-dose methotrexate, including 2 patients with high-grade B-cell lymphoma with MYC rearrangement and 1 patient who discontinued treatment after the first rituximab cycle owing to grade 4 tumor lysis syndrome. In patients with activated B-cell DLBCL, the 2-year PFS was 77% and 2-year OS was 87%. Possible secondary malignancies were documented in 3 patients.
References
1. Jain P, Fayad LE, Rosenwald A, Young KH, O’Brien S. Recent advances in de novo CD5+ diffuse large B cell lymphoma. Am J Hematol. 2013;88(9):798-802.
2. Miyazaki K, Yamaguchi M, Suzuki R, et al. CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab. Ann Oncol. 2011;22(7):1601-1607.
3. Miyazaki K, Asano N, Yamada T, et al. Dose-adjusted (DA)—EPOCH-R with high-dose methotrexate for newly diagnosed CD-positive diffuse large B-cell lymphoma (CD+ DLBCL): interim results from a phase II study [ASH abstract 3029]. Blood. 2016;128(suppl).
4. Miyazaki K, Asano N, Yamada T, et al. Dose-adjusted (DA)-EPOCH-R with high-dose methotrexate (HD-MTX) for newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL): primary analysis of PEARL5 study [ASCO abstract 7561]. J Clin Oncol. 2018;36(15 suppl).
Advances in Aggressive Lymphoma From the 2018 American Society of Clinical Oncology Annual Meeting: Commentary
Frederick L. Locke, MD
Vice Chair and Associate Member
Department of Blood and Marrow Transplant and Cellular Immunotherapy
Moffitt Cancer Center
Tampa, Florida
Michael D. Jain, MD, PhD
Transplant Physician
Department of Blood and Marrow Transplant and Cellular Immunotherapy
Moffitt Cancer Center
Department of Oncologic Sciences
University of South Florida
Morsani College of Medicine
Tampa, Florida
Several presentations at the 2018 American Society of Clinical Oncology annual meeting focused on the management of patients with aggressive lymphoma, such as diffuse large B-cell lymphoma (DLBCL). Studies provided updated data on the use of the chimeric antigen receptor (CAR) T-cell therapies, such as axicabtagene ciloleucel. New data were also presented on the use of radiotherapy after rituximab plus cyclophosphamide, doxorubicin, prednisone, and vincristine (R-CHOP) and for the novel therapies lisocabtagene maraleucel and polatuzumab vedotin.
CAR T-Cell Therapy
CD19 CAR T-cell therapy is now approved by the US Food and Drug Administration (FDA) for relapsed/refractory DLBCL and histological variants. Two products are approved: axicabtagene ciloleucel, which is co-stimulated by CD28, and tisagenlecleucel, which is costimulated by 4-1BB. Before the advent of CAR T-cell therapy, this patient population had an extremely poor overall survival.
Dr Frederick Locke presented an analysis of the durability response in ZUMA-1 (A Phase 1-2 Multi-Center Study Evaluating KTE-C19 in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma), the pivotal phase 2 study of the CAR T-cell therapy axicabtagene ciloleucel in patients with refractory large B-cell lymphoma.1,2 The ZUMA-1 trial met its primary endpoint—the rate of objective response—at the interim and primary analyses.2 The objective response rate was 82%, with a complete response rate of 54%. At a median follow-up of 15.4 months, these rates were 42% vs 40%, respectively. At 18 months, the overall rate of survival was 52%. These data led the FDA to approve axicabtagene ciloleucel in patients with non-Hodgkin lymphoma whose disease progressed despite 2 or more lines of therapy. The ZUMA-1 study provided data for 108 patients. Patients who achieved a complete response had an extremely good chance of remaining in response beyond 1 year.2 At a median follow-up of 15.4 months, the median duration of response for patients achieving a complete response was not reached. Patients who at best achieved a partial response following axicabtagene ciloleucel had a median duration of response of only 1.9 months. This finding, however, ignores the fact that many patients who achieved a complete response had initially achieved a partial response.
More than half of the progressive events in the ZUMA-1 study occurred by month 3. The study authors aimed to define the treatment practice for patients at 3 months, which appeared to be the clinically relevant time point to understand outcomes. They performed a time-to-response analysis for patients with an objective response or a complete response. They looked at the partial response and complete response rates at month 3 as prognostic factors for progression-free survival (PFS). The analysis found that 41% of patients who achieved a partial response eventually converted to a complete response. Most of those conversions occurred by the 3-month time point. However, some of them occurred as late as 1 year after therapy. Many patients had a partial response by 1 month, and their response could deepen over time. An analysis of PFS landmarked at 3 months after the administration of therapy showed that among patients with a complete response, the median PFS was not reached. Similarly, among patients with a partial response at 3 months, median PFS had not been reached after a median follow-up of 15.4 months. Perhaps most interesting, the study showed that the rates of 12-month PFS were almost identical in patients with a partial response or a complete response (78% vs 79%).
In conclusion, this analysis showed that patients can achieve a complete response as late as 1 year after infusion of axicabtagene ciloleucel. Patients with a partial or complete response at month 3 had a nearly 80% likelihood of maintaining a response at month 12. Perhaps most importantly, these data suggest that among patients who received a single CAR T-cell therapy infusion and achieved a response by 3 months, consolidative therapy is not needed to maintain that response. In fact, response at 3 months may be prognostic for long-term remission.
Another analysis of data from ZUMA-1 evaluated response to axicabtagene ciloleucel according to the number of prior lines of therapy at the time of enrollment.3 Safety and efficacy outcomes were assessed according to the number of lines of prior therapy: 1 to 2; 3; 4; or 5 or more. (Salvage chemotherapy and autologous transplant were considered a single line of therapy.) The analysis identified no differences according to previous lines of therapy in terms of the product characteristics, such as the CD4-to-CD8 ratio, the number of naive and central memory T cells, and the transduction rate. There were some differences in baseline patient characteristics. For example, patients with 5 or more prior lines of therapy had a higher disease stage and a higher International Prognostic Index (IPI) score at the time of enrollment, as would be expected because their disease was more refractory. There were differences in the response rates to axicabtagene ciloleucel according to the number of prior lines of therapy. The objective response rate decreased in patients with more lines of therapy. Among patients with 1 to 2 prior lines of therapy, the response rate was 91%, vs 38% among patients with 5 or more. The rates of ongoing response at 1 year were 47% vs 23%, respectively.
The analysis further evaluated the impact of disease burden on response to therapy. Patients with more prior lines of therapy had increased disease burden as evaluated by the sum of the product of the diameters of their reference lesions on computed tomography (CT) scans. Patients with the highest disease burden had the lowest chance for an ongoing response at 1 year. The objective responses were otherwise similar. Those patients with more disease burden tended to have more severe adverse events, particularly neurologic toxicity, and they had a greater need for tocilizumab or corticosteroids. This finding suggests that the more disease burden a patient has, the less effective axicabtagene ciloleucel will be. The ZUMA-1 trial did not allow for bridging therapy after collection of CAR T cells, so patients whose disease continued to grow may have had a decreased likelihood of responding to therapy or achieving a durable response.2 Also important to note is that these data suggest that earlier referral for CAR T-cell therapy is preferable.
Dr Vinodh Pillai presented a study on the correlation between pre-CAR CD19 expression with responses and relapses after CAR T-cell therapy.4 The findings were similar to those seen in the ZUMA-1 trial.3 Increased tumor burden was predictive for poor expansion of the CAR T-cell product in vivo and for lower rates of response and durable response. These data again suggest that early referral and bridging chemotherapy could improve response rates in patients with DLBCL.
Dr Jordan Gauthier presented results from a study evaluating the duration of response after CD19-specific CAR T-cell therapy among patients with relapsed/ refractory B-cell non-Hodgkin lymphoma.5 CAR T-cell therapy leads to durable remissions in approximately 40% of patients.2 It is important to understand the factors that affect response in this nascent field. The study by Dr Gauthier used a 4-1BB costimulated CD19 CAR T-cell product that is administered in a defined 1-to-1 ratio of CD4-positive and CD8-positive CAR T cells. The study found similar results to those reported with other CD19 CAR T-cell products. CAR T-cell expansion, as measured by a higher peak CAR T-cell level in the patient and a larger cumulative area under the curve, correlated with improved outcome. It appears that some of the clinical factors that affect response to chemotherapy also impact response to CAR T cells. Poorer outcome was associated with high tumor burden and a high score on the IPI, which consists of age, performance status, lactate dehydrogenase, extranodal disease, and stage. Tumor characteristics, such as indolent histology, and product characteristics, such as the proportion of CD8-positive CAR T cells, also impacted outcome. Based on these results, the next step will be to determine whether interventions such as tumor debulking or CAR T-cell product modification can improve the outcome of patients in the poor-risk group.
Radiotherapy After R-CHOP
Dr Michael Pfreundschuh described results from the 2-by-2 randomized controlled UNFOLDER trial (Unfavorable Low-Risk Patients Treated With Densification of R-Chemo Regimens), a German trial that evaluated radiotherapy to bulky and extranodal disease in combination with 6 cycles of R-CHOP-14 or R-CHOP-21 in young DLBCL patients with a good prognosis.6 Patients with DLBCL are often cured by upfront R-CHOP therapy. However, patients with bulky and extranodal disease may require consolidated radiotherapy at the end of R-CHOP therapy. The results of the UNFOLDER trial were highly anticipated, as this study aimed to determine if radiotherapy improves the outcome of young, good-risk patients with bulky or extranodal disease. This 4-arm, randomized controlled trial had a 2-by-2 design. It enrolled patients younger than 60 years with IPI scores of 0 to 1. In the first randomization, patients received R-CHOP every 2 weeks (R-CHOP-14) or every 3 weeks (R-CHOP-21) for 6 cycles. The results of this part of the trial were previously presented.7 There was no difference in outcome whether R-CHOP was given every 2 weeks or 3 weeks.
The presentation by Dr Pfreundschuh provided data for the second randomization.6 One cohort received treatment with radiotherapy, 39.6 gray, delivered to bulky and extranodal sites. The other cohort received no radiotherapy, just observation. At the planned interim analysis of 285 patients, the primary endpoint, event-free survival, was superior in patients assigned to radiation therapy. The nonradiotherapy arms were therefore closed. However, one of the events that met the primary outcome of event-free survival was whether patients received additional therapy. As expected, the partial response rate (by CT imaging) was higher in the nonradiotherapy arm than the radiotherapy arm (11% vs 2%). This finding led the trial investigators to more frequently prescribe radiotherapy to patients in the nonradiotherapy arm, which then counted as an event. For this reason, more events were reported in the nonradiotherapy arm.
The secondary outcome of 3-year PFS was statistically similar, at 89% with radiotherapy vs 81% without (P=.221). The 3-year overall response for both treatment groups was 93%. This study may be underpowered to evaluate the PFS trend. In addition, the follow-up of 66 months may not be long enough to exhibit any negative consequences of radiotherapy on overall survival. This trial therefore does not answer the question of whether end-of-treatment radiotherapy should be administered to patients with bulky or extranodal disease, patients in partial remission, or any patients at all. In this trial, patients in the observation group who had a partial response at the end of treatment crossed over to the radiotherapy group. Another aspect to consider is that the study used CT scans, and not positron emission tomography (PET)/CT scans, to evaluate the end-of-treatment response. PET may be a better tool to stratify patients for further therapy. Indeed, the OPTIMAL >60 study (Improvement of Therapy of Elderly Patients With CD20+ DLBCL Using Rituximab Optimized and Liposomal Vincristine) in elderly patients with DLBCL, conducted by the same group, suggested that radiotherapy can be avoided in end-of-treatment PET-negative patients according to a nonrandomized comparison.8
Novel Therapies
Dr Jeremy Abramson presented an updated analysis of safety and long-term clinical outcomes in the pivotal TRANSCEND NHL 001 trial (Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-Cell Non-Hodgkin Lymphoma), which evaluated lisocabtagene maraleucel (also known as JCAR017) in relapsed/refractory aggressive lymphoma.9,10 This trial consisted of a dose-finding cohort followed by a dose-expansion cohort. All of the patients with DLBCL received lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide, and 134 underwent leukapheresis. Lisocabtagene maraleucel was administered to 114 patients, but only 102 received a product with the conforming 1-to-1 ratio of CD4-to-CD8. Among these 102 patients, some received multiple infusions to achieve the appropriate dose, whereas others received a single infusion.
The study provided analysis for the full cohort of 102 patients, which consisted of patients in the dose-finding and dose-escalation cohorts, as well as for a core subset of 72 patients, defined as those with DLBCL who met the criteria for the pivotal dose cohort. Nearly all patients developed some treatment-emergent adverse events. Approximately 65% had CAR T-cell related adverse events, the most common of which were neutropenia and other cytopenias. Cytokine release syndrome was seen in approximately 37% of patients, and reported neurologic toxicities were low. In the full cohort, any-grade cytokine release syndrome was seen in 37% of patients, but only 1% developed grade 3 to 4. Any-grade neurotoxicity occurred in 23% of patients, and grade 3 to 4 was reported in 13%.
There were high response rates among patients with DLBCL. The objective response rate was 75% in the full cohort and 80% in the core cohort. The 6-month complete response rate was 34% vs 41%, respectively, suggesting that the durability of lisocabtagene maraleucel is similar to that of other CAR T-cell products approved by the FDA for large-cell lymphoma.
Data were presented for a cohort analysis of patients with poor-risk DLBCL. Importantly, the 6-month objective response rate exceeded 60% in patients with double or triple hits and was approximately 45% in chemorefractory patients. Again, these rates are similar to those seen with other CAR T-cell products approved for large-cell lymphoma. The durability of responses was encouraging. Among patients with a complete response, the median duration of response was not reached.
Lisocabtagene maraleucel had a manageable safety profile at the dose levels evaluated. It is important to note that this trial allowed for bridging chemotherapy, which likely reduced tumor burden before infusion of CAR T cells and may have affected the toxicity rates.
A randomized phase 1b/2 trial evaluated the addition of polatuzumab vedotin to bendamustine and rituximab in patients with relapsed/refractory follicular lymphoma or DLBCL who were ineligible for transplant.11 Polatuzumab vedotin is an antibody drug conjugate that targets CD79b. Antibody-drug conjugates bind to the targets on tumor cells and then are endocytosed into the cell. There, the drug conjugate—in this case, a strong antimitotic drug known as monomethyl auristatin E (MMAE)—is cleaved off the antibody and exerts activity within the cell. This activity is reminiscent of a commonly used drug, brentuximab vedotin, which targets CD30 and is approved for Hodgkin lymphoma and other lymphoid malignancies.12 Polatuzumab vedotin targets CD79b, a transmembrane protein that is associated with the B-cell receptor universally expressed in DLBCL and follicular lymphoma. This protein transduces signaling downstream of the B-cell receptor, and many lymphomas are characterized by tonic or chronic active signaling through CD79b.13-15 In fact, mutations for CD79b are found in some patients with lymphoma, and CD79b may be a driver mutation in some cancers. Therefore, CD79b is an exciting target for antibody-drug conjugate therapy.
The trial enrolled 80 patients with follicular lymphoma and 80 with DLBCL. In each group, patients were randomly assigned to treatment with polatuzumab vedotin plus bendamustine and rituximab or bendamustine and rituximab alone. Dr Laurie Sehn presented efficacy and toxicity data based on an intention-to-treat analysis after 15 months of follow-up.11 The complete response rate was measured by PET/CT. Among patients with DLBCL, the PET complete response rate was 40% with polatuzumab vedotin plus bendamustine and rituximab vs 15% with bendamustine and rituximab alone. The median PFS was 6.7 months vs 2.0 months, respectively, and the median overall survival was 11.8 months vs 4.7 months. Among patients with follicular lymphoma, there was no significant difference in the rates of complete response or PFS between the treatment groups.
There was increased toxicity in the polatuzumab vedotin group. The peripheral neuropathies that occurred were generally low-grade and reversible; only 1 patient developed grade 3 peripheral neuropathy. There was an increased rate of grade 3 to 5 cytopenias and febrile neutropenia, but infectious rates were not higher. Overall, polatuzumab vedotin appeared to be tolerable.
The findings in DLBCL are important because patients with relapsed/refractory disease have a poor outcome. The most effective treatment in this patient population, CD19 CAR T-cell therapy, may not be feasible or available for all patients. It is exciting to have a new drug that is active in DLBCL. Future trials will define the optimal combination regimen for polatuzumab vedotin and determine whether it can be a successful component of frontline therapy in previously untreated patients.
Disclosures
Dr Locke has served as a scientific advisor to Kite Pharma and as a consultant to Cellular Biomedicine Group Inc. Dr Jain has no real or apparent conflicts of interest to report.
References
1. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma [ASCO abstract 3003]. J Clin Oncol. 2018;36(15 suppl).
2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
3. Locke FL, Ghobadi A, Lekakis LJ, et al. Outcomes by prior lines of therapy in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with refractory large B-cell lymphoma [ASCO abstract 3039]. J Clin Oncol. 2018;36(15 suppl).
4. Pillai V, Rosenthal J, Muralidharan K, et al. Correlation of pre-CAR CD19 expression with responses and relapses after CAR T cell therapy [ASCO abstract 3051]. J Clin Oncol. 2018;36(15 suppl).
5. Gauthier J, Hirayama AV, Hay KA, et al. Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma [ASCO abstract 7567]. J Clin Oncol. 2018;36(15 suppl).
6. Pfreundschuh M, Murawski N, Ziepert M, et al. Radiotherapy to bulky and extralymphatic disease in combination with 6×R-CHOP-14 or R-CHOP-21 in young good-prognosis DLBCL patients: results of the 2×2 randomized UNFOLDER trial of the DSHNHL/GLA [ASCO abstract 7574]. J Clin Oncol. 2018;36(15 suppl).
7. ClinicalTrials.gov. Rituximab and combination chemotherapy with or without radiation therapy in treating patients with B-cell non-Hodgkin’s lymphoma. https://clinicaltrials.gov/ct2/show/NCT00278408. Identifier: NCT00278408. Accessed July 24, 2018.
8. Pfreundschuh M, Christofyllakis K, Altmann B, et al. Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL [ASCO abstract 7506]. J Clin Oncol. 2017;35(15 suppl).
9. Abramson JS, Palomba ML, Gordon LI, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort [ASH abstract 581]. Blood. 2017;130(suppl 1).
10. Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long-term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL [ASCO abstract 7505]. J Clin Oncol. 2018;36(15 suppl).
11. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL [ASCO abstract 7507]. J Clin Oncol. 2018;36(15 suppl).
12. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
13. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88-92.
14. Young RM, Wu T, Schmitz R, et al. Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. Proc Natl Acad Sci U S A. 2015;112(44):13447-13454.
15. Phelan JD, Young RM, Webster DE, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma [published online June 18, 2018]. Nature. doi:10.1038/s41586-018-0290-0.