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Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma.

ABSTRACT: New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

SUBMITTER: Ward JP

PROVIDER: S-EPMC8972094 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma.

Ward Jeffrey P JP Berrien-Elliott Melissa M MM Gomez Felicia F Luo Jingqin J Becker-Hapak Michelle M Cashen Amanda F AF Wagner-Johnston Nina D ND Maddocks Kami K Mosior Matthew M Foster Mark M Krysiak Kilannin K Schmidt Alina A Skidmore Zachary L ZL Desai Sweta S Watkins Marcus P MP Fischer Anne A Griffith Malachi M Griffith Obi L OL Fehniger Todd A TA Bartlett Nancy L NL

Blood 20220301 13

New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in re ...[more]

PMID: 34780623

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Project description:Objective: To evaluate the cost-effectiveness of brentuximab vedotin in patients with R/R sALCL from a UK NHS perspective. Methods: A partitioned survival model used clinical outcomes for brentuximab vedotin from the pivotal phase-2 single-arm trial of brentuximab vedotin in 58 patients with R/R sALCL (SG035-0004; NCT00866047), over a lifetime (30-year) time horizon. Comparison with conventional chemotherapy was based on data from the Canadian British Columbia Cancer Agency registry from 40 patients starting salvage chemotherapy after front-line treatment between 1980 and 2012. Survival was extrapolated using parametric distributions, with brentuximab vedotin risk after the trial period assumed equal to conventional chemotherapy. Other modelling assumptions were based on a systematic literature review and clinical expert opinion. Results: Based on statistical extrapolation, brentuximab vedotin was associated with 3.1 years longer duration in the progression-free survival health state and an overall survival improvement of 5.4 years, prior to discounting. In addition, brentuximab vedotin was associated with 2.5 quality-adjusted life years (QALYs) gained at a total incremental cost of £88 556, resulting in an incremental cost-effectiveness ratio (ICER) of approximately £35 400. Sensitivity analyses of alternative model assumptions provided ICERs ranging from approximately £28 100 to £61 900. Comparing only first-line salvage patients reduced the ICER to £26 800 per QALY gained. Conversely, considering only patients with Eastern Corporative Oncology Group performance status of 0 or 1 increased the ICER to approximately £38 200. At a willingness-to-pay threshold of £50 000, the estimated probability that brentuximab vedotin is cost-effective compared with conventional chemotherapy was 86.5%. Conclusion: Compared to conventional chemotherapy, and considering the full survival period, brentuximab vedotin may provide a valuable treatment choice for patients with R/R sALCL, a population with limited therapeutic options.

Project description:BackgroundWe previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized.Patients and methodsPatients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV.ResultsOf the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%.ConclusionsSecond-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).

Dataset Information

Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma.

Publications

Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma.

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