P1064: BRENTUXIMAB VEDOTIN, NIVOLUMAB, DOXORUBICIN, AND DACARBAZINE FOR ADVANCED STAGE CLASSICAL HODGKIN LYMPHOMA: UPDATED EFFICACY AND SAFETY RESULTS FROM THE SINGLE ARM PHASE 2 STUDY
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SUBMITTER: Yasenchak C
PROVIDER: S-EPMC10431501 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).
| S-EPMC10111342 | biostudies-literature
Project description:The arrival of the CD30 directed antibody-drug conjugate, brentuximab vedotin (BV), has altered the approach to patients with classical Hodgkin lymphoma. Since initial approval in 2011, BV has been extensively studied in previously untreated and relapsed/refractory patients. Treatment indications for the antibody-drug conjugate have been expanded from the previously treated population to include maintenance therapy after autologous stem cell transplantation and recently, combination with chemotherapy in newly diagnosed advanced stage patients. This article will review the evolution of BV in classical Hodgkin lymphoma, detailing the studies that led to the approved indications and discussion of recent trials in combination with chemotherapy and immunotherapy.
| S-EPMC6910100 | biostudies-literature
Project description:Classical Hodgkin lymphoma (HL) relapses after or is refractory to upfront multiagent chemotherapy in 20%-30% of patients. Effective salvage therapy for relapsed or refractory HL is limited, and advancements are needed. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, has demonstrated significant activity and manageable toxicities in advanced HL. Currently approved as a monotherapy for patients with HL that is relapsed or refractory to multiple lines of chemotherapy or autologous stem cell transplantation, BV is now being evaluated earlier in the course of disease and in combination with other therapies. This review discusses the successful translation of BV from its conception to the clinical setting and highlights ongoing trials that may ultimately expand its role in relapsed or refractory HL and improve outcomes for patients.
| S-EPMC4418463 | biostudies-literature
Project description:Brentuximab vedotin (BV) is an effective and well-tolerated treatment for patients with classical Hodgkin lymphoma (HL). It was initially approved by the US FDA for the treatment of HL after failure of autologous hematopoietic stem cell transplant (autoHSCT) or after failure of at least two prior lines of multiagent chemotherapy in patients who are not transplant candidates, and then subsequently, as consolidation therapy after autoHSCT in patients who are at high risk for relapse. However, the role of BV in the treatment of HL is evolving. BV has shown promising efficacy as a salvage treatment in the second-line setting prior to autoHSCT. Most recently, the ECHELON-1 trial demonstrated that BV combined with AVD for the treatment of newly diagnosed advanced stage HL improved modified progression-free survival (mPFS) compared with standard ABVD. Based on these results, the US FDA has approved BV as part of the initial treatment of advanced stage HL. With the approval of BV as front-line therapy, depending on how widely the use of BV plus AVD is adopted, the role of BV in the treatment of patients with relapsed or refractory (rel/ref) HL may need to be redefined. BV retreatment can be effective, and studies of rational BV-based combination regimens may help to improve response rates and overcome BV resistance. Furthermore, BV has been demonstrated to be effective in the initial treatment of elderly or unfit patients, and ongoing studies are evaluating the addition of BV to initial chemotherapy in patients with early stage HL.
| S-EPMC6130098 | biostudies-literature
Project description:Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
| S-EPMC8247884 | biostudies-literature
Project description:KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (>90%) and through week 24 (>80%) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31]; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74]; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT.
| S-EPMC8791579 | biostudies-literature
Project description:Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-γ, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.
| S-EPMC5791838 | biostudies-literature
Project description:The KEYNOTE-013 study was conducted to evaluate pembrolizumab monotherapy in hematologic malignancies; classical Hodgkin lymphoma (cHL) was an independent expansion cohort. We present long-term results based on >4 years of median follow-up for the cHL cohort. The trial enrolled cHL patients who experienced relapse after, were ineligible for, or declined autologous stem cell transplantation and experienced progression with or did not respond to brentuximab vedotin. Patients received IV pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete response (CR) rate by central review. Enrolled patients (N = 31) had received a median of 5 therapies (range, 2 to 15). After a median follow-up of 52.8 months (range, 7.0 to 57.6 months), CR rate was 19%, and median duration of response (DOR) was not reached; 24-month and 36-month DOR rates were both 50% by the Kaplan-Meier method. Median overall survival was not reached; 36-month overall survival was 81%. Six patients (19%) experienced grade 3 treatment-related adverse events (AEs); there were no grade 4 or 5 treatment-related AEs. With long-term follow-up among a heavily pretreated cohort, pembrolizumab had a favorable safety profile; some patients maintained long-term response with pembrolizumab years after end of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01953692.
| S-EPMC7322954 | biostudies-literature
Project description:Intravenous brentuximab vedotin (ADCETRIS®) is a targeted antibody-drug conjugate (ADC) active against CD30-positive cancer cells such as those associated with classical Hodgkin lymphoma (HL). In noncomparative, phase 2 trials and in the real-world setting, salvage therapy with brentuximab vedotin resulted in high objective response (complete plus partial remission) rates in patients with relapsed or refractory CD30-positive HL, including as retreatment in patients who had an objective response to previous brentuximab vedotin therapy and subsequently relapsed. These beneficial outcomes were durable during long-term follow-up. As consolidation therapy after autologous haematopoietic stem cell transplant (ASCT) in the multinational, phase 3 AETHERA trial, brentuximab vedotin prolonged progression-free-survival (PFS) compared with placebo at a median follow-up of 30 months (primary analysis), with a 43% reduction in the risk of disease progression or death. The beneficial effects of brentuximab vedotin consolidation therapy were maintained during long-term follow-up. In the clinical trial and real-world setting, brentuximab vedotin had an acceptable tolerability and safety profile, with most adverse events manageable with dose reductions and/or delays [including peripheral sensory neuropathy (PSN) and neutropenia]. With a paucity of treatments available for many patients with relapsed or refractory HL, brentuximab vedotin represents an important option for the management of patients who have failed high-dose chemotherapy/ASCT or at least two prior chemotherapy regimens and as post-ASCT consolidation therapy in patients who are at increased risk/high-risk of relapse or progression after ASCT.
| S-EPMC7102329 | biostudies-literature
Project description:To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a durable increase in soluble PD1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV + N and BV + I + N) compared with BV + I (P < 0.05). Nonresponders and patients with short progression-free survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (P < 0.05). The results suggest a circulating tumor-immune-derived signature of BV ± I ± N treatment resistance that may be useful for patient stratification in combination checkpoint therapy.SignificanceIdentification of multi-omic immune markers from peripheral blood may help elucidate resistance mechanisms to checkpoint inhibitor and antibody-drug conjugate combinations with potential implications for treatment decisions in relapsed HL.
| S-EPMC11247952 | biostudies-literature