Brentuximab Vedotin In Combination Research Articles

Brentuximab Vedotin in Combination with Methotrexate, L-Asparaginase, and Dexamethasone (B-MAD) As Frontline Treatment for Patients with Extranodal NK/T-Cell Lymphoma

Introduction Extranodal natural killer/T-cell lymphoma (ENKTL) is a unique lymphoma associated with Epstein-Barr virus infection. It is more common in Asia than in the Western. The prognosis is usually poor, especially in advanced disease, and no standard treatment exists. Brentuximab vedotin (BV) is a drug-conjugated monoclonal antibody which targets the cell-membrane protein CD30 linked to the potent anti-tubulin agent. Due to frequent expression of CD30 in ENKTL, we investigated the safety and efficacy of BV in combination with methotrexate, L-asparaginase, and dexamethasone (B-MAD) as frontline treatment in Thai patients with ENKTL. Methods The Thai Lymphoma Study Group conducted a prospective, multicenter phase I/II study and enrolled patients aged 18-60 years with newly diagnosed ENKTL between December 2018 and December 2021 from 9 hospitals in Thailand. Patients with localized ENKTL (stage I/II) received concurrent weekly cisplatin and involved-field radiation (IFRT) 40-50 Gy, followed by 3 cycles of B-MAD. Patients with advanced ENKTL (stage III/IV) received only B-MAD for 6 cycles. BV in combination with standard dose MAD chemotherapy was given every 21 days. The primary objective was to determine the safety and optimal dose of BV in B-MAD regimen using a 3+3 dose escalation design. The secondary objective was to evaluate the overall response rate (ORR) at the end of B-MAD treatment, safety, progression-free survival and overall survival. An analysis was performed at the data cutoff date of June 30, 2023. Results Thirty-four patients (pts.) were enrolled; 23 had localized and 11 had advanced diseases. The median age was 42 years (range, 18-59). Four pts. in the localized group did not receive B-MAD due to disease progression during concurrent cisplatin and IFRT (n=3) and consent withdrawal (n=1). Six pts. received B-MAD in phase I study (3 pts. at 1.2 mg/kg and 3 pts. at 1.8 mg/kg of BV). No dose-limiting toxicity was observed among six patients, therefore the recommended dose of BV in phase II study was 1.8 mg/kg. Of 30 evaluable pts., 20 (66.7%) achieved complete response (CR), 5 (16.7%) had partial response, and 5 (16.7%) progressed after treatment. The response rates (ORR/CR rate) in localized and advanced diseases were 89.5%/78.9% and 72.7%/45.5%, respectively. A total of 190 adverse events (AEs) were reported. The most common AEs were anemia 19/190 (10%), leukopenia 9/190 (4.7%), neutropenia 9/190 (4.7%), hypoalbuminemia 9/190 (4.7%), peripheral neuropathy 7/190 (3.7%), elevated ALT 7/190 (3.7%), and elevated serum creatinine level 5/190 (2.6%), respectively. Twenty-four events were classified as grade ≥ 3 including anemia (4/24), leukopenia (7/24), neutropenia (7/24), and elevated ALT (1/24), respectively. A total of 21 serious adverse events (SAEs) were reported. The causes of SAE were varied as follows: acute kidney injury 2/21, pneumonia 2/21, leukopenia 1/21, neutropenia 1/21, and thrombocytopenia 1/21. Most of the SAEs were suspected to be related to the treatment. Two cases of acute kidney injury related to methotrexate and one case of hypersensitivity reactions to L-asparaginase were reported as SAEs. They were manageable and completely resolved upon follow-up. There were no treatment-related deaths. At the data cutoff date, after the median follow up of 11.6 months, 25 pts. were alive, 7 experienced progressions, and 5 had died. Two pts. had progression in the central nervous system. Conclusion Treatment with standard-dose of BV in combination with MAD chemotherapy was well tolerated and showed encouraging efficacy in patients with newly diagnosed ENKTL. Evaluation of long-term survival data is ongoing. (ClinicalTrials.gov identifier: NCT03246750)

PET4 Response As an Independent Predictor of Long-Term Outcomes in ECHELON2 (A+CHP Vs. CHOP) in CD30+PTCL

Background: Peripheral T-cell lymphomas (PTCLs) are uncommon, heterogeneous, and often aggressive subtypes of lymphoma characterized by a high risk of progression even after combination chemotherapy. The phase III, ECHELON-2 trial showed that the combination of brentuximab vedotin with chemotherapy (A+CHP) in patients (pts) with CD30-positive PTCLs improved progression-free survival (PFS) and overall survival (OS) compared to CHOP. In PTCL, positron emission tomography (PET) is a valuable way to assess disease burden and stage at the time of diagnosis and evaluate treatment response. Prior retrospective studies have shown that interim and end of treatment PET may predict outcomes; however, there are no prospective studies confirming their predictive value. In the ECHELON-2 study, PET4 outcomes were prospectively collected, and the objective of this exploratory analysis is to investigate the potential for interim PET scans to predict treatment response and long-term outcomes. Objective: To evaluate the role of interim 18F-FDG PET imaging (PET4) in predicting end of treatment (EOT) response, progression free survival (PFS), and overall survival (OS) in pts (pts) with CD30+PTCL treated with A+CHP or CHOP in the ECHELON-2 trial. Methods: The ECHELON-2 trial included prospective 18F-FDG PET scans and assessment of treatment response including long-term PFS per investigator and OS. PET4 status was based on Deauville score by Independent Review Facility (IRF) assessment using scans at the cycle 4 response assessment. Deauville scores 1-3 are considered negative (PET4neg) and 4-5 positive (PET4pos). EOT response is the best response after completion of study treatment and prior to long term follow up per Cheson 2007 by IRF assessment. Kaplan-Meier methods were used to estimate PFS and OS; p-values are based on stratified log-rank tests. All analyses are exploratory, and p-values are descriptive. Results: In this study, 452 pts were included, with 226 randomized to the A+CHP treatment arm and 226 to the CHOP treatment arm; median follow up was 66.8 months (range 0-90). Of randomized pts, 32 pts in the A+CHP arm and 41 pts in the CHOP arm were not evaluable for PET4. The overall results showed that the PET4neg evaluable subgroup had a higher proportion of pts achieving complete responses (CR) than PET4pos (80% vs. 9%) at EOT (Table 1). In pts assessed for PET4, pts who were PET4neg had improved PFS and OS in both the A+CHP and CHOP treatment arms (Figure 1). For A+CHP pts, those who achieved PET4neg had an improved PFS [HR 0.36, CI-95 (0.19-0.66), p=0.0006] and OS [HR 0.38, CI-95 (0.18-0.78), p=0.0060] compared to those who were PET4pos. Similarly, pts in the CHOP arm who achieved PET4neg had an improved PFS [HR 0.26, CI-95 (0.17-0.41), p<0.0001] and OS [HR 0.24, CI-95 (0.14-0.41), p< 0.0001] compared to those who were PET4pos. Among pts with anaplastic large cell lymphoma (sALCL) (n=316), 19 pts in the A+CHP arm and 32 in the CHOP arm were not evaluable for PET4. The results in this subgroup show that 128/143 (90%) A+CHP pts who had PET4 assessments achieved PET4neg. These pts experienced improved PFS [HR 0.28, CI-95 (0.14-0.60), p=0.0004] and OS [HR 0.38, CI-95 (0.16-0.94), p 0.0292] compared to PET4pos pts. For CHOP pts who had PET4 assessments 98/122 (80%), achieved PET4neg; these pts experienced improved PFS [HR 0.31, CI-95 (0.12-0.55), p<0.0001] and improved OS [HR 0.25, CI-95 (0.12-0.25), p= 0.0002] compared to PET4pos pts. Conclusion: In an exploratory analysis of interim PET imaging as part of the ECHELON-2 study, PET4neg by Deauville was associated with improved PFS and OS in both the A+CHP and CHOP arms. Our findings support the use of PET4 response in PTCL as a predictor of outcomes in both the A+CHP and CHOP pts. These findings emphasize the potential of PET scans to enhance risk stratification, individualize therapy decisions, and improve pt outcomes in the management of PTCLs. Further analysis will be presented at the meeting.

The combination of brentuximab vedotin and chidamide synergistically suppresses the proliferation of T-cell lymphoma cells through the enhancement of apoptosis

PurposePeripheral T-cell lymphoma (PTCL) is an aggressive disease with a poor prognosis. Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody linked to a microtubule-disrupting agent, has been approved for the treatment of PTCL. We evaluated a new effective combination partner of BV using non-clinical approaches that could potentially identify agents capable of improving survival times for patients with PTCL.MethodsA high-throughput screening test was used to select the most synergistic partner of BV from 14 candidate drugs that were under development or available in clinical practice for PTCL. HH cells, originating from an aggressive cutaneous T-cell lymphoma, were used as an experimental model of PTCL. Apoptotic effects of the synergistic partner of BV were further investigated in vitro and in vivo using HH-cell xenograft mice.ResultsChidamide (tucidinostat), a novel histone deacetylase inhibitor, was found to have the greatest synergistic effect with BV on HH cells. The combined effects of chidamide and BV were demonstrated in a study of HH-cell xenograft mice; mean tumor size following combined treatment was 22% of that observed in the control group, compared with 71% and 58% following chidamide and BV monotherapy, respectively. Further investigations in vitro and in vivo revealed that the levels of an anti-apoptotic protein, Bcl-2, and a rate-limiting factor of DNA replication, CDC45, were reduced in HH cells treated with chidamide combined with BV compared with the control group.ConclusionThe use of chidamide in conjunction with BV may positively affect and enhance T-cellular apoptotic pathways without offsetting each other.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced Stage Classical Hodgkin Lymphoma: Efficacy and Safety Results from the Single Arm Phase 2 Study

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate approved for multiple cancer types, including previously untreated stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in adults. The combination of BV and nivolumab are both individually active and well tolerated in patients with cHL and have distinct and complementary mechanisms of action. BV and nivolumab have been previously studied in combination and with multiagent chemotherapy as BV+AD (omitting vinblastine) and N+AVD. It was hypothesized that the combination of BV and nivolumab with doxorubicin and dacarbazine (AN+AD) would result in high response rates and a well-tolerated safety profile with potentially less toxicity than vinblastine-containing regimens. SGN35-027 (NCT03646123; EudraCT Number 2020-004027-17; Part B) is an open-label, multiple-part, multicenter, phase 2 clinical trial. Preliminary results of this study showed promising efficacy (objective response rate [ORR] 93%; complete response [CR] rate 88% at end of therapy [EOT]) with no cases of febrile neutropenia or grade 5 adverse events (AEs) (Lee ASCO 2022). Of the patients with stage III or IV cHL who relapse, most will relapse within 18 to 24 months of treatment initiation. Methods: Part B enrolled patients with stage II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Patients received up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D]). The primary efficacy endpoint was CR rate at EOT. Key secondary endpoints included safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. Results: Fifty-eight patients were enrolled; all but 1 patient received ≥1 dose of study drug (data cutoff 22 May 2023). Median age was 35 years (range, 19-78 years). Among efficacy evaluable patients (n = 56), ORR (CR+ PR) at EOT was 95% (95% CI: 85.1, 98.9); CR rate was 89% (95% CI: 78.1, 96.0) (Table 1). A total of 88.3% (95% CI: 75.7, 94.6) of responders had a DOR of at least 24 months, and 88.4% (95% CI: 76.0, 95.0) of responders had a DOCR of at least 24 months. Seven patients (12%) had a PFS event: 6 with disease progression and 1 who died (sepsis, outside safety reporting period). The estimated PFS rate at 24 months was 88.3% (95% CI: 75.7, 94.6) (Figure 1). Median follow-up was 24.2 months (95% CI: 23.4, 26.9). The most common treatment-related AEs of any grade were nausea (37 patients [65%]), fatigue (28 patients [49%]), and peripheral sensory neuropathy (25 patients [44%]). Of the patients with treatment-related peripheral sensory neuropathy, most (23 of 25 patients [92%]) were grade 1 or 2; the remaining 2 patients had grade 3 peripheral sensory neuropathy. Dose modifications due to peripheral sensory neuropathy occurred in 9 patients (16%). Grade ≥3 treatment-related AEs occurred in 19 patients (33%) (most common: alanine aminotransferase increased in 6 [11%] and neutropenia in 5 [9%]). No febrile neutropenia or Grade 5 AEs occurred. Treatment-related serious AEs (SAEs) occurred in 8 patients (14%). Seven patients (12%) had a treatment-emergent AE that led to discontinuation of BV. Treatment-emergent immune-mediated AEs (IMAEs) occurred in 19 patients (33%); treatment-emergent IMAEs that occurred in ≥5% of patients were hypothyroidism (5 patients [9%]) and pneumonitis and rash maculopapular (3 patients [5%] each). All cases of pneumonitis resolved. Conclusions: The use of 2 active, targeted agents with distinct and complementary mechanisms of action for the frontline treatment of advanced stage cHL resulted in promising efficacy, safety, and tolerability. These results demonstrate continued tolerability of AN+AD with no new safety signals observed. AN+AD may provide a future first-line treatment option for patients with advanced stage cHL; long-term follow-up is ongoing.

Brentuximab Vedotin in Combination with Nivolumab in CD30+ Malignancies Refractory to Brentuximab Vedotin

Introduction Brentuximab vedotin (BV), in combination with multi-agent chemotherapy, is considered a standard of care for newly diagnosed CD30+ lymphomas. Despite high reported efficacy, some patients fail to respond to initial BV exposure and many more eventually progress despite ongoing BV therapy. In addition to direct cytotoxicity, BV may also induce immunogenic cell death (Gardai, et al. Cancer Res 2015) and foster a reduction of regulatory T-cells (Herrera, et al. Blood 2018) that may synergize with immune checkpoint inhibitors. To date, the high response rates reported with BV and anti-PD-1 combinations have been limited to patients naïve to both of these agents (Advani, et al. Blood 2021). To address the more clinically relevant scenario of prior BV +/- anti-PD-1 exposure, we designed a study to evaluate the combination of BV and nivolumab in patients with CD30+ lymphoma refractory to prior BV, including those with prior anti-PD-1 therapy. We report the final safety, efficacy and correlative analysis of BV in combination with nivolumab in R/R CD30+ lymphomas refractory to BV. Methods We conducted an open-label trial (NCT01703949) involving patients 18 years and older with CD30+ lymphomas refractory to BV therapy. Refractoriness was defined as lack of disease response or progression within 6 months following a minimum of 2 cycles of BV. BV was given at 1.8 mg/kg in combination with nivolumab at 3 mg/kg every 3 weeks for 4 cycles. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival, overall survival, time to next treatment, safety and tolerability and immune response biomarkers. Results As of July 27, 2023, 19 patients have enrolled and 17 have initiated therapy (Table 1). Fourteen patients had classical Hodgkin lymphoma (cHL), 2 had ALK-negative anaplastic large cell lymphoma (ALK- ALCL) and 3 had CD30+ mycosis fungoides (MF). Median age was 35 (range 27-71) years and the median number of prior regimens was 5 (range 1-9), including a median of 6 prior cycles of BV (range 2-19). All patients had BV-refractory disease including 16 (84%) who were non-responsive to and 3 (16%) who relapsed within 6 months of BV. Five (26%) patients with cHL received prior anti-PD-1 therapy and 4 (21%) had anti-PD-1 refractory disease. Median time from last BV and anti-PD-1 therapy to study treatment was 5.2 and 1.1 months, respectively. Eight (42%) patients had prior autologous stem cell transplant. Of response evaluable patients, the ORR and CR rate was 44% and 6% after 2 cycles and 44% and 19% after 4 cycles of therapy. Of patients who were refractory to prior BV and anti-PD-1 therapy, 1 (25%) and 1 (25%) achieved a PR and CR, respectively. ORR and CR rate was 43% and 14% for patients with cHL, 100% and 50% for patients with ALK- ALCL, and 100% and 100% for patients with MF, respectively. At completion of study, 1 patient with cHL, 1 with MF and 2 with cHL continued BV with nivolumab, BV monotherapy and nivolumab monotherapy, respectively. Median time to progression and next therapy was 4.5 (range 1.8-45.6) and 5.0 (range 1.8-45.6) months, respectively. Of the 3 patients who achieved a CR after 4 cycles of therapy, 2 (67%) continued treatment (1 with BV and nivolumab and 1 with BV monotherapy), and 1 (33%) has been on surveillance for 45.6 months with no evidence of relapse. At a median follow-up of 21.7 (range 0.5-60.4) months, 15 (79%) patients are alive with 3 in CR. Eleven (58%) and 8 (42%) patients reported no and grade 1 peripheral neuropathy (PN) at baseline, respectively. At end of treatment, 12 (63%) and 1 (5%) patients reported grade 1 and 2 PN, respectively. No patients experienced grade ≥3 PN, transaminitis, infections or infusion reactions. One (5%) patient had a 1-week dose delay due to grade 1 ALT/AST elevation. Two (11%) deaths were noted on study; one patient developed respiratory failure secondary to pneumonitis and influenza and another patient experienced cardiac arrest due to benzodiazepine withdrawal. Correlative PD-1 levels drawn at baseline and at the end of treatment did not correlate with response. Conclusions Despite the presence of BV-refractory disease, 4 cycles of BV and nivolumab is tolerable and associated with encouraging efficacy in patients with heavily treated CD30+ lymphoma. This treatment option may have increasing relevance as more patients receive BV or anti-PD-1 therapy as part of initial treatment.

Brentuximab vedotin + AVD in cHL: cost impact on adverse events, toxicity, second malignancies, end-of-life and subsequent lines of therapy in Italy

Introduction: In classical Hodgkin lymphoma (cHL), the delayed effects of therapies, such as second malignancies and toxicity, and the high relapse rate are potentially associated with an expense for the National Health Service (NHS). Objective: The objective of the study was to estimate the impact of introducing the combination of brentuximab vedotin (Adcetris®), doxorubicin, vinblastine and dacarbazine (A+AVD) for the first line (1L) treatment of stage III/IV cHL on costs associated with adverse events (AEs), pulmonary toxicity, second malignancies, end-of-life and second and subsequent lines (2L+) treatments. Method: The incidence of the events analysed was derived from clinical trials and Italian reports. Unit costs were estimated based on the national tariffs and the Italian literature. The results were modelled and extrapolated to the population in two scenarios, a current one without A+AVD and a future one in which A+AVD is introduced. The time horizon was six years and the perspective is that of the Italian NHS. Results: The introduction of A+AVD in 1L is associated with a reduction in the costs of AEs, pulmonary toxicity, second malignancies and end-of-life following 1L and in the acquisition costs of 2L+ treatments of approximately € 10,400/patient corresponding to a total saving of € 18.46 M over six years for the NHS; this saving grows as the use of A+AVD increases. Conclusion: The introduction of A+AVD for the 1L treatment of stage III/IV cHL is associated with a reduction in costs for the NHS for the management of AEs, pulmonary toxicity, second malignancies, end-of-life and 2L+ treatments.

Consolidative Radio therapy in Place of Autologous Stem Cell Transplant in Patients with Low-Risk Relapsed/Refractory (R/R) Classic Hodgkin Lymphoma (cHL) Treated with Nivolumab plus Brentuximab Vedotin: CheckMate 744

Standard of care treatment for patients with relapsed and refractory classic Hodgkin lymphoma (RRHL) involves second line therapy followed by high dose therapy and autologous stem cell transplant (HDT/ASCT) and carries with it significant costs and toxicities to the patient. Some patients with RRHL may not require such intensive therapy, especially in the era of targeted chemotherapy and checkpoint inhibitors. CheckMate 744 (NCT02927769) evaluated a novel second-line therapy that omits HDT/ASCT by combining brentuximab vedotin (BV) and a nivolumab (N) followed by consolidative ISRT for low risk RRHL. Pts were aged 5-30 y and had one prior treatment without HDT/ASCT. Low-risk RRHL were those at relapse without B symptoms or extranodal disease, limited sites of relapse (≤4 sites of disease above the diaphragm or ≤3 sites above/below the diaphragm) AND with initial Stage IA, IIA with relapse <1 year if they received ≤3 cycles of chemotherapy and no RT OR Stage IA/B, IIA/B, IIIA ≥ 1 year. Patients received 4 cycles of N + BV induction. Patients with complete metabolic response (CMR) received an additional 2 cycles of N + BV before RT consolidation. Patients with suboptimal response received 2 cycles of BV + bendamustine intensification. Those patients achieving CMR proceeded to RT consolidation. RT was delivered to a dose of 30-30.6 Gy at 1.5-1.8 Gy/fraction to an ISRT volume. Among 28 pts treated, the median age (range) was 17 (6-27) years old and 64% of patients were aged < 18 y. Most (79%) pts had stage II disease at diagnosis and 82% had relapsed ≥ 12 months after first line treatment. Of 27 pts continuing in study after induction N + BV, 6 received bendamustine + BV intensification, and 92.9% achieved complete metabolic response. Twenty-two patients received RT consolidation. RT consolidation was delivered using 3D-CRT, IMRT, or proton therapy. After a median (range) follow-up of 31.8 (2.2-55.1) months, the 3-y event-free survival rate and progression-free survival were 86.9% (69.5-94.7%) and 95% (76.7-99%), respectively. A novel combination of N + BV followed by ISRT was an effective second line therapy. This treatment regimen allowed patients to forgo high dose therapy and transplant in favor of consolidative radiotherapy using ISRT. Larger studies challenging the role of high dose therapy and transplant are needed for RRHL.

Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity.

Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the "gold-standard" test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B-cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous Epstein-Barr virus-reactive CD8+ T cells potentiating the activity of anti-PD-1 therapy. Together, these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.

Daratumumab and brentuximab vedotin combination therapy in T-cell acute lymphoblastic leukemia refractory to conventional chemotherapy and allogeneic stem cell transplant.

Not available.

Brentuximab vedotin with AVD for stage II–IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial

Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per μL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. National Institutes of Health and National Cancer Institute.

Safety of Concurrent Radiation Therapy With Brentuximab Vedotin in the Treatment of Lymphoma

Purpose: Radiation therapy (RT) and the antibody-drug conjugate brentuximab vedotin (BV) are standard-of-care treatment options for patients with certain B and T-cell lymphomas; however, there are limited data exploring the safety of concurrent BV and RT (BVRT). We performed a single institutional retrospective review of 44 patients who received BVRT. Twenty percent of patients (9/44) developed new grade 2 or higher (G2+) hematologic toxicity (HT) after BVRT, which was associated with radiation dose (median dose of 35 Gy in those with new G2+ HT compared with 15 Gy in those without; P < .001). Acute G2+ elevation in aspartate transaminase or alanine transaminase level was associated with administration of concurrent chemotherapy with BVRT (57% vs 21%; P=.047) but was not associated with any RT factors. Local control (LC) was achieved in 24 of 42 patients (57%) with available follow-up. Ten patients (23%) proceeded to stem cell transplant or cellular therapy after BVRT at a median of 48 days (interquartile range, 27-188 days). At last follow-up, 10 patients (23%) remained without evidence of disease. Our analysis demonstrates that the combination of BV and RT is well tolerated, though care should be taken during RT planning to reduce the risk of HT. This combination can be considered for patients in need of both local and systemic disease control.

Brentuximab-vedotin in combination with cyclophosphamide, doxorubicin, prednisolone for the treatment of aggressive CD30-positive cutaneous T-cell lymphomas

Aggressive CD30-positive cutaneous T-cell lymphomas (CD30+CTCL) are associated with unfavorable prognosis. Anthracycline-based polychemotherapy (CHOP) and brentuximab-vedotin (BV) monotherapy are related to poor outcomes in case of extracutaneous involvement or rapidly-progressing disease. Our objective was to assess the effectiveness of BV + CHP in aggressive CD30+CTCL. We included 7 patients treated with BV + CHP from April 2015 to January 2022: 4 had mycosis fungoides with large-cell transformation, 2 had primary cutaneous anaplastic large-cell lymphoma, and 1 harbored a primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma. After a median [IQR] follow-up of 17.2 [13.2–21.0] months, 6/7 patients achieved an ORR lasting ≥4 months. The median [IQR] duration of response was 9.5 [5.9–11.1] months and the median [IQR] progression free survival was 14.9 [11.6–16.4] months. Four patients displayed progression with a median (range) time to next treatment of 15.8 (6.5–16.3) months. Two grade-3 adverse events were reported: febrile neutropenia and thromboembolic event. BV + CHP displayed substantial antitumor activity and favorable safety profile in 7 patients with aggressive CD30+CTCL.

CD30 as a therapeutic target in adult haematological malignancies: Where are we now?

CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti-CD30 CAR-T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti-CD30 therapies that have emerged to date.

Abstract 3253: CD30 is a marker of activated effector regulatory T cells in solid tumors providing clinical rationale for the combination of brentuximab vedotin and PD-1 inhibitors

Abstract Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis by preventing excessive inflammation in normal tissues. In cancer, Tregs hamper antitumor immunosurveillance and may be a resistance mechanism to anti-PD-1 therapies. In preclinical cancer models, Treg depletion enhances antitumor cytotoxic immune responses, but systemic and persistent Treg removal can elicit immunopathology. Therapeutic strategies that selectively deplete highly suppressive activated intratumoral Tregs may avoid immune-related toxicities and amplify the activity of antitumor CD8 T cells during PD-1 blockade. CD30 is a member of the TNF receptor superfamily and is expressed by a subset of activated lymphocytes and various lymphomas. Here, transcriptomics and flow cytometry data from tumor and peripherally derived Tregs demonstrated CD30 is enriched on intratumoral Tregs. Among peripheral Tregs, CD30 expression was associated with an activated effector phenotype (FoxP3hiCD45RA-, fraction II). Further, treatment of dissociated NSCLC tumor spheroids with anti-PD-1 resulted in upregulated CD30 expression by Tregs but not intratumoral CD4 or CD8 T cells, which is consistent with Treg reactivation and supports CD30 as an activated Treg target. In vitro, CD30 expression on Tregs was dependent on signaling through the TCR and was significantly amplified by IL-2 and IL-15, suggesting CD30 may identify a subpopulation of activated antigen-specific Tregs. Brentuximab vedotin (BV) is an antibody-drug conjugate approved for clinical use in multiple types of lymphomas including cHL and PTCL. BV consists of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE). The activity of BV in lymphomas is thought to primarily result from tumor-directed intracellular MMAE release leading to apoptosis, though multiple immunomodulatory effects of BV have also been suggested. We have demonstrated through in vitro and in vivo preclinical model systems of human T cell activation that BV can selectively deplete CD30-expressing Tregs, amplifying cytotoxic CD8 T cell expansion. These and Treg CD30 expression data motivated the clinical exploration of BV plus pembrolizumab in metastatic PD-1 refractory melanoma and NSCLC (NCT04609566). Consistent with preclinical data, preliminary biomarker analysis from these studies showed a small but significant decrease in Tregs (CD4+CD25+CD127low/-) in peripheral blood after treatment with BV plus pembrolizumab. Further, limited on-treatment biopsies showed a trend toward increased intratumoral CD8:Treg (FoxP3) ratio in some patients receiving combination therapy. These data support the ongoing evaluation of BV in combination with PD-1 inhibitors in solid tumors and a potential additional mechanism of action for BV. Citation Format: Ryan A. Heiser, Bryan M. Grogan, Reice D. James, Michelle L. Ulrich, Jason D. Berndt, Brian P. O'Connor, Shyra J. Gardai, Hailing Lu, Scott M. Knowles. CD30 is a marker of activated effector regulatory T cells in solid tumors providing clinical rationale for the combination of brentuximab vedotin and PD-1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3253.

Retrospective Analysis With Propensity Score Matching of Peripheral T-Cell Lymphoma Treated Frontline With Brentuximab Vedotin and Chemotherapy.

Since Food and Drug Administration approval of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) as initial therapy for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), there has been limited research on real-world patient characteristics, treatment patterns, and clinical outcomes. We retrospectively analyzed claims of patients with PTCL treated with frontline A + CHP or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) using the Symphony Health Solutions database. Adults with International Classification of Diseases-9/10 PTCL diagnosis codes who initiated A + CHP or CHOP between November 2018 and July 2021 were included. A 1:1 propensity score matching analysis was performed that adjusted for potential confounders between groups. A total of 1344 patients were included (A + CHP, n = 749; CHOP, n = 595). Before matching, 61% were men; median age at index was 62 (A + CHP) and 69 (CHOP) years. The most common A + CHP-treated PTCL subtypes were systemic anaplastic large cell lymphoma (sALCL; 51%), PTCL-not otherwise specified (NOS; 30%), and angioimmunoblastic T-cell lymphoma (AITL; 12%); the most common CHOP-treated subtypes were PTCL-NOS (51%) and AITL (19%). After matching, similar proportions of patients treated with A + CHP and CHOP received granulocyte colony-stimulating factor (89% vs. 86%, P = .3). Fewer patients treated with A + CHP received subsequent therapy than CHOP overall (20% vs. 30%, P < .001) and specifically with the sALCL subtype (15% vs. 28%, P = .025). Characteristics and management of this real-world PTCL population who were older and had a higher comorbidity burden than that in the ECHELON-2 trial demonstrate the importance of retrospective studies when assessing the impact of new regimens on clinical practice.

Comparative clinical and economic evaluation of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in the 1&lt;sup&gt;st&lt;/sup&gt; line therapy for adult patients with diffuse large B-cell lymphoma

Aim . To assess the pharmacoeconomic feasibility of using polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in 1 st line therapy of adult patients with diffuse large B-cell lymphoma in the Russian healthcare system, taking into account the currently used therapeutic practices in oncohematology. Materials and methods . The design of the study is a retrospective analysis of literature data. Clinical and economic analysis (incremental cost–effectiveness analysis, case-based approach) was performed using sensitivity assessment. The sources of data on the effectiveness of the analyzed drugs were publications on clinical trials, on the cost of drugs – the state register of maximum selling prices, data from the manufacturer. Results . An incremental cost–effectiveness analysis was performed using a case-based approach comparing the cost of progression-free life-year gained. Brentuximab vedotin, already included in the list of vital and essential drugs and provided at the expense of budgetary funds, was chosen as the reference drug. It has been established that the cost of progression-free life-year gained (ICER) with the use of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in 1 st line therapy of adult patients with diffuse large B-cell lymphoma by 60.8 %, or 41.6 million rubles, lower than the cost of progression-free life-year gained when using brentuximab vedotin in combination with doxorubicin, vinblastine and dacarbazine in the 1 st line therapy of patients with CD30-positive classical Hodgkin’s lymphoma. Sensitivity assessment showed the stability of the obtained results of clinical and economic analysis to changes in the cost of drugs in compared therapy regimens. The results were sensitive to changes in the efficacy of the compared regimens. Conclusion . The obtained results of the clinical and economic analysis demonstrated that the use of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisolone (R-CHP) in the 1 st line therapy of adult patients with diffuse large B-cell lymphoma in the Russian healthcare system is economically appropriate.

Estimating long-term progression-free and overall survival in patients with peripheral T-cell lymphoma: A US population-based oncology simulation model based on 5-year results from the ECHELON-2 trial.

BACKGROUND: The ECHELON-2 5-year update showed continued clinically meaningful improvements in progression-free survival (PFS) and overall survival with frontline (1L) A+CHP (brentuximab vedotin in combination with cyclophosphamide, doxorubicin, prednisone) vs CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in CD30-expressing peripheral T-cell lymphomas (PTCLs). OBJECTIVE: To estimate PTCL annual prevalence in the United States in 2031 without and with A+CHP using data from the ECHELON-2 5-year update. METHODS: Population-level outcomes were estimated using a dynamic oncology simulation model. Utilization of 1L CHOP (65% utilization) and CHOP plus etoposide (35% utilization) were varied over time and compared with scenarios incorporating 1L A+CHP (20%-50% utilization; base case: 40% utilization) per expert clinicians' opinion. Additional inputs included PTCL incidence and PFS for consolidation and post-1L therapies from published sources. PFS (51.4% [95% CI = 42.8%-59.4%] vs 43.0% [35.8%-50.0%]) and overall survival (hazard ratio = 0.72 [0.53-0.99]) for A+CHP and CHOP came from ECHELON-2. RESULTS: In 2031, an estimated 2,082 patients will be diagnosed with PTCL. Approximately 1,412 additional patients will be alive and progression free, and 106 fewer patients will require second-line therapy with 40% A+CHP utilization vs no A+CHP utilization. Varying 1L A+CHP utilization from 20%-50% vs no 1L A+CHP utilization added 732 to 1,752 patients alive and progression free. CONCLUSIONS: In this oncology simulation model, the improvements in survival outcomes seen with A+CHP vs CHOP in the ECHELON-2 5-year results translated into more estimated patients with PTCL progression free and alive for at least 5 years following 1L A+CHP vs CHOP and a decreased need for post-1L therapy. DISCLOSURES: This study was funded by Seagen Inc. Dr Liu and Dr Yu are employees and shareholders of Seagen Inc. Mr Bloudek is and Dr Mordi was an employee of Curta Health, which received funding from Seagen Inc. for the conduct of this study. Dr Burke received consulting fees from Genentech/Roche, AbbVie, Seattle Genetics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem, MorphoSys, Kura, Epizyme, BeiGene, Kymera, Novartis, Bristol Myers Squibb, TG Therapeutics, Lilly, and Nurix; and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events in speakers bureaus for BeiGene and Seagen Inc. Dr Phillips received consulting fees from AstraZeneca, MorphoSys, Epizyme, Roche/Genentech, Epizyme Eli Lilly, AbbVie, BeiGene, Pharmacyclics, Bristol Myers Squibb, Xencor, Seagen Inc., TG Therapeutics, Bayer, Incyte, and Gilead; and received payment for honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Epizyme and Seagen Inc.

Brentuximab vedotin in combination with doxorubicin, vinblastine and dacarbazine for first-line treatment of stage IV HL: cost impact on subsequent lines in Italy

Introduction: This study estimates the change in the costs of second-line or later (2L+) treatments compared to the current scenario, associated with the introduction of brentuximab vedotin (Adcetris®) (BV) in combination with doxorubicin, vinblastine and dacarbazine (A+AVD) for the treatment of previously untreated (1L) patients with stage IV classical Hodgkin’s lymphoma (cHL). Methods: An economic model has been developed that estimates the variation in treatment costs of 2L+ associated with the introduction of BV in 1L from the point of view of the Italian National Health System over a time horizon of 3 years. The population eligible to receive a treatment of 2L+ has been estimated from the literature, considering an increasing consumption in the three years of A+AVD in 1L. Two main scenarios and several alternative scenarios were considered to address the uncertainty that characterizes the distribution of market shares of 2L+ treatments. Results: In the baseline scenario, over three years, the introduction of BV in 1L is associated with a cumulative reduction in treatment costs of 2L+ of € 1.74 M. In all scenarios, a reduction in treatment costs of 2L+ is confirmed, with a total saving that varies between € 5.6 M and € 1.3 M compared to the main scenarios. Conclusions: The present analysis shows that the introduction of A+AVD in 1L for the treatment of stage IV CD30+ cHL patients is associated with a reduction in treatment costs of 2L+, even if there are some limitations related to the uncertainty of real cost and population estimates.

Primary Breast Anaplastic Large-Cell Lymphoma

Abstract We reported a rare case and experience of successfully treating primary anaplastic large-cell lymphoma (ALCL) of the breast with no history of breast implants, using a combination of novel brentuximab vedotin and chemotherapy. A 78-year-old woman presented with a painless lump over the left breast. The computed tomography scan revealed a 2.6-cm tumor in the left upper quadrant of the breast, along with enlarged lymph nodes in the left axilla, exhibiting similar imaging features to breast carcinoma. The definitive diagnosis was based on histopathology and immunohistochemistry stains consistent with ALCL. The patient received brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) chemotherapy, as well as involved site radiation therapy (ISRT). The following image showed almost complete remission.

Phase I Trial of Brentuximab Vedotin Plus Cyclosporine in Relapsed/Refractory Hodgkin Lymphoma

Introduction Treatment of relapsed/refractory (R/R) Hodgkin lymphoma (HL) following failure of brentuximab vedotin (BV) and PD-1 blockade is a major unmet need. Resistance to BV is associated with multidrug resistance gene 1 (MDR1) overexpression. There are pre-clinical data showing that MDR1 inhibitors such as cyclosporine (CsA) or verapamil (VRP) are synergistic with BV in BV-resistant HL cell lines. Preliminary results of a phase I study evaluating the safety and efficacy of combination of BV with CsA and VRP in R/R HL were previously reported. Here we report the final results of the completed study. Methods This is a single center, open-label phase I investigator-initiated study. Patients (pts) with HL whose disease had relapsed or was refractory to ≥1 prior lines of therapy were enrolled. The dose finding portion followed a 3+3 design with 4 planned dose levels (DL). BV was given at 1.2 mg/kg (DL1) or 1.8 mg/kg (DL2-4) intravenously every 3 weeks. Planned dose of CsA was 5 mg/kg (DL1-2) or 7.5 mg/kg (DL3-4) orally twice daily on days 1-5. Planned dose of VRP was 120 mg orally four times daily on days 1-5 (DL4). Each cycle was 3 weeks. Once the maximum tolerated dose (MTD) was determined, BV-refractory pts were enrolled in an expansion cohort at the MTD. Primary objective was to determine the MTD and safety of the combination. Secondary objectives were overall response rate (ORR), complete response (CR) rate, response duration (DOR), overall survival (OS), and progression-free survival (PFS). Results Twenty-nine pts were enrolled onto the study, 14 in the dose-finding portion and 15 in the dose expansion BV-refractory cohort. With respect to baseline characteristics, 38% of patients were female, 69% had advanced stage disease, 45% had extranodal disease, and 24% had B symptoms. Median age was 36 (20-69) and pts had a median of 5 (3-12) prior lines of therapy. All had prior BV (only 2 BV-sensitive) and 27 had prior PD-1 blockade. Four pts were treated on DL1, 22 on DL2, and 3 on DL3. MTD was DL2. DLTs observed were: DL1 10-day CsA (n=1) grade (Gr) 3 hyperbilirubinemia, abdominal pain, and hypertension, DL2 (n=1) Gr3 abdominal pain and Gr3-4 neutropenia, DL3 (n=2) Gr3 bone pain/constipation/Gr4 lymphopenia (n=1) and Gr3 hyperglycemia (n=1). Median duration of treatment was 3 (1-16) cycles. Most frequent adverse events (AEs) were nausea (90%), hypertension (90%), anemia (86%), fatigue (76%), neutropenia (76%), and leukopenia (76%). All pts had Gr3+ AEs with most frequent being neutropenia (62%). Reasons for treatment discontinuation included death (n=4), disease progression (n=10), toxicity (n=2), patient refusal (n=8), loss to follow-up (n=2), MD decision (n=1), proceeding to HCT (n=1), and study completion (n=1). Treatment-related death occurred in 3 pts (pneumonitis at DL1, respiratory failure and hypotension at DL2). The ORR/CR was 62%/24%. The median DOR and PFS was 5 months and median OS was not reached. Discussion The combination of BV and CsA was effective in BV-refractory R/R HL but was also associated with toxicity, including treatment-related deaths that led to early termination of the clinical trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal