Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL),

Abstract Abstract 3711 Background: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Trials with brentuximab vedotin have previously reported results in patients with relapsed or refractory HL or sALCL. In a pivotal HL trial, complete remissions (CRs) were observed in 35 of 102 patients (34%) with a median duration of 20.5 months (Chen 2011). Thirty-three of 58 patients (57%) with sALCL achieved CRs with a median duration of 13.2 months in a phase 2 trial (Pro 2011). In both of these studies, a maximum of 16 cycles was permitted; patients with HL received a median of 10 cycles and those with sALCL, 7 cycles. This case series presents a retrospective analysis on a subset of patients who have received prolonged treatment (>16 cycles) with brentuximab vedotin in a treatment-extension study (ClinicalTrials.gov #NCT00947856). Methods: Brentuximab vedotin 1.2 or 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment in 1 of 4 preceding studies. Consecutive cycles of treatment were then administered in the extension study until disease progression, unacceptable toxicity, or withdrawal of consent. Antitumor activity in this case series was based on objective response assessments per the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: Fifteen patients have received >16 consecutive cycles of treatment with brentuximab vedotin. The median age of patients was 35 years (range 14–74); 9 patients were female. Patients had relapsed or refractory CD30-positive HL (10) or sALCL (5) and had received a median of 3 prior therapies (range 1–14). Nine patients had previously failed autologous stem cell transplant (SCT), and 2 of these patients had additionally failed an allogeneic SCT. The median number of treatment cycles was 19 (range 17–29). At the time of the analysis, 2 patients had discontinued treatment; neither patient had discontinued due to an adverse event (AE). AEs among patients were generally mild, which enabled continued treatment beyond the initial study. Across all cycles of treatment, AEs in >30% of patients were peripheral sensory neuropathy (73%), fatigue (53%), upper respiratory tract infection (53%), cough (40%), alopecia, diarrhea, neutropenia, and pyrexia (33% each). The only AE which occurred for the first time after Cycle 16 in more than 1 patient was neutropenia (n=2). Peripheral neuropathy events (by Standardised MedDRA Query) of Grade 1 or 2 were experienced by 87% of patients; no Grade 3 or 4 events of peripheral neuropathy were observed. Peripheral neuropathy was managed with dose reductions and dose delays; resolution or improvement of peripheral neuropathy was observed in over half of the patients (7 of 13) with a median time to resolution or improvement of 3.1 weeks (range 0.1–8). Best clinical responses in patients were 11 CRs, including CRs achieved by all 5 patients with sALCL, 2 partial remissions (PRs), and 2 patients with stable disease. Four of 11 patients evolved from a PR to achieve a CR; the median time from first dose to achievement of CR was 12 weeks (range 5.4–48.9). The median duration of objective response has not been reached; the durations ranged from 6.5+ to 21.8+ months. At the time of the analysis, 14 patients were alive and free of documented progression, and the median progression-free survival had not been reached (range 11.8+ to 23+ months). Conclusions: Among patients with relapsed or refractory HL or sALCL who have enrolled in a treatment-extension study, 15 have received >16 consecutive cycles of treatment with brentuximab vedotin. The safety profile of brentuximab vedotin did not meaningfully change with treatment beyond 16 cycles. Durations of response (11 CR and 2 PR) ranged from 6.5+ to 21.8+ months, with 13 patients still receiving treatment. Updated safety and durability of response will be presented at the meeting. Disclosures: Forero-Torres: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Berryman:Seattle Genetics, Inc.: Research Funding; Soligenix: Research Funding; Gloucester Pharmaceuticals: Research Funding. Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Spectrum: Research Funding; Piramal: Research Funding; Merck: Research Funding; Calistoga: Research Funding; Abbott: Research Funding; Pfizer: Research Funding; SBIO: Research Funding; Gilead: Research Funding; Genzyme: Speakers Bureau; Amgen: Speakers Bureau; Cellular Therapeutics Inc.: Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Purdue Pharma: Consultancy; Celgene: Consultancy; Merck: Research Funding. Olshefski:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Speakers Bureau; Cephalon: Speakers Bureau; Millennium: Speakers Bureau.

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A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results.

Blood ◽

10.1182/blood.v120.21.2746.2746 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2746-2746 ◽

Cited By ~ 7

Author(s):

Eric D. Jacobsen ◽

Ranjana H. Advani ◽

Yasuhiro Oki ◽

Jeff Sharman ◽

Steven M. Horwitz ◽

...

Keyword(s):

Antitumor Activity ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Cell Lymphoma ◽

Objective Response ◽

Brentuximab Vedotin ◽

Grey Zone ◽

Advisory Committees

Abstract Abstract 2746 Background: Brentuximab vedotin (ADCETRIS®) is a CD30-directed antibody-drug conjugate approved for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Several non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphomas (PTCL) have variable quantitative and qualitative expression of CD30. As a result of the high objective response rate (86%) and durable complete remissions (CR) observed in a pivotal phase 2 study in ALCL, a study was initiated to investigate the efficacy and safety of brentuximab vedotin in other NHLs that express the CD30 antigen. Methods: A phase 2, open-label, single-arm, multicenter study is currently ongoing to evaluate the antitumor activity of brentuximab vedotin in approximately 75 patients with relapsed or refractory CD30-positive NHL (ClinicalTrials.gov NCT01421667). Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Efficacy variables will be analyzed by total patients, WHO NHL classification, DLBCL (excluding peripheral mediastinal large B-cell lymphoma [PMBL] due to differing treatment paradigms and outcomes for this DLBCL subtype), and by each individual disease. The correlation between antitumor activity and quantitative CD30 expression is also being explored. Results: Fifty-three patients with various CD30-positive NHLs have been enrolled to date (35 with B-cell neoplasms and 18 with mature T-/NK-cell neoplasms). Twenty-nine (55%) patients had refractory disease, 19 (36%) had relapsed since their most recent prior therapy, and 5 (9%) had primary refractory disease (did not achieve a CR with frontline therapy or relapsed within 3 months of completing frontline therapy). Diagnoses include DLBCL (assorted disease subtypes, n=22), angioimmunoblastic T-cell lymphoma (AITL, n=9), PTCL-NOS (n=8), grey zone lymphoma (n=5), PMBL (n=4), follicular lymphoma (n=3), post-transplant lymphoproliferative disorder (n=1), and cutaneous T-cell lymphoma (n=1). The median age is 64 years (range 16–83) and 30 patients (57%) are male. Patients have received a median of 3 prior systemic therapies and 6 patients have received prior stem cell transplants. Of the 36 patients who have had a response assessment to date, 12 (33%) have achieved an objective response (5 CR, 7 partial remissions [PR]). The ORR for B-cell NHLs is 36% (9/25), and 27% (3/11) for mature T-/NK-cell NHLs. Thus far, responses are particularly noteworthy in DLBCL (excluding PMBL) where 7 of 15 patients (47%) have responded (3 CR, 4 PR), in AITL where 3 of 5 patients (60%) have responded (2 CR, 1 PR), and in grey zone lymphoma where 2 of 5 patients (40%) have achieved a PR. Median duration of response has not been reached. Of the 12 responding patients, 7 remain on treatment, 3 discontinued due to a patient decision (non-adverse event), and 2 due to adverse events of neutropenia (related) and pneumocystis jiroveci pneumonia (unrelated). CD30 expression levels for patients with a CR or PR were widely variable and ranged from <1% to 90%. Treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients include fatigue (26%), diarrhea (16%), nausea (16%), pyrexia (16%), neutropenia (14%), dyspnea (12%), and abdominal pain (10%), and TEAEs considered related to study drug include fatigue (16%) and neutropenia (14%). Most AEs have been Grade 1 or 2. Grade 3 dyspnea, hyponatremia, and decreased white blood cell count have occurred in 2 patients each, while Grade 3 neutropenia has occurred in 3 patients. Two patients have experienced Grade 4 neutropenia. Peripheral neuropathy events have been Grade 1 or 2. Conclusions: In this interim analysis of 53 patients (36 with response evaluations), compelling antitumor activity has been demonstrated in both B-cell and mature T-/NK-cell NHLs, in particular DLBCL, AITL, and grey zone lymphoma. Due to the range of CD30 expression in patients achieving an objective response, more data are needed to determine if there is a correlation between CD30 expression and antitumor activity. Preliminary safety data are consistent with the safety profile of brentuximab vedotin. Disclosures: Jacobsen: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Sharman:Seattle Genetics, Inc.: Research Funding. Horwitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Allos Therapeutics: Consultancy, Research Funding; Merck: Honoraria; Genzyme: Research Funding; Infinity Pharmaceuticals: Research Funding. Forero-Torres:Seattle Geentics, Inc.: Research Funding, Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siddiqi:Seattle Genetics, Inc.: Consultancy, Research Funding. Grove:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other.

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Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Blood ◽

10.1182/blood.v118.21.443.443 ◽

2011 ◽

Vol 118 (21) ◽

pp. 443-443 ◽

Cited By ~ 9

Author(s):

Ranjana H. Advani ◽

Andrei R. Shustov ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership

Abstract Abstract 443 Background: Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods: Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results: 58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions: Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures: Advani: Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Blood ◽

10.1182/blood.v120.21.2745.2745 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2745-2745 ◽

Cited By ~ 3

Author(s):

Barbara Pro ◽

Ranjana H. Advani ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Frontline Treatment ◽

Long Term Follow Up ◽

Alk Positive

Abstract Abstract 2745 Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive malignancy that accounts for 2–5% of all non-Hodgkin lymphoma (NHL) cases. Approximately 40–65% of patients with sALCL develop recurrent disease after frontline treatment and few effective treatment options exist for this population. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing MMAE. A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); long-term follow-up data from this ongoing trial are presented. Methods: Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 58 patients were enrolled at 22 clinical sites in the US, Canada, and Europe. The median age was 52 years (range 14–76) and 57% were male. 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the ORR was 86% (50 of 58 patients) and the CR rate was 59% (34 of 58 patients). At the time of this analysis (datacut April 2012), all patients had discontinued treatment and the median observation time from first dose was 22.8 months (range, 0.8–32.2). The median duration of objective response for all patients was 13.2 months (range, 0.1–27.7+) and the median duration of response for patients who obtained a CR has not yet been met (range, 0.7–27.7+). Of the patients who achieved a CR, over half (18 of 34; 53%) were in continued remission at the time of this analysis. The median progression-free survival (PFS) for all patients was 14.6 months and the median overall survival has not yet been reached. After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The median PFS has not yet been met for the group of patients who achieved a CR and received a subsequent SCT (range, 8.1–29+), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 months (range, 2.6–26+). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity regardless of baseline disease characteristics, tumor burden, or prior treatment history. Median PFS did not appear to be influenced by ALK status; in the subgroup of ALK-positive patients (n=16) PFS was 14.6 months versus 14.3 months for ALK-negative patients (n=42). The median overall survival has not yet been met for either ALK-positive or ALK-negative patients. The most common (reported in ≥20% of patients) adverse events (AEs) observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined by a Standardised MedDRA Query; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in peripheral neuropathy has occurred in 79% of patients with neuropathy events (26 of 33 patients) and the median time to resolution or improvement was 13.4 weeks (range, 0.3–48.7). Conclusions: 34 of 58 patients (59%) with relapsed or refractory sALCL obtained a durable CR with brentuximab vedotin and treatment was associated with manageable toxicity. PFS did not appear to be influenced by ALK status. These long-term follow-up results underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is planned to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas. Disclosures: Pro: Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Real Life Experience of Brentuximab Vedotin Plus CHP As First-Line Treatment in CD30 + Peripheral T-Cell Lymphomas

Blood ◽

10.1182/blood-2021-149506 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4543-4543

Author(s):

Domingo Domenech Eva ◽

Juan-Manuel Sancho ◽

Eva González-Barca ◽

Nicholas Kelleher ◽

Marta Rodriguez-Luaces ◽

...

Keyword(s):

Peripheral Neuropathy ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Advisory Committees ◽

Variable Expression ◽

T Cell Lymphomas ◽

Peripheral T Cell Lymphomas

Abstract INTRODUCTION: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas classically treated with CHOP or CHOP-like regimens, with poor outcomes. CD30 is universally expressed and is pathognomonic in systemic anaplastic large cell lymphoma (sALCL), with variable expression among non-sALCL PTCL subtypes (40-60%). Recent data of frontline treatment with Brentuximab Vedotin (BV), an anti-CD30 monoclonal antibody, plus CHOP has demonstrated significant improvement in survival (ECHELON-2 clinical trial), becoming the new standard of care for sALCL in Europe. PATIENT AND METHODS: From February 2019 to April 2021, 21 patients with de novo newly diagnosed CD30+ PTCL have been treated with the combination of BV-CHP, in the centers of the Catalan Institute of Oncology in Spain. Survival curves were plotted by the Kaplan-Meier method. RESULTS: Clinical characteristics at diagnosis are shown in the table. Of interest, 5 of the 11 ALK negative ALCL patients were diagnosed of breast implant associated ALCL (BIA-ALCL) with extracapsular involvement. The number of cycles administrated were 108, with a median of 6 cycles per patient (range 1-6), all of them with G-CSF primary prophylaxis. At the time of this report, 1 patient was still on treatment and 2 patients without the final evaluation. Seven cycles (6%) were delayed (3 due to infection, 2 due to neutropenia grade 2, and 2 due to causes not related with chemotherapy).An adverse event was reported in 45 (44%) cycles, being the most frequent peripheral neuropathy in 14, nausea/vomiting in 9 and anemia in 8; all of them grade 1-2. Treatment was discontinued after 1 cycle in 1 patient due to progression. Of the 18 evaluable patients, the overall response rate (ORR) was of 83%, with 72% complete responses and 11% partial responses. Consolidative autologous stem cell transplant (ASCT) was performed in 5 patients. With a median follow-up of 14 months (limits: 1-24), 1-year progression-free survival (PFS) and overall survival (OS) was 68.2% (95% CI 44.6-91.7) and 82.2% (95% CI 63.9-100), respectively. CONCLUSIONS: Brentuximab Vedotin plus CHP is an effective regimen for CD30 positive PTCL, with a high rate of response. This combination presents a manageable safety profile, with the majority of patients completing the planned treatment. The incidence and severity of side effects are low, being peripheral neuropathy and neutropenia the most frequent. Figure 1 Figure 1. Disclosures Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. González-Barca: Janssen: Consultancy, Honoraria, Other: Travel; EUSA Pharma: Consultancy, Honoraria; Kyowa Kirin: Consultancy; Roche: Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau. Sureda: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Allogeneic Transplant Following Brentuximab Vedotin Treatment in Patients with Relapsed or Refractory CD30+ Lymphomas

Blood ◽

10.1182/blood.v118.21.3091.3091 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3091-3091 ◽

Cited By ~ 5

Author(s):

Tim Illidge ◽

Reda Bouabdallah ◽

Robert W. Chen ◽

Ajay K. Gopal ◽

Craig H. Moskowitz ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Objective Response ◽

Sensory Neuropathy ◽

Brentuximab Vedotin ◽

Peripheral Sensory Neuropathy ◽

Advisory Committees ◽

Peripheral Sensory

Abstract Abstract 3091 Background: Allogeneic stem cell transplant (allo-SCT) for relapsed or refractory lymphoma is often limited by the amount of residual tumor burden following cytoreductive therapy. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). In recent phase 2 trials, brentuximab vedotin induced objective responses in 75% of patients with Hodgkin lymphoma (HL) (Chen 2011) and 86% of patients with systemic ALCL (sALCL) (Pro 2011). Fifteen of 160 patients (9%) who participated in these two phase 2 studies received an allo-SCT as their first subsequent antitumor therapy after treatment with brentuximab vedotin. This case series describes the initial experience of these patients. Methods: Patients received 1.8 mg/kg brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Antitumor activity was based on objective response assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). After discontinuing brentuximab vedotin, patients were followed for survival/disease status and information regarding subsequent therapy, including allo-SCT, was collected. Results: Fifteen patients (7 with HL and 8 with sALCL) received an allo-SCT as their first subsequent antitumor therapy following brentuximab vedotin treatment. The median age was 28.0 years (range 17–61 years) and the majority (67%) were female. The median time since initial HL/sALCL diagnosis was 27.3 months (range 6.2–108 months). The median number of therapies patients had received prior to brentuximab vedotin was 3.0 (range 2–5) and 12 patients had previously received an autologous SCT. Patients received a median of 9.0 cycles (range 4–16) of brentuximab vedotin and all 15 patients achieved an objective response per independent radiological review; best response was CR for 12 patients (5 with HL and 7 with sALCL) and PR for 3 patients (2 with HL and 1 with sALCL). The median time to objective response was 1.4 months (range 1.2–2.6 months) and all 15 patients maintained an objective response at the time of the last assessment prior to allo-SCT. The median time between the last dose of brentuximab vedotin and the start of the SCT conditioning regimen was 1.4 months (range 0.6–3.3 months). Thirteen of the 15 patients (87%) are alive and remain in follow-up post allo-SCT. The median duration of follow-up from first dose of brentuximab vedotin is 16.9 months (range 8.2–21.1 months). Five patients (1 with HL and 4 with sALCL) have either progressed or died post-transplant. Four of these 5 patients had achieved a CR with brentuximab vedotin treatment. Of the 2 patients who died (both patients with sALCL who had achieved a CR with brentuximab vedotin treatment), one death was disease-related (not formally restaged) and the other was due to transplant-related complications. The median PFS at the time of this analysis is 21.1 months (range 8.2–21.1 months). Treatment-emergent adverse events that occurred prior to allo-SCT in >20% of patients were peripheral sensory neuropathy and pyrexia (53%; n=8), diarrhea and neutropenia (47%; n=7), nausea (33%; n=5), and chills and dyspnea (27%; n=4). Thirteen of 15 patients (87%) experienced AEs of ≥ Grade 3 prior to allo-SCT; the most common (reported in >10% of patients) were neutropenia (47%; n=7), anemia and thrombocytopenia (27%; n=4), and abdominal pain, pain, and peripheral sensory neuropathy (13%; n=2). Two patients discontinued brentuximab vedotin treatment due to an AE (peripheral sensory neuropathy) before subsequently receiving allo-SCT. Conclusions: Treatment with brentuximab vedotin provided cytoreduction in patients with relapsed or refractory HL and sALCL, many of whom had failed a prior autologous SCT. Thirteen of the 15 patients (87%) achieved an objective response with brentuximab vedotin treatment prior to allo-SCT and remain in follow-up at the time of this analysis. Ten of the 15 patients (67%) remain in remission. Our results suggest that brentuximab vedotin may be an option for reducing tumor burden to facilitate a consolidative allo-SCT and warrants further study. Disclosures: Illidge: Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Bouabdallah:Seattle Genetics, Inc.: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Spectrum: Research Funding; Piramal: Research Funding; Merck: Research Funding; Calistoga: Research Funding; Abbott: Research Funding; Pfizer: Research Funding; SBIO: Research Funding; Gilead: Research Funding; Genzyme: Speakers Bureau; Amgen: Speakers Bureau; Cellular Therapeutics Inc.: Speakers Bureau. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Plexxicon: Research Funding. Ramchandren:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Shustov:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria. Tilly:Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau. Trippett:Seattle Genetics, Inc.: Research Funding; OSI Pharmaceuticals: DSMB Chair. Grove:Seattle Genetics, Inc.: Employment; Seattle Genetics, Inc.: Equity Ownership. Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

Blood ◽

10.1182/blood.v122.21.848.848 ◽

2013 ◽

Vol 122 (21) ◽

pp. 848-848 ◽

Cited By ~ 22

Author(s):

Nancy L. Bartlett ◽

Jeff P. Sharman ◽

Yasuhiro Oki ◽

Ranjana H. Advani ◽

Celeste M. Bello ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Objective Response ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Board Membership

Abstract Background Brentuximab vedotin (ADCETRIS®) is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Variable CD30 expression has been demonstrated in several B-cell non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBL). Methods A phase 2, open-label, single-arm study is ongoing to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms (Clinical Trials.gov NCT01421667). CD30 expression is determined by immunohistochemistry per local laboratory; any level of CD30-positive expression is permitted for enrollment. Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Correlation between antitumor activity and quantitative CD30 expression is also being explored. This subset analysis presents interim data for patients with relapsed/refractory Bcell neoplasms. Results Sixty-two B-cell lymphoma patients with variable CD30 expression by central review (range 0–100%) have been enrolled to date. Diagnoses include DLBCL (n=44) and other B-cell neoplasms (n=18) [grey zone lymphoma (n=6), PMBL (n=6), follicular lymphoma (n=3), and post-transplant lymphoproliferative disorder (n=3)]. The median age of all patients was 55 years (range, 16–85 years), and the majority had an ECOG performance status of 0/1 (92%). Patients had received a median of 2 prior therapies (range, 1 to 19); 11 (18%) had received prior stem cell transplant. Forty patients (65%) had primary refractory disease, and 47 patients (76%) were refractory to their most recent prior therapy. Fourteen patients (23%) had never responded to any prior therapy. At the time of this analysis, patients had received a median of 3 cycles of treatment (range, 1–17 cycles), with a median duration of treatment of 10.5 weeks (range, 2.4 to 57.1 weeks). Twelve (19%) patients remain on treatment. Of the 43 efficacy evaluable DLBCL patients, 40% achieved an objective response [7 complete remission (CR), 10 partial remission (PR)]; the median duration of objective response was 36 weeks (range, 0.1+ to 62.3+ weeks). Of the 18 efficacy evaluable patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs). The median duration of objective response was 21.7 weeks (range, 6.1 to 37.1 weeks). CD30 expression levels for patients with a CR or PR were variable and ranged from <1% to 90%. There was no statistical correlation between CD30 expression and response rate. Treatment-emergent adverse events (AEs) occurring in >20% of patients included fatigue (40%), nausea and neutropenia (37% each), pyrexia (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), and anemia and constipation (21% each). Peripheral neuropathy events have been primarily Grade 1 or 2. Neutropenia (29%) was the only Grade 3/4 related AE observed in >10% of patients. AEs led to treatment discontinuation in 6 patients; the most common reason was peripheral sensory neuropathy (2 patients). Conclusions In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin. Forty percent of DLBCL patients achieved an objective response, with median remission duration of >8 months and a notable proportion of complete remissions. No correlation between CD30 expression and response rate has been observed to date. Safety data are consistent with the profile of brentuximab vedotin. This study continues to enroll patients and updated results will be presented at the meeting. Disclosures: Bartlett: Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Advani:Millennium: Advisory/scientific board membership, Advisory/scientific board membership Other, Research Funding; Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding; Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pharmacyclics, Inc.: Research Funding; Janssen R&D: Research Funding; Allos Therapeutics: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbott: Research Funding. Bello:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Spectrum pharmaceuticals: Speakers Bureau. Winter:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Jacobsen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding.

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Brentuximab Vedotin in Front-Line Therapy of Hodgkin Lymphoma (HL) and CD30-Expressing Peripheral T-Cell Lymphoma (PTCL) in Adults Age 60 and Above

Blood ◽

10.1182/blood-2019-122968 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2852-2852

Author(s):

Christopher A. Yasenchak ◽

Rodolfo Bordoni ◽

Victor Yazbeck ◽

Dipti Patel-Donnelly ◽

Timothy Larson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Objective Response ◽

Brentuximab Vedotin ◽

Front Line ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Frontline Treatment ◽

Treatment Naïve

Background Despite the advances in therapy of classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL) over the years, the outcomes seen in younger patients with the disease have not been attained in patients ≥60 years of age. Studies cite 5-year progression-free survival (PFS) and freedom from treatment failure rates of 30%-45% in older patients with HL, as compared to rates of 75%-80% expected in younger patients (Evens 2008; Proctor 2009). In a recent retrospective study of patients >60 years of age diagnosed with PTCL between 2008-2014, a multivariate analysis demonstrated that a Charlson Comorbidity Index (CCI) ≥2 and high IPI score (3-5) were independent risk factors for worse overall survival (OS) and PFS (Zhao 2016). Similarly, multivariate analysis of registry data from Sweden shows that a CCI ≥2, when adjusted for age, is independently associated with worse OS and PFS outcomes (Ellin 2018). There is no standard treatment regimen for elderly patients with cHL and PTCL, and co-morbidities including depressed cardiac and renal function limit the ability to use combination chemotherapy, and represent a high unmet need. Brentuximab vedotin (BV, ADCETRIS®) is a CD30-directed antibody-drug conjugate (ADC) consisting of the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. Following the binding of BV to CD30-expressing cells, the ADC-CD30 complex is internalized, and MMAE released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. Single-agent BV has demonstrated robust activity in patients with HL refractory to several lines of chemotherapy and the ECHELON-1 study (Connors 2017) established its efficacy in combination with chemotherapy for the front line treatment of HL. In a phase 2 study of single-agent BV in 27 patients aged ≥ 60 years with HL, there was an objective response rate of 92%, with 73% achieving complete remission (Forero-Torres, 2015). For CD30-expressing PTCL, single-agent BV is an active and well-tolerated treatment for patients with relapsed or refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the addition of BV to combination chemotherapy in the frontline treatment improves both PFS and OS (Horwitz 2018). In the elderly patient populations who are not candidates for multi-agent chemotherapy, frontline treatment with single-agent BV may have the potential to be an active and well-tolerated treatment. Study Design Two additional cohorts have been added to the SGN35-015 phase 2 open-label study (NCT01716806) to evaluate the efficacy and tolerability of BV as monotherapy in treatment-naive patients with cHL, which excludes nodular lymphocyte-predominant HL (Part E) or treatment-naive patients with CD30-expressing PTCL (Part F). The primary objective of these cohorts is to assess objective response rates of single-agent BV as frontline therapy in patients ≥60 years of age and ineligible for conventional chemotherapy for HL (Part E) or CD30-expressing PTCL (Part F). Eligible patients in Parts E and F must be ≥75 years or ≥60 years of age and have one of the following: confirmed ejection fraction <45% or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2, as determined by the Modification of Diet in Renal Disease study equation. Approximately 30 evaluable patients will be enrolled in Parts E and F of the study and administered BV 1.8 mg/kg as a single intravenous infusion on Day 1 of each 21-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Treatment response will be assessed by spiral CT scans of the chest, abdomen, and pelvis and PET scans at Cycles 2, 6, and 11. Response assessment will be determined by blinded independent central review. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Phillips & Gilmore: Honoraria; Genentech: Speakers Bureau; Merck: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Mei:Seattle Genetics, Inc.: Research Funding.

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Retrospective Analysis of the Safety and Efficacy of Brentuximab Vedotin in Patients Aged 60 Years or Older with Relapsed or Refractory CD30+ Hematologic Malignancies

Blood ◽

10.1182/blood.v120.21.3687.3687 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3687-3687 ◽

Cited By ~ 2

Author(s):

Michelle A. Fanale ◽

Nancy L. Bartlett ◽

Andres Forero-Torres ◽

Anas Younes ◽

Robert W. Chen ◽

...

Keyword(s):

Antitumor Activity ◽

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Sensory Neuropathy ◽

Hematologic Malignancies ◽

Brentuximab Vedotin ◽

Phase 2 ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 3687 Background Patients ≥60 years of age comprise a significant portion of the population with hematologic malignancies. In addition, advanced age is a known negative prognostic indicator in many cancers including CD30+ malignancies such as Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL). Novel treatments with significant antitumor activity and increased tolerability are needed in this patient population that is often underrepresented in clinical trials. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) comprised of the microtubule-disrupting agent monomethyl auristatin E (MMAE) conjugated to an antibody that binds human CD30. This ADC has been studied in 2 phase 2 single-arm studies of patients aged ≥12 years with relapsed or refractory CD30+ lymphomas (median age 36.5, 13% ≥60). Brentuximab vedotin (1.8 mg/kg) administered once per 3-week cycle demonstrated objective response rates (ORRs) of 75% and 86% and complete remission (CR) rates of 34% and 57%, in HL and sALCL patients respectively. These objective responses were durable with a median duration of 6.7 and 13.0 months, respectively. The 3 most common adverse events (AEs) in HL and sALCL patients were peripheral sensory neuropathy (42% HL, 41% sALCL), nausea (35% HL, 40% sALCL), and fatigue (34% HL, 38% sALCL). Grade ≥3 neutropenia was observed in 20% of HL patients and 21% of sALCL patients. Methods This study presents a retrospective analysis of a subset of 40 patients aged 60 years or older with relapsed or refractory CD30+ lymphomas who received brentuximab vedotin in 1 or more of 7 clinical studies. Patients enrolled in the hepatic/renal impairment arm of a brentuximab vedotin pharmacokinetics study were excluded. The dosing schedule was either weekly (range 0.6–1.0 mg/kg) or every 3 weeks (range 1.2–2.7 mg/kg) with most patients receiving 1.8 mg/kg IV every 3 weeks. Antitumor activity was assessed by best response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). AEs were continually monitored in all studies from the start of dosing to 30 days after the last dose. Results The median age of patients was 66 years (range 60–82). There were 22 sALCL patients and 15 HL patients (median age 66.5 and 68.0 years, respectively) in the analysis set. Three patients (8%) were diagnosed with other CD30+ lymphomas and had a median age of 62.0 years. The majority of patients were male (65%). Patients had received a median of 2.0 prior cancer-related systemic therapies (range 1–6) and 34 of 40 had received a prior stem cell transplant. Baseline B symptoms were reported in 8 patients (20%). Patients received a median of 7.5 cycles (range 1–22) of single-agent brentuximab vedotin treatment with a median dose intensity of 0.56 mg/kg/week (range 0.3–0.9). All sALCL patients and 53% of HL patients achieved an objective response (CR rate, 50% and 40%, respectively). Across diagnoses, the ORR was 78% with 43% of patients achieving a CR. The median duration of response was 13.0 months for sALCL patients and was not reached in HL patients at the time of analysis. Resolution of B symptoms was observed in half of the patients (4 of 8) who presented with baseline B symptoms. Treatment-emergent AEs of any grade (incidence ≥30%) included fatigue (58%), peripheral sensory neuropathy (58%), and nausea (38%). Treatment-emergent AEs ≥ Grade 3 in severity (incidence ≥20%) included neutropenia (25%) and anemia (20%). Serious adverse events (SAEs) were reported in 53% of patients with the most common (≥10%) being mental status changes (10%). AEs leading to treatment discontinuation occurred in 30% of patients. Death occurred within 30 days of the last dose in 1 patient with the cause of death considered unrelated to brentuximab vedotin or disease. Overall, 30% of patients received growth-factor support. Conclusions Brentuximab vedotin showed substantial antitumor activity and evidence of B-symptom resolution in these patients ≥60 years of age. Antitumor activity and the durability of clinical responses were consistent with those observed in the phase 2 studies of patients aged ≥12 years. AEs of fatigue and sensory neuropathy were more frequent in the older population, while other AEs such as nausea and neutropenia occurred with a similar incidence as in the phase 2 studies. Future studies will explore the safety and efficacy of brentuximab vedotin in earlier lines of therapy for this underserved population. Disclosures: Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Friedberg:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Zain:Seattle Genetics, Inc.: Honoraria, Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽

10.1182/blood-2019-122775 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4739-4739

Author(s):

Pieter Sonneveld ◽

Maria-Victoria Mateos ◽

Adrián Alegre ◽

Thierry Facon ◽

Cyrille Hulin ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Research Funding ◽

Indirect Comparison ◽

Employment Equity ◽

Advisory Committees ◽

Post Transplant ◽

Post Induction ◽

Adjusted Indirect Comparison ◽

Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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