Moskowitz, Craig H.

Abstract Introduction This phase 1/2 study evaluated the safety and antitumor activity of brentuximab vedotin (BV) administered in combination with nivolumab (Nivo) in adult patients (pts) with relapsed/refractory classic Hodgkin lymphoma (R/R cHL) who have failed frontline therapy (NCT02572167). Results from Parts 1 & 2 have been previously reported, wherein safety, efficacy, and biomarkers consistent with immune activation were observed in pts with R/R cHL (Herrera et al., Blood 2018). In Part 3, patients were treated with BV + Nivo on Day 1 of each cycle. In contrast, pts in Parts 1 & 2 received BV on C1D1 and Nivo on C1D8 with concurrent admin on subsequent cycles. Herein we present safety, efficacy, and biomarker results for Part 3 and updated progression free survival (PFS) from Parts 1 & 2. Methods Pts in Parts 1 & 2 received up to four 21-day cycles of staggered dosing (day 1 BV 1.8 mg/kg, day 8 Nivo 3 mg/kg in Cycle 1) and concurrent thereafter, with steroid and antihistamine premedication. Pts in Part 3 received up to four 21-day cycles of concurrent BV + Nivo on Day 1 with antihistamine premedication. Following Cycle 4 response assessment (Lugano Classification Revised Staging System with the incorporation of the Lymphoma Response to Immunomodulatory Therapy Criteria [LYRIC, 2016]) responding pts were eligible to undergo autologous stem cell transplant (ASCT). Results 30 pts were treated in Part 3 and all were evaluable for efficacy. Pt characteristics included the following: median age 31.5 yrs (range; 20 - 66), 63% female, 93% prior ABVD, 37% primary refractory HL, 30% relapsed within 1year of frontline therapy, 30% with extranodal disease and 17% with bulky disease at enrollment. 28 pts completed all 4 cycles. 1 pt discontinued treatment (tx) due to an adverse event (AE; Grade 3 [G3] elevated Gamma-Glutamyltransferase) and 1 pt due to progressive disease (PD). The latter pt eventually died due to PD. All pts are off tx and have been observed through the safety reporting period. 37% of pts experienced a G3 or higher tx emergent AE prior to ASCT. 30% of the pts experienced infusion related reactions (IRRs), which occurred most frequently during Cycle 2. Potential G3 or higher immune-related AEs (IRAEs), excluding IRRs, occurred in 2 pts, one of whom required steroids for G4 pneumonitis, which subsequently resolved. Among the 30 efficacy evaluable pts, the complete response (CR) rate was 80% (24/30), with an objective response rate (ORR) of 93%. 47% of pts (14) had a Deauville ≤2, and 17% (5) had Deauville 3. 5 pts with CR had a Deauville >3 and met LYRIC criteria for IR-2. 4/5 pts had a negative follow-up biopsy that confirmed CR and in 1 pt the PET finding was considered to be a false positive as contrast enhanced CT did not reveal any abnormality. All 5 pts proceeded directly to ASCT and remain in CR at follow-up. Among all treated patients, 25 went directly to ASCT after completing BV + Nivo tx with a median 6.8 x 106 CD34+ cells/kg (range 1-20) collected. Median times to neutrophil and platelet engraftment were 12 and 14 days, respectively. 4 pts required additional salvage therapy subsequent to study tx. Patients were followed for a median of 6 months from ASCT (N=25, range 0.8-8.8) and 10 months from first dose (N=30, range 1.8-12.7). The estimated 9-month PFS rate in all-treated pts was 88%. This is comparable to all-treated pts in Parts 1 & 2, whose estimated 9 and 15 month PFS were 86% and 82%, respectively (Fig 2). Biomarker testing was performed on peripheral blood samples, included immunophenotyping, serum cytokine analysis, and TCRβ sequencing. Concurrent dosing of BV+ Nivo resulted in increased levels of both activated and dividing CD4+ and CD8+ T cells, as well as increased regulatory T-cells and circulating plasmablasts. Cytokines and chemokines associated with innate and adaptive immune activation, including Type I and Type II interferons, IL-18, and IP-10, were significantly upregulated following BV + Nivo, while TARC levels were significantly diminished following therapy. TCRβ sequencing revealed clonal expansion in the periphery following BV + Nivo. Conclusion A concurrent dosing schedule of BV + Nivo was well tolerated with a high CR rate of 80%. Biomarkers evaluated in Part 3 indicate immune activation in the periphery following BV + Nivo. Cumulatively, the results in Part 3, along with the durable remissions noted in Parts 1 & 2, support BV + Nivo combination as an encouraging first salvage therapy prior to ASCT in pts with R/R cHL. Disclosures Advani: Forty Seven: Research Funding; Infinity: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Agensys: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Merck: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vose:Celgene: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Incyte Corp.: Research Funding; Roche: Honoraria; Novartis: Honoraria, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta Pharma: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Feldman:Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Portola: Research Funding; Janssen: Speakers Bureau; KITE: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Christian:Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:LAM Therapeutics: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Takeda: Research Funding. Moskowitz:Celgene: Consultancy; Merck & Co: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Ogden:Seattle Genetics, Inc: Employment, Equity Ownership. Taft:Seattle Genetics: Employment, Equity Ownership. Zak:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Galderisi:Seattle Genetics: Employment, Equity Ownership. Herrera:Immune Design: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding.

Abstract Abstract 586 Background: Dacetuzumab (SGN-40), a humanized monoclonal antibody that targets CD40, mediates antitumor activity through multiple mechanisms of action, including effector cell functions (ADCC/ADCP) and direct apoptotic signal transduction. Ongoing evaluation of the molecule has led to 2 additional key findings: a gene signature that predicts sensitivity to single-agent dacetuzumab, and upregulation of the pro-apoptotic and chemosensitizing transcription factor TAp63αa when dacetuzumab is combined with rituximab (R) and gemcitabine (GEM). In prior single-agent dacetuzumab trials, several patients who were immediately treated with GEM after progressing achieved unexpected responses. These observations provided rationale for further analysis of the combination of dacetuzumab, R and GEM. Methods: A phase 1b dose-escalation study to evaluate the safety and adverse event profile of dacetuzumab, R and GEM was conducted in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at cohort-specific doses of 8 or 12 mg/kg IV weekly in combination with R (375 mg/m2 IV for 1 cycle, then once/28-day cycle) and GEM (1000 mg/m2 IV weekly or biweekly) in a 3 + 3 dose-escalation scheme. A maximum number of 8 cycles was permitted. Eligible patients included those with de novo DLBCL, including transformed lymphoma and follicular grade 3, who failed potentially curative therapy. Results: Thirty-one patients with a median age of 68 years (range 29–80) were enrolled and treated in the study (3 patients in each of 3 cohorts + 22 in an expansion cohort). The median number of prior regimens was 3 (range 1–18); 10 patients (32%) had transformed histology and 4 (13%) had prior ASCT. The median number of cycles received was 3 (range 1–8), although 11 patients are still on treatment. Three patients in the first cohort required dose reduction of GEM due to transient, non-dose-limiting thrombocytopenia. The protocol was thus amended to administer GEM on a biweekly schedule. No dose-limiting toxicity was observed, and MTD was not defined. Based on pharmacokinetic modeling suggesting no significant difference in exposure between dose levels, 8 mg/kg of dacetuzumab was chosen as the dose for the expansion cohort. The combination of dacetuzumab, R and GEM was generally well tolerated. Across all cohorts, the most common adverse events (> 15%) were nausea (42%), thrombocytopenia (35%), fatigue (32%), headache (29%), anorexia (19%), dyspnea (19%), pyrexia (19%), diarrhea (16%), and neutropenia (16%), the majority of which were Grade 1 or 2. Grade 3/4 adverse events related to dacetuzumab occurred infrequently. One patient experienced Grade 3 stress cardiomyopathy that resolved; this patient had a history of congestive heart failure. One patient developed pneumonitis in the left lung and acute respiratory distress syndrome, and subsequently died due to pulmonary toxicity; this patient had received prior radiation therapy to the left chest. There was preliminary evidence of antitumor activity. Of the 28 patients with response assessments, 7 patients achieved CR, 8 PR, 7 SD, and 6 PD per investigator assessment of response, yielding an objective response rate of 54%. Of interest, 1 patient who previously failed ASCT achieved a CR and was able to undergo allogeneic transplant. To date, this patient remains in CR. Conclusion: The combination of dacetuzumab, R and biweekly GEM was generally well tolerated. Evidence of antitumor activity with this combination is encouraging as multiple responses were observed in a population with heavily pre-treated patients. Further investigation with a randomized trial is warranted to more fully characterize safety and efficacy and to determine if sensitivity to this combination correlates with the previously identified single-agent predictive gene signature. Disclosures: Forero-Torres: Seattle Genetics, Inc.: Research Funding. Off Label Use: Gemcitabine has not been FDA approved for treatment of lymphoma. Dacetuzumab is an investigational agent.. Bartlett:Seattle Genetics, Inc.: Research Funding. Nasta:Seattle Genetics, Inc.: Research Funding; Genentech: Speakers Bureau. Northfelt:Seattle Genetics, Inc.: Research Funding. Beaven:Seattle Genetics, Inc.: Research Funding. Myint:Seattle Genetics, Inc.: Research Funding. Whiting:Seattle Genetics, Inc.: Employment, Equity Ownership. Drachman:Seattle Genetics, Inc.: Employment, Equity Ownership. Moskowitz:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 1638 Introduction: Hodgkin lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most of the patients can be cured with modern treatment strategies. However, about 20% of patients still die due to relapse or progressive disease. Recently, elevated numbers of tumor-associated macrophages in diagnostic pretreatment and relapse biopsies have been associated with poor long-term outcomes. Furthermore, high expression of CSF1R on the malignant Hodgkin Reed Sternberg cells has been linked to shorter progression-free survival, providing the rationale to test PLX3397, a highly selective inhibitor of CSF1R (also known as Fms) and Kit receptor tyrosine kinases, in HL patients. Patients and Methods: Patients with relapsed or refractory HL were enrolled in this single-agent multicenter trial. All patients had progressed after or were ineligible for autologous stem cell transplantation, had radiographically measurable disease, and had discontinued all previous HL therapy. Patients were treated with oral PLX3397 at a dose of 900 mg/day continuously until occurrence of unacceptable toxicity or disease progression. The primary endpoint was the objective response rate according to the 2007 consensus criteria. Results: A total of 20 patients were enrolled (9 male, 11 female, median age 36 years). Six patients had tumor reduction ranging between 3% and 54% including one partial remission (overall response rate of 5%) (Figure). The median duration of progression-free survival was 56 days. The most common drug-related adverse effects were asthenia, fatigue, hair depigmentation, anemia, leukopenia, and increased LDH, all of which were grade 1 or 2 except for one grade 3 neutropenia. CD14dim/16+ labeled peripheral blood monocytes were markedly reduced in all patients at 4 weeks vs. Baseline (median=83% reduction, range of 44%-96% reduction), confirming inhibition of CSF1R signaling. Increases were observed for adiponectin in 82% of patients (median=2.6-fold, range 1.2 to 12-fold) and for CSF-1 in 94% of patients (median=4.0-fold, range 1.4 to 16.5-fold), also consistent with CSF1R inhibition. Archival formalin-fixed paraffin-embedded lymphoma tissues of sufficient quality were available for 12 patients. Biopsy material was obtained from either initial diagnosis or after relapse. CD68+ and CD163+ macrophages were highly elevated (>25% cellularity) in 42% and 58% of patients, respectively. The number of tumor-associated macrophages was not significantly associated with a reduction in lesion size after PLX3397 treatment in this small study cohort. Discussion: In this phase 2 clinical trial, PLX3397 at a dose of 900 mg/day showed limited activity in this heavily pretreated patient cohort. However, target inhibition of both Fms and Kit was clearly demonstrated. Although the efficacy of single agent PLX3397 in this study population was modest, the manageable safety profile and evidence of target inhibition may warrant further testing in combination therapy trials. Disclosures: 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. Gascoyne:Plexxikon Inc.: Consultancy, Research Funding. West:Plexxikon Inc.: Employment. Nolop:Plexxikon Inc.: Employment. Steidl:Plexxikon Inc.: Research Funding.

Abstract Abstract 3701 Background: Salvage chemotherapy and autologous stem cell transplantation (ASCT) in the management of relapsed or refractory Hodgkin's lymphoma (HL) results in prolonged disease-free survival in only around 50% of patients (pts). Median survival following relapse from ASCT is estimated at 2.4 years, with poor outcomes in those experiencing relapse or progressive disease within one year from ASCT (Horning 2008 et al). Recently, a pivotal multicenter Phase 2 trial investigated the efficacy of brentuximab vedotin (BV) in pts with recurrent HL following ASCT. The study demonstrated an overall response rate of 75% and median duration of response of 6.7 months. Furthermore, 34% of patients achieved a complete response (CR), with a median progression free survival of 29 months (mos). Whether treatment with BV renders an OS benefit in pts with relapsed or refractory disease after ASCT remains to be determined. Objective: 1) To compare OS in pts with relapsed HL after receiving ASCT in a cohort of 102 HL pts treated with BV, with 756 pts from 6 international centers before the introduction of BV. 2) To evaluate predictors of durable CR in pts treated with BV. Methods: Kaplan-Meier method was used to depict time-to-event outcomes, including OS. The Chi-square test was used to evaluate the association between two categorical variables and log-rank test to compare time-to-event endpoints among pt groups. Based on the univariate proportional hazard model, we examined whether certain variables (sex, stage at diagnosis, number of prior treatments, and time to CR) were predictors of CR duration in pts receiving BV. Results: In the non-randomized comparison between those with relapsed-refractory HL following ASCT who received BV and those who did not, pts were well matched by age, with a relatively higher percentage of females treated on the pivotal study. Dates of progression from ASCT ranged from 1996–2009 in the BV group and 1981–2003 in the international cohort. Median follow-up after ASCT for the censored observations of pts who received BV and those in the international cohort was 49.4 and 58.8 mos. The difference in median OS was statistically significant (p<0.0001) between those receiving BV and those not exposed to the drug (91.49 vs. 27.99 mos). Improvement in OS was irrespective of time to relapse from ASCT, despite previous studies noting a higher risk of recurrence in pts relapsing within 12 mos of ASCT (Sureda 2005 et al). Neither age nor sex was found to impact OS. In the subgroup analysis of pts achieving a CR with BV, univariate analysis of duration of CR and PFS uncovered no significant factors, while only stage of disease at initial diagnosis had a significant effect on OS (P=0.0004). Disease status characterized as relapsed vs. refractory had borderline significance with a positive impact on OS (P=0.0581). No significant associations were noted between the variables and duration of response post BV stratified into periods of less or greater than 12 mos. However, among those pts who experienced a duration of CR greater than 12 mos, 81.8% (n=18) had an initial CR after receiving ≤ 4 doses of BV, compared with 58.3% entering CR after receiving > 4 doses. Conclusions: While the impact of BV on OS can only be determined through a randomized clinical trial, our analysis indicated that treatment with BV in pts with relapsed/refractory HL following ASCT is associated with prolonged OS when compared with historical control patients. Those who achieve a rapid CR with BV may also have a longer duration of response. A randomized clinical trial is ongoing to evaluate prospectively the efficacy of BV following ASCT. Disclosures: Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene: Consultancy. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ramchandren:Seattle Genetics, Inc.: Speakers Bureau. Forero-Torres:Seattle Genetics: Research Funding. Moskowitz:Seattle Genetics: Speakers Bureau. Connors:Seattle Genetics, Inc.: Research Funding. de Vos:Seattle Genetics: Speakers Bureau. Engert:Takeda: Honoraria, Research Funding; Millennium: Honoraria, Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Morschhauser:Takeda: Honoraria. Younes:Seattle Genetics: Honoraria.

AbstractThe investigators present results on the long-term value and limitations of early interim positron emission tomography (PET) scanning in advanced Hodgkin lymphoma.

Key Points BV and Nivo were well-tolerated in patients with R/R HL, with less than 10% of patients treated with systemic steroids for immune-related AEs. The complete response rate was 61% (82% objective response rate), and patients were able to undergo stem cell transplant without adverse impact.

Purpose Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. Patients and Methods In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. Results The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Conclusion The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.