Sims, Robert B.

Abstract Background The majority of patients with relapsed/refractory (R/R) DLBCL who relapse after hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy, or who are not candidates for HSCT or CAR-T, have poor outcomes and need novel therapies (Crump 2017). Brentuximab vedotin (BV) was the first antibody-drug conjugate to be approved in multiple cancer types (Gauzy-Lazo 2020). The combination of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent monomethyl auristatin E drives the anticancer activity of BV by inducing cell cycle arrest and apoptosis (Sutherland 2006). Lenalidomide may enhance the activity of BV through immune-mediated mechanisms. In a phase 1 trial (NCT02086604) in which 37 patients with R/R DLBCL were treated with BV + lenalidomide, the objective response rate (ORR) was 56.7% (73.3% in CD30+ patients). The median duration of remission was 13.2 months in patients with a complete response (CR) or partial response (PR) and 11.7 months in patients with a CR, PR, or stable disease (SD) >6 months. The median progression-free survival (PFS) and overall survival (OS) were 10.2 months and 14.3 months, respectively, and results were similar in the CD30+ and CD30 <1% groups (manuscript submitted). The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents provide a strong rationale for this combination in multiple relapsed and heavily pretreated patients with R/R DLBCL. Study Design and Methods ECHELON-3 (NCT04404283) is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV versus placebo, in combination with lenalidomide and rituximab, in patients with R/R DLBCL. Key eligibility criteria will include patients ≥18 years of age with R/R DLBCL with an eligible subtype, ≥2 prior lines of systemic therapy and ineligible for stem cell transplant or CAR-T therapy, Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose-avid disease by positron emission tomography (PET), and bidimensional measurable disease of at least 1.5 cm by computed tomography (CT). Patients with a history of another malignancy within the past 2 years, any uncontrolled Grade ≥3 infection, Grade ≥2 peripheral neuropathy, or previous exposure to BV or lenalidomide will not be eligible. After completing the safety run-in period, patients (n=400) will be randomized 1:1 to receive either BV (1.2 mg/kg intravenously every 3 weeks [Q3W]) or placebo (intravenously Q3W) in combination with lenalidomide (20 mg orally daily) and rituximab (1400 mg subcutaneously Q3W from Cycle 2, with 375 mg/m 2 intravenously on Cycle 1 Day 1). Treatment may continue while there is clinical benefit (SD or better) without progression or unacceptable toxicity. Patients will be stratified by CD30 expression (≥1% [positive] vs <1% [negative]), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (germinal center B-cell [GCB] or non-GCB). The dual primary endpoints are PFS per blinded independent central review (BICR) in the intention-to-treat (ITT) and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of objective response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014). Radiographic disease evaluations, including contrast-enhanced CT and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks thereafter. PET is not required after CR is achieved For the analyses of PFS per BICR, the stratified log-rank test will be used to compare PFS between the 2 treatment groups. Hazard ratios will be estimated using the stratified Cox regression model. PFS will also be summarized using the Kaplan-Meier method. Similar methods will be used to estimate OS and other time-to-event efficacy endpoints. The study is currently enrolling and will be open in 16 countries. Disclosures Bartlett: Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Harwin: Sarah Cannon Research Institute: Other: Grants, Research Funding. Sims: Seagen Inc.: Current Employment. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding.

TPS7571 Background: The majority of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Brentuximab vedotin (BV) is a CD30-directed ADC and preclinical data provide a strong rationale for combining BV, lenalidomide, and rituximab in the treatment of R/R DLBCL. In addition, in a phase 1 trial in which 37 pts with R/R DLBCL were treated with BV + lenalidomide, the ORR was 56.7% (73.3% in CD30+ pts; manuscript in preparation). The median duration of remission was 13.2 months in pts with a CR or PR and 11.7 months in pts with CR, PR, or stable disease > 6 months. The PFS and median OS were 11.2 months and 14.3 months, respectively and results were similar in the CD30+ and CD30 < 1% groups. The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents, make the combination a viable option in multiply relapsed and heavily pretreated pts. Methods: This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV vs placebo, in combination with lenalidomide + rituximab, in subjects with R/R DLBCL (NCT04404283). Prior to randomization, there will be a safety and PK run-in period where 6 pts will receive BV, lenalidomide + rituximab, and safety and PK will be evaluated after the first cycle of treatment; 6/6 subjects have been enrolled. Key eligibility criteria include: pts aged ≥18 with R/R DLBCL with an eligible subtype; ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; ECOG 0 to 2; fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT. Patients (n = 400) will be randomized 1:1 to receive either BV or placebo in combination with lenalidomide + rituximab and will be stratified by CD30 expression (positive [ ≥1%] versus < 1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (GCB or non-GCB). The primary endpoints are PFS per BICR in the ITT and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks. PET is not required after CR is achieved. The trial is currently enrolling and will be open in 16 countries. Clinical trial information: NCT04404283.

Background Majority of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Preclinical data provides a strong rationale for combining brentuximab vedotin, lenalidomide, and rituximab in the treatment of R/R DLBCL. In a phase 1 trial, 37 subjects with R/R DLBCL were treated with brentuximab vedotin in combination with lenalidomide. The objective response rate (ORR) (proportion of subjects with complete response [CR] or partial response [PR]) for all subjects was 56.7% (21 of 37 subjects). For the CD30-positive population, the ORR was 73.3% (11 of 15 subjects), whereas the ORR for the CD30 &lt;1% population was 45.6% (10/22). The median follow-up time was 14.3 months (range: 1 to 56.7 months). The median duration of remission for subjects with CR or PR was 13.2 months (range: 3.2 to 55.2 months). For subjects with CR, PR, or stable disease (SD) &gt;6 months, the median duration of remission was 11.70 months (range: 3.2 to 55.2 months). The progression-free survival (PFS) and overall survival (OS) results appear similar in both the CD30-positive and CD30 &lt;1% groups. The PFS in the combined population is 10.2 months and the median OS is 14.2 months (manuscript in preparation). Study Design and Methods This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of brentuximab vedotin in combination with lenalidomide and rituximab versus placebo in combination with lenalidomide and rituximab for the treatment of subjects with R/R DLBCL (NCT04404283). Key eligibility criteria include the following: subjects aged 18 and older with R/R DLBCL with an eligible subtype; subjects must have ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; subjects must have an ECOG performance status score of 0 to 2; subjects must have a fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT, as assessed by the site radiologist. Subjects (n=400) will be randomized 1:1 to receive either brentuximab vedotin or placebo in combination with lenalidomide and rituximab and will be stratified by CD30 expression (positive [≥1%] versus &lt;1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (germinal-center B-cell-like (GCB) or non-GCB). Cell of origin (GCB or non-GCB) will be histologically determined by local pathology assessment. Disease response will be assessed by a blinded independent central review (BICR) and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET/CT, will be assessed at baseline, then every 6 weeks from randomization for 12 months, then every 12 weeks (±3 days). PET/CTs will be discontinued if negative. For the primary efficacy analyses of PFS per BICR in the intent-to-treat population and in CD30-positive subjects, the stratified log-rank test will be used to compare PFS between the 2 treatment groups. The hazard ratio will be estimated using a stratified Cox regression model. PFS will also be summarized using the Kaplan-Meier method. Similar methods will be used for the secondary efficacy endpoint of OS, and other time-to-event efficacy endpoints. The trial will have sites open in the US and multiple countries in Europe and Asia, with enrollment planning to begin in the second half of 2020. Disclosures Bartlett: Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding. Yasenchak:Takeda: Honoraria; BeiGene: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Nowakowski:Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding.

Abstract Abstract 636 Cellular vaccine may offer additional benefit as consolidative therapy after autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously from two phase II studies the survival of MM patients who received APC8020 (autologous antigen presenting cell vaccine) after ASCT (Lacy, AJH '09, (84): 799; Lin, ASH annual meeting 2010, abstract 1958). To determine if there was an outcome advantage for additional consolidative vaccine therapy after ASCT, we performed this matched case control analysis comparing the survival of patients who received ASCT only (control) at Mayo Clinic to those who received APC8020 after ASCT in the same time period. Forty-three study patients accrued between July 1998 and March 2002 were eligible for matching. To reduce bias from disease risks and transplant-related mortality, control patients were required to be alive and progression free six months after transplant and have a M-spike value of < 2g/dL at 4 mos (1st study) or 9 mos (2nd study) after transplant, similar to post-ASCT patients who were enrolled in the two APC8020 studies. A total of 111 control patients were eligible for matching. Control patients were matched to study patients by age (+/− 5 yrs), ISS (International Staging System) stage, and plasma cell labeling index (PLCI, either >= 3 or < 3). A matched control was not identified for one study patient. Of the remaining 42 study patients, all had at least one matched control patient. Thirty-two patients had 2 matched controls. Cox proportional hazards analysis showed that there was no statistically significant difference in time to progression between the study and control patients (HR 1.54, 95% CI 0.92 – 2.58, p = 0.1). However the overall survival is significantly improved among the study patients (HR 0.54, 95% CI 0.30 – 0.99, p = 0.05). This analysis is the only known report of long-term follow-up of the largest group of MM patients treated with APC8020 vaccine. While many current prognostic tests were not available at the time of the initial vaccine studies, the control patients in this analysis were matched by known disease risks that are still in use today. The survival advantage in study patients remained statistically significant compared to matched controls. Interestingly, the time to progression is unchanged between study and control patients. This is similar to other reports of vaccine therapy such as in sipuleucel-T (Provenge™) in prostate cancer where an overall survival benefit is seen without change in progression-free survival. A larger, randomized phase III study is needed to confirm the encouraging survival benefit of this treatment modality in MM. Further insight into the mechanisms of action of APC8020 is needed to improve our understanding of the role of this therapy in the context of current practice of MM maintenance therapies. Disclosures: Sims: Dendreon Corporation: Employment.

AbstractPurpose: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu–expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor.Experimental Design: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment.Results: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-γ enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting &gt;48 weeks.Conclusions: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu–expressing breast, ovarian, and colorectal cancer are warranted. (Clin Cancer Res 2009;15(18):5937–44)