Citations

7540 Background: Tafasitamab is a humanized, Fc-modified anti-CD19 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity and phagocytosis. It is FDA-approved with LEN for adult patients (pts) with relapsed/refractory (R/R) DLBCL ineligible for autologous stem cell transplantation. First-MIND (NCT04134936) is a Phase Ib, open-label, randomized study of tafa + R-CHOP or tafa + LEN + R-CHOP in newly diagnosed DLBCL. Methods: Eligible pts were ≥18 years, treatment-naïve, with histologically confirmed DLBCL not otherwise specified, international prognostic index (IPI) 2–5 and ECOG performance status (PS) 0–2. Pts with known double- or triple-hit and transformed lymphoma were excluded. Treatment (Tx) comprised six 21-day cycles of tafa (12 mg/kg IV, Day [D] 1, 8, 15) + R-CHOP (arm A) or tafa (12 mg/kg IV, D1, 8, 15) + LEN (25 mg orally, D1–10) + R-CHOP (arm B). G-CSF and VTE prophylaxis was mandatory. Primary objective is safety; secondary objectives are ORR, PET-CR rate at end of Tx, PFS, long-term safety, pharmacokinetics, immunogenicity. Results: From Dec 2019 to Aug 2020, 83 pts were screened in Europe and the US; 66 were randomized (33 per arm). Data cut-off for this analysis: 9 Dec 2020; study is ongoing. Median age was 64.5 years (range 20–86). Overall, 30% (20/66) of pts were ≥70 years and many had high-risk disease: IPI 2 29%, IPI 3 46%, IPI 4 26%. ECOG PS: 47% of pts were ECOG PS 0, 44% PS 1, 9% PS 2. Most pts had stage III/IV disease (92%); 46% had bulky disease. All pts experienced a treatment-emergent adverse event (TEAE). Grade ≥3 neutropenia and thrombocytopenia occurred in 54.5% and 12.1% (arm A) and 66.7% and 30.3% (arm B) of pts, respectively (Table). Serious TEAEs occurred in 42.4% (arm A) and 51.5% (arm B) of pts. There were three deaths, unrelated to tafa and/or LEN (sepsis, urosepsis, and COVID-19 pneumonia). R-CHOP dose intensity was maintained in both arms. Among 60 pts who completed tumor assessments after cycle 3, ORR was 89.7% (arm A) and 93.5% (arm B). Conclusions: These data suggest R-CHOP + tafa or tafa + LEN is tolerable in pts with Tx-naïve DLBCL and that R-CHOP dosing is not affected. Toxicities are similar to those expected with R-CHOP or R-CHOP + LEN. Updated safety and early efficacy data will be presented at the conference. Clinical trial information: NCT04134936. [Table: see text]

Background: Previous studies have demonstrated success in using autogenous bone graft for arthrodesis in patients with failed surgeries of the hallux. These patients have several causes for pain and dysfunction preoperatively, including a shortened first ray, nonunion, and poor hallux alignment. Methods: In this study, a consecutive series of 36 patients (38 procedures) were treated with a patellar wedge interposition structural allograft to salvage bone loss from great toe arthrodesis malunion, painful joint replacement, failed osteotomy, or infection of the great toe metatarsophalangeal (MP) joint with shortening of the first ray. The goals of the surgery were to restore length to the first ray and provide a stable MP joint fusion to relieve pain. The 38 treated toes were evaluated for preoperative and postoperative American Orthopaedic Foot & Ankle Society (AOFAS) MP scores, subjective patient outcome scores, and clinically successful fusion of the hallux. Results: At a minimum 1-year follow-up (mean, 3.2 years), all but 2 feet healed with a solid fusion, and all healed patients reported good or excellent outcomes. AOFAS MP scores averaged 43.5 preoperatively and 77.2 postoperatively. Three patients with infection as cause for nonunion of the initial procedure were treated with staged procedures, including the use of a temporary antibiotic spacer and mini external fixator; all 3 healed without recurrent infection. One patient had a fracture of her allograft following her interposition arthrodesis, but it fused successfully after a second interposition arthrodesis surgery. Two patients developed a nonunion of the revision arthrodesis. Conclusion: The use of an interposition patellar wedge allograft can restore length to the first ray and provide successful salvage of arthrodesis nonunions and bone loss from failed hemiarthroplasty and total joint implants of the great toe MP joint. Level of Evidence: Level IV, retrospective case series.

Introduction Approximately 15-20% of treatment-naïve patients with diffuse large B-cell lymphoma (DLBCL) have CD20-low tumors, while CD19 is homogeneously expressed in >90% of cases of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. 2009). CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation and is therefore an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized, Fc-enhanced, anti-CD19 monoclonal antibody with improved antibody-dependent cellular cytotoxicity and phagocytosis. Monotherapy with tafasitamab has shown clinical activity in relapsed/refractory (R/R) non-Hodgkin's lymphoma (Jurczak W, et al. 2018). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, combined treatment of tafasitamab with lenalidomide resulted in a high proportion of patients having a complete response (Salles GA, et al. 2020). First-MIND (NCT04134936) is a Phase Ib, randomized study of tafasitamab + R-CHOP (Arm A) or tafasitamab + lenalidomide + R-CHOP (Arm B) in patients with newly diagnosed DLBCL. Here, we report data from the safety run-in phase. Study design and methods Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index [IPI] 2-5) and an ECOG performance status of 0-2. Known double- or triple-hit lymphoma and transformed lymphoma are excluded. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Day [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) + lenalidomide (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). Granulocyte-colony stimulating factor prophylaxis was mandatory in all patients. The study includes a safety run-in phase and a main phase. In the safety run-in phase, 24 patients were enrolled. The primary objective is to assess safety; secondary objectives include ORR, PET-CR rate at end of treatment, PFS, event-free survival, long-term safety, pharmacokinetics and immunogenicity of tafasitamab. Exploratory objectives include the assessment of circulating cell-free tumor DNA. Approximately 60 patients will be recruited in 9 countries across Europe and the US. Results Recruitment is ongoing. Thirty-six patients were randomized; 18 in each arm. The data presented for the safety run-in phase consist of 24 patients: 13 patients in Arm A and 11 patients in Arm B. All completed the first treatment cycle; 88% of patients entered into Cycle 2 and 50% of patients entered into Cycle 3 of treatment. At baseline, their median age was 67 years (range: 47-76; Arm A) and 65 years (range: 40-74; Arm B). Overall, 33% of patients were male and 67% female; IPI scores were: IPI 2, 33%; IPI 3, 42%; IPI 4, 25%. Most patients had advanced stages III/IV (92%) and approximately 50% had bulky disease. Cell of origin was determined to be germinal center B-cell (GCB) DLBCL in 13%, non-GCB DLBCL in 42% and not yet classified in 46% of cases. A total of 248 treatment-emergent adverse events (AEs) by system organ class were documented: 111 in Arm A and 137 in Arm B. Grade ≥3 neutropenia was observed in 54% (Arm A) and 46% (Arm B) of patients. Thrombocytopenia Grade ≥3 was observed in 8% (Arm A) and 18% (Arm B) of patients. Diarrhea, fatigue and vomiting were comparable between the two arms. Febrile neutropenia was uncommon in both arms, with one event each (Figure 1). To date, 23 serious AEs were observed: 11 in Arm A (Grade 2, 1; Grade 3, 6; Grade 4, 4) and 12 in Arm B (Grade 2, 3; Grade 3, 7; Grade 4, 2). One suspected unexpected serious adverse reaction was reported in Arm B - pneumocystis jirovecii pneumonia. No treatment-associated deaths occurred. Conclusions R-CHOP can be safely combined with tafasitamab or tafasitamab + lenalidomide in patients with treatment-naïve DLBCL. Toxicities appear to be similar to what is expected with R-CHOP alone or in combination with lenalidomide. Enrollment is ongoing and updated safety and early efficacy data will be presented at the meeting. Disclosures Belada: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. André:Takeda: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; Celgene: Other, Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Stevens:Amgen, MorphoSys: Consultancy. Trněný:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses. Pérez Persona:Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Klöpfer:MorphoSys AG: Current Employment. Brackertz:MorphoSys AG: Current Employment. Lohrmann:MorphoSys AG: Current Employment. Lahiry:MorphoSys AG: Current Employment. Shah:MorphoSys AG: Current Employment. Fingerle-Rowson:MorphoSys AG: Current Employment. Brugger:MorphoSys AG: Current Employment. Burke:Epizyme: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy.

Abstract Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) in adults. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) remains the standard of care for newly diagnosed DLBCL, with cure rates of 60-70%. However, more effective front-line options are needed to further improve outcomes, particularly in high-risk patients (Sehn LH, Gascoyne RD. Blood 2015;125:22). Approximately 15-20% of treatment-naïve patients with DLBCL have CD20-low expressing tumors, while CD19 is expressed in >90% of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. Blood 2009;113:3773; Prevodnik VK, et al. Diagnostic Pathol 2011;6:33). CD19 is a B-lymphocyte lineage-specific surface antigen that is widely expressed in mature B-cell malignancies, including DLBCL. CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation, and is, therefore, an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized anti-CD19 monoclonal antibody with an engineered constant region (Fc) that enhances Fc-γ receptor binding affinity on effector cells, thereby enhancing antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Preliminary data in DLBCL cell lines suggest that combined targeting of CD19 and CD20 with tafasitamab and rituximab, respectively, could have synergistic cytotoxic effects. Monotherapy with tafasitamab has shown clinical activity and acceptable safety in a Phase I study in relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (NCT01161511) and in a Phase IIa study in R/R NHL (NCT01685008). In patients with R/R DLBCL, treatment with single agent tafasitamab until progression led to a 26% objective response rate (ORR) with several long-term responses (Jurczak W, et al. Ann Oncol 2018; 29:1266). Preclinical in vitro and in vivo data have demonstrated increased combinatorial antitumor effects with tafasitamab and the immunomodulatory agent lenalidomide (LEN). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, treatment with tafasitamab/LEN achieved an ORR of 60%, a complete response (CR) rate of 42.5% and a median progression-free survival (PFS) of 12.1 months (Salles GA, et al. ICML 2019; Abstr 124). This combination received breakthrough therapy designation by the US Food and Drug Administration. Study design and methods First-MIND is a Phase Ib, open-label, multicenter, randomized trial of tafasitamab/R-CHOP or tafasitamab/LEN/R-CHOP in patients with newly diagnosed DLBCL (Figure 1). Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index 2-5). Key exclusion criteria include known double- or triple-hit lymphoma, and transformed or composite lymphoma. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Days [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) and LEN (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). The trial includes a safety run-in phase and a main phase. In the safety run-in phase, 12 patients will be enrolled in each arm. If no unexpected safety signals suspected to be related to the addition of tafasitamab ± LEN to R-CHOP are observed, an additional 18 patients will be enrolled in each arm in the main phase. The primary objective of the trial is to assess safety; secondary objectives include evaluation of efficacy (ORR and PET-assessed CR rate at end of treatment, PFS, overall survival, event-free survival, time to next anti-lymphoma treatment), long-term safety and pharmacokinetics, and immunogenicity of tafasitamab in each arm. Exploratory objectives will include the assessment of biomarkers in peripheral blood (natural killer [NK] cell count, cell-free circulating tumor DNA) and tumor tissue (DLBCL cell of origin, NK cell or macrophage count/gene expression profile, CD19 and CD20 expression) that may be relevant to the mechanism of action and/or response to study treatment. As this is a Phase Ib study to primarily explore safety, no formal statistical hypothesis is considered for the sample size calculation; approximately 60 patients will be recruited across Europe and the US. Disclosures Burke: Gilead: Consultancy; Roche/Genentech: Consultancy; Celgene: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Consultancy, Research Funding; Kite: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Nowakowski:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Rosenwald:MorphoSys: Consultancy. Salles:Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Staber:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trněný:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria. Westin:Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Brugger:MorphoSys: Employment; AstraZeneca: Equity Ownership. Fingerle-Rowson:MorphoSys AG: Employment. Klanova:MorphoSys AG: Employment. Würth:MorphoSys AG: Employment. Truemper:Janssen Oncology: Consultancy; Nordic Nanovector: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Roche: Research Funding; Mundipharma: Research Funding.

Abstract Introduction RCHOP is the standard frontline treatment for patients with DLBCL. However, for patients with high-intermediate or high-risk disease (IPI 3-5), outcomes are suboptimal, with an estimated 3-year PFS of about 55%. In addition to IPI, an additional factor associated with an increased risk include non-GCB cell of origin. Brentuximab vedotin, an ADC targeting CD30, has demonstrated single-agent activity in relapsed/refractory DLBCL patients. Of note, higher ORR and CR, as well as longer duration of PFS, were observed in those patients with CD30 detected on tumor cells by routine IHC. Methods This phase 2 study was designed to evaluate combination therapy using brentuximab vedotin (BV) and standard RCHOP chemotherapy as frontline treatment in patients with high-intermediate/high risk (standard IPI score 3-5 or age-adjusted IPI [aaIPI] score 2-3) DLBCL, regardless of CD30 expression (ClinicalTrials.gov NCT01925612). Patients were randomized to receive either 1.2 mg/kg BV+RCHOP or 1.8 mg/kg BV+RCHOP for up to 6 cycles of treatment. BV was given on Day 1 of every 21-day cycle. Response was assessed per investigator using Cheson 2007. AEs, physical examination findings, and laboratory testing were utilized to characterize safety. Tumor cell CD30 expression was measured by IHC and gene expression analysis; soluble CD30 was measured in plasma. Tumor microenvironment was also evaluated for frequency of immune-infiltrating cells. The primary endpoints for this study were the tolerability of each regimen and the CR rate at the end of treatment (EOT). Key secondary endpoints included progression-free survival (PFS). Additional exploratory endpoints included CD30 expression on tumor specimens (CD30- defined as <1% per IHC) and correlation of CD30 expression and response. Results Twenty-nine patients were treated with 1.2 mg/kg BV+RCHOP and 22 patients were treated with 1.8 mg/kg BV+RCHOP. Over half (63%) were high-intermediate risk (IPI 3, aaIPI 2) and 37% were high risk (IPI 4-5, aaIPI 3). Most had Stage IV disease (71%) and 27% had an ECOG score of 2. AEs in ≥50% of patients included peripheral sensory neuropathy (63%), fatigue (61%), nausea (55%), and diarrhea (53%). Grade 3 or higher events occurred in 76% of patients; the most frequent were neutropenia (33%) and febrile neutropenia (31%). The PET-negative CR rate was 69% overall; CD30+ patients had a CR rate of 76% (19/25) compared with 63% (12/19) in CD30- patients by IHC. Although PFS data are still immature (median follow up of 8 months), the estimated PFS rate at 12 months was 82% (95% CI: 58, 93) in CD30+ patients and 56% (95% CI: 32, 75) in CD30- patients. 60% (3/5) of patients with CD30- ABC-DLBCL progressed versus 27% (3/11) of CD30+ ABC-DLBCL patients. Four patients with EBV+ DLBCL were treated and all achieved CR; 3 EBV+ patients remain in remission after a median follow-up of 12 months. Within the microenvironment, a higher percentage of CD3+ T-cells was observed in patients with CR (23%; range, 4-80%) than in those with PR (14%; range, 10-15%) or PD (11%; range, 5-15%). Of the 32 patients who have not yet progressed, 50% had ≥20% CD3+ cells compared to 18% of patients with PD (2/11). Other factors, including soluble CD30 levels and infiltrating CD68+ cells, were not associated with clinical outcomes. Conclusions Interim results demonstrate that adding BV to RCHOP results in a high rate of CR in this population of IPI 3-5 DLBCL. Patients with CD30-expression in the tumor appear to have a higher CR rate and fewer early progression events than patients with CD30- DLBCL. Furthermore, subsets of patients who have a particularly poor prognosis (CD30+ ABC subtype and EBV+ DLBCL) appeared to have a favorable outcome with BV+RCHOP. Evaluation of the tumor microenvironment showed that higher frequencies of infiltrating CD3+ cells were observed in the CR group, suggesting possible immunologic correlates of response. However, CD30 expression appears to have greater prognostic significance in this study despite the relatively small sample size. These results are intriguing and merit further testing in a randomized trial. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US 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. The drug is being evaluated in this study for use as frontline treatment in patients with high-intermediate/high risk DLBCL in combination with multiagent chemotherapy. . Halwani:Abbvie: Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Takeda/Millenium: Research Funding; BMS: Research Funding; Seattle Genetics, Inc.: Other: Travel expenses, Research Funding; Roche/Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Budde:Merck: Research Funding; Ikara Inc: Patents & Royalties; Atara Biotherapeutics: Consultancy; Seattle Genetics, Inc.: Research Funding. Burke:Millenium/Takeda: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel expenses; Gilead: Consultancy; Janssen: Consultancy; Seattle Genetics, Inc.: Research Funding. Farber:Seattle Genetics, Inc.: Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Kolibaba:GSK: Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Knapp:Celgene: Research Funding; Heron Pharmaceuticals: Other: Travel expenses, Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Brystol-Myers Squibb: Research Funding; Genentech: Honoraria, Other: Travel expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; EMD Serono: Research Funding. Li:Seattle Genetics, Inc.: Employment, Equity Ownership. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Yimer:Seattle Genetics, Inc.: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

Purpose This trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma. Patients and Methods Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m2 intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m2 IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m2 IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS). Results A total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively). Conclusion The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting.