Bartlett, Nancy L.

7506 Background: Optimal consolidative therapy for primary central nervous system lymphoma (PCNSL) is not defined. Avoidance of whole brain radiation may reduce risk of neurotoxicity. Non-radiation consolidative options include myeloablative chemotherapy with autologous stem cell transplantation (HDT/ASCT) or non-myeloablative chemotherapy. Methods: This is a randomized phase 2, National Clinical Trials Network study of induction methotrexate (MTX) (8 g/m2 days 1, 15), temozolomide (TMZ) (150-200 mg/m2 D7-11), and rituximab (RTX) (C1 D3, 10, 17, 24 and C2 D3, 10 ) in four 28-day cycles followed by one cycle of cytarabine (ARA-C) (2 g/m2 BID, D1, 2) (MTRA). After induction, patients (pts) received consolidation with thiotepa (5 mg/kg BID, D -5, -4) plus carmustine (400 mg/m2, day -6) and ASCT (Arm A) or one cycle of ARA-C (2 g/m2 BID, D1-4) plus infusional etoposide (40 mg/kg over 96h) (Arm B). Pts were stratified on age and performance status and randomized 1:1 before induction. The primary endpoint was progression-free survival (PFS) from randomization. With 110 pts, there was 84% power to detect an improvement in PFS using a log-rank test (1-sided α= 10%), assuming a median PFS of 3 months for pts who progress during induction, and a median PFS of 2 years (yrs) for Arm B and 4.5 yrs for Arm A consolidation. This report includes the results for the primary endpoint analysis. Results: 113 pts (median age 61 yrs, range 33-75) were randomized (Arm A: 57, Arm B: 56) across 27 centers. 108 eligible pts who received induction therapy were included in the primary endpoint analysis (Arm A: 54, Arm B: 54). 72/108 pts started consolidation and 70/72 completed consolidation per protocol (Arm A: 36, Arm B: 34). With a median follow-up of 3.8 years, median PFS from randomization was 6 yrs (95% CI 3.9-not reached) in Arm A vs 2.4 yrs (95% CI 0.6-not reached) in Arm B (p = 0.02). However, more pts randomized to Arm B went off treatment before consolidation due to progression or death (28% vs 11%, p = 0.05). PFS landmarked at start of consolidation demonstrated a trend for improved PFS favoring Arm A (HR 0.58, 95% CI 0.25-1.36; p = 0.21). Median OS was not reached in either arm, and 3-yr estimates were 83% (95% CI 69-91; Arm A) vs 72% (95% CI 57-82; Arm B). Toxicities were similar between arms with no treatment-related mortality during consolidation. Conclusions: MTRA induction followed by myeloablative consolidation (Arm A) had improved PFS vs MTRA induction followed by non-myeloablative consolidation (Arm B), though more progressions or deaths leading to treatment discontinuation prior to consolidation in Arm B were noted. Both consolidation regimens were well-tolerated with encouraging PFS and OS in newly-diagnosed PCNSL. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01511562.

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

AbstractThis phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Abstract Introduction Brentuximab vedotin (BV) is an ADC directed against CD30, a receptor expressed by malignant Reed-Sternberg (RS) cells present in the inflammatory/immune cell microenvironment of classical Hodgkin lymphomas (cHL). Through induction of immunogenic cell death, BV may prime an antitumor immune response via microtubule disruption of CD30-expressing RS cells (Gardai 2015). Tumor cells expressing PD-1 ligands use the PD-1 pathway to evade an immune response. Nivolumab (Nivo) blocks the PD-1 receptor, inhibits binding of PD-1 ligands, and restores an effective antitumor immune response. Targeted killing of CD30-expressing RS cells, concurrent with restoration of the immune response, may lead to higher complete response (CR) rates in patients (pts) with relapsed or refractory cHL (R/R HL), as well as improved durability of responses post autologous stem cell transplant (ASCT). Here we present updated results from the phase 1/2 study of BV + Nivo in pts with R/R HL. Methods BV + Nivo was evaluated in cHL that had relapsed or was refractory to frontline (FL) chemotherapy in adult pts (NCT02572167). Pts were excluded if they had received prior salvage therapy, BV or immuno-oncology therapy, or allogeneic SCT or ASCT. Pts were treated in 21-day cycles for up to 4 cycles. In Parts 1 and 2 of the trial, BV (1.8 mg/kg) was given on Cycle 1 Day 1 and Nivo (3 mg/kg) on Cycle 1 Day 8. For Cycles 2-4, BV and Nivo were given on Day 1. After the Cycle 4 response assessment, pts were eligible to undergo ASCT. The investigators assessed response per the Lugano Classification (Cheson 2014). Results 62 pts with R/R HL were enrolled in Parts 1 and 2; 61 pts received BV + Nivo, of whom 58 completed treatment (tx). 4 pts discontinued the study due to pt decision (2), AE (1), and investigator decision (1). Median age was 36 years, 52% were female, and 90% had received FL ABVD. 45% of pts had primary refractory disease and 31% experienced relapse within 1 year of FL therapy. Infusion-related reactions (IRRs) occurred in 41% of pts. Tx emergent AEs occurred in 98% of pts prior to ASCT (33% G3, 5% G4). Excluding IRRs, potential immune-related AEs (IrAEs) occurred in 84% of pts (10% G3, 3% G4) with 5 pts (8%) treated with systemic steroids for G4 pneumonitis, G4 pneumonitis and colitis, G2 pneumonitis, G3 diarrhea and G2 colitis, and G3 AST elevation. Among the 60 efficacy-evaluable pts, the CR rate was 62%, (48% of CR pts had Deauville ≤ 2) with an objective response rate of 85%; 5 pts (8%) had stable disease and 4 pts (7%) progressed on tx. At the time of this analysis, 39 pts had initiated ASCT with a median 5.1x106 CD34+ cells/kg (range; 3-60) collected. Median times to neutrophil and platelet engraftment were 12 and 15 days, respectively. Pts were followed for a median of 3 months from ASCT (N=39, range; 0-12) and 5.7 months from first dose (N=61, range; 1-17). BV and Nivo effects on the immune system were evaluated by peripheral blood immunophenotyping, serum cytokine/chemokine analyses, T-cell receptor sequencing, and intracellular cytokine staining. The first dose of BV resulted in elevation of pro-inflammatory cytokines and chemokines and concurrent reduction in serum TARC levels, with these results maintained post Nivo. We observed a reduction in Tregs and other T cell subsets after the first dose of BV with an elevation of T cell subsets post BV + Nivo. While TCR clonality in the periphery did not change over the course of the trial, T cell clonal expansion was observed post BV + Nivo, concurrent with T cell elevation measured by flow cytometry. Ex vivo peptide stimulation of PBMCs isolated from blood revealed the enhanced ability of T cell subsets to respond to MHC I and MHC II antigens following BV + Nivo compared to baseline: e.g., effector memory CD8+ T cells from some pts displayed increased intracellular IL-2, and TNFa after stimulation with MHCI and MHCII peptide pools compared to baseline, potentially indicating elevated activation status of the immune system following combination tx. Conclusion R/R HL remains an unmet clinical need despite recent medical advances. These data suggest the combination BV + Nivo is a well tolerated and an active salvage therapy with a high rate of CR (62%) that has no adverse impact on stem cell collection. The safety and activity of this novel combination support further exploration in an ongoing pivotal phase 3 trial in pts with R/R HL who have either already received or are considered ineligible for ASCT (NCT03138499). Disclosures Herrera: Seattle Genetics: Research Funding; Merck: Consultancy; Genentech: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy. Moskowitz: Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Bartlett: Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; KITE: 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, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vose: Merck: Research Funding; Kite: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Allos Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Research Funding; Onyx: Research Funding; Seattle Genetics: Research Funding; US Biotest: Research Funding; Bristol-Myers Squibb: Research Funding. Ramchandren: Seattle Genetics: Consultancy; MERCK: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Feldman: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Kite Pharma: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. LaCasce: BMS: Consultancy; Forty Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding. Ansell: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding. Moskowitz: Celgene: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Fenton: Seattle Genetics: Employment, Equity Ownership. Ogden: Seattle Genetics: Employment, Equity Ownership. Taft: Seattle Genetics: Employment, Research Funding. Zhang: Seattle Genetics: Employment, Research Funding. Kato: Bristol-Myers Squibb: Employment, Equity Ownership; Seattle Genetic: Research Funding. Campbell: Seattle Genetics: Employment, Equity Ownership; CTI BioPharma: Employment, Equity Ownership. Advani: Agensys: Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; FortySeven: Research Funding; Nanostring: Consultancy; Celgene: Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding; Juno Therapeutics: Consultancy; Kura: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Cell Medica: Research Funding; Sutro: Consultancy.

Introduction Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the first 5 years (Radford et al, BMJ 1997). In the phase 3 ECHELON-1 study (NCT01712490), treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved modified progression-free survival (PFS) in patients (pts) with newly-diagnosed Stage III/IV cHL compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (Connors et al, NEJM 2018). 3- and 4-year follow-up (Straus et al, Blood 2020; Bartlett et al, Blood 2019) reported durable PFS benefit with A+AVD vs ABVD in the intent-to-treat (ITT) population that was consistent across most key pt subgroups, irrespective of interim positron emission tomography (PET) scan status, disease stage, and baseline disease risk factor score. We report updated efficacy and safety results for pts in the ECHELON-1 study after a median follow-up of 55.6 months. Methods In this evaluation of longer follow-up, an exploratory analysis of PFS (time from randomization to relapse, progression, or death from any cause) per investigator (INV) was conducted, with a cutoff date of May 18, 2020. Pts with previously untreated Stage III or IV cHL were randomized 1:1 to receive up to six cycles of A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of a 28-day cycle. An interim PET scan after cycle 2 (PET2) was required. Resolution and improvement (defined as improvement by ≥1 grade from worst grade as of the latest assessment) of peripheral neuropathy (PN) in pts with ongoing symptoms at the end of treatment (EoT) were monitored during the extended follow-up period. The rate of secondary malignancies, and the incidence and outcomes of pregnancies among pts and their partners were also assessed. Results With extended follow-up (median 55.6 months; 95% CI 55.2-56.7) estimated 5-year PFS rates were 82.0% (95% CI 78.7-84.8) for A+AVD and 75.2% (95% CI 71.5-78.4) for ABVD. Overall, PFS per INV favored A+AVD over ABVD (HR 0.691; 95% CI 0.543-0.880; p=0.003) (Table). Exploratory subgroup analyses by PET2 status and age demonstrated PFS benefits regardless of PET2 status (Table); estimated 5-year PFS per INV with A+AVD vs ABVD in the ITT population was 84.7% vs 78.8% in PET2-negative pts (HR 0.676; 95% CI 0.512-0.892; p=0.005), and 60.6% vs 45.9% in PET2-positive pts (HR 0.703; 95% CI 0.393-1.256; p=0.230). PFS benefit with A+AVD over ABVD was also independent of the number of International Prognostic Factors Project (IPFP) risk factors (Figure). After a median follow-up of almost 5-years, 84% (370/442) and 86% (245/286) of pts with treatment-emergent PN reported complete resolution or improvement of symptoms in the A+AVD and ABVD arms, respectively. Median time to complete resolution of PN events that were ongoing at EoT was 30 weeks (range 0-262) in the A+AVD arm and 16 weeks (range 0-267) in the ABVD arm; median time to improvement was 49 weeks (range 8-270) and 12 weeks (range 2-70) , respectively. Of the 132 (30%) pts with ongoing PN in the A+AVD arm, 77 (17%), 39 (9%), 15 (3%) and 1 (&lt;1%) experienced a maximum severity of grade 1, 2, 3 or 4, respectively. In the ABVD arm, PN was ongoing in 61 pts (21%); maximum severity was grade 1, 2, 3 or 4 in 40 (14%), 17 (6%), 4 (1%) and 0 pts, respectively. A total of 124 pregnancies were reported among pts and their partners (40 female and 30 male pts in the A+AVD arm; 26 female and 28 male pts in the ABVD arm). The proportion of live births was similar between arms for female pts (26/40 in the A+AVD arm and 17/26 in the ABVD arm, 65% in each arm) and for male pts' partners (19/30 [63%] in the A+AVD arm and 20/28 [71%] in the ABVD arm). No stillbirths were recorded. Additional follow-up at an estimated median of ~5 years and secondary malignancy data will be presented. Conclusions After a median follow-up of 55.6 months, A+AVD continues to demonstrate a robust and durable treatment benefit independent of disease stage, risk factor score, and PET2 status. In addition, compared with ABVD, treatment adaptation by interim PET2 status is not required and bleomycin exposure is avoided. The sustained PFS benefit with A+AVD is coupled with a manageable safety profile with symptoms of PN improving or resolving over time and similar pregnancy rates in both treatment arms. The benefits observed with A+AVD at this important milestone suggest that A+AVD is an attractive treatment option for all pts with previously untreated Stage III or IV cHL. Disclosures Straus: Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Connors:Seattle Genetics: Other: Sponsorship to educational presentations; Takeda: Other: Sponsorship to educational presentations. Illés:Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Lech-Marańda:Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy; Roche, Amgen, Gilead: Speakers Bureau. Feldman:KITE: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Morphosis: Other: Ad board; AstraZeneca: Other: Ad board; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Smolewski:Roche Poland: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sandoz: Honoraria; Morphosis: Honoraria. Savage:Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding. Walewski:Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Research Funding. Ramchandren:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Zinzani:Eusapharma: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hutchings:Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding; Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Kim:JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; ADC Therapeutics: Research Funding; AI Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding. Younes:HCM: Consultancy; Daiichi Sankyo: Consultancy; Curis: Consultancy; BMS: Consultancy; Novartis: Consultancy; Epizyme: Consultancy; BioPath: Consultancy; AstraZeneca: Current Employment; Janssen: Consultancy; Takeda: Consultancy. Gallamini:Takeda: Other: Speaker. Liu:Takeda Pharmaceuticals: Current Employment. Little:Takeda: Current Employment, Current equity holder in publicly-traded company. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: 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; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.

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.

Background FDG-PET is used in staging and response assessments in patients (pts) with DLBCL. An analysis of 158 pts with DLBCL receiving R-CHOP or DA-EPOCH-R on CALGB/Alliance 50303 failed to show an association between the interim PET (iPET, after cycle 2 of therapy) visual 5-point scale score (5-PS) by central review and progression-free survival (PFS) or overall survival (OS), but did show a significant association between percent change in FDG uptake from baseline to after cycle 2 (∆SUV) and PFS/OS (Schoder et al. 2020). As central review of FDG-PET is not feasible in routine practice, we retrospectively compared local vs central readings, and determined associations from local imaging data with PFS/OS. Methods 126 pts at baseline and 109 at iPET had local imaging data submitted across 21 institutions. Visual scores 1-3 defined PET- and scores 4-5 defined PET+ disease. ∆SUV was defined as the percent change in the maximum SUV at any site (maxSUV) from baseline to iPET. Continuous ∆SUV and categorized ∆SUV (&lt;66% vs &gt;66%) were analyzed. Differences in quantitative measures were calculated as the local minus central result. The Kappa statistic estimated agreement in PET and ∆SUV groups between local and central review. PFS and OS distributions for local PET and ∆SUV groups were landmarked at iPET, estimated with the Kaplan-Meier method, and compared using the log-rank test. Results At baseline, maxSUV was reported locally and centrally in 118 pts. Median maxSUV was 24.3 (range: 5.9-77.3) by local review and 24.3 (range: 5.9-77.0) by central review. The median difference in maxSUV was 0 (range: -12.9 to 21.9), with 50% of differences between -1.1 and 0.1, and 90% of differences between -7.8 and 4.1. In 106 pts with visual iPET 5-PS results, 52 (49.1%) were PET+ by local review and 37 (34.9%) by central review. Agreement in local and central review was moderate (kappa=0.53), occurring in 81 pts (76.4%; 32 PET+ and 49 PET-). Disagreement occurred in 25 patients, 20 with local PET+ but central PET- and 5 with local PET- but central PET+. iPET maxSUV was reported locally and centrally in 90 pts. Median maxSUV was 3.4 (range: 0-18.3) by local review and 3.3 (range: 1.2-18.2) by central review. The median difference in maxSUV was 0 (range: -8.6 to 2.4), with 50% of differences between -0.3 and 0.4, and 90% of differences between -4.4 and 1.8. ∆SUV was calculated in 87 pts. Median ∆SUV was 84.6% (range: -3.0% to 95.9%) by local review and 85.1% (range: -34.9% to 95.8%) by central review. The median difference in ∆SUV was -0.3 (range: -19.6 to 31.9), with 50% of differences between -2.1 and 1.1, and 90% of differences between -7.1 and 12.3. ∆SUV was &lt;66% in 12 (13.8%) pts by local review and 12 pts by central review. Agreement in local and central review was high (kappa=0.81), occurring in 83 pts (95.4%; 10 with ∆SUV &lt;66%, 73 with ∆SUV &gt;66%). Disagreement occurred in 4 pts, 2 in each direction. Using local data, PFS and OS estimates were numerically lower in pts with iPET+ vs iPET- disease, but did not reach statistical significance (p=0.12 and p=0.15). Two-year estimates for PFS were 79% (95% CI 68-91%) and 89% (95% CI 81-98%), and 2-year estimates for OS were 84% (95% CI 75-95%) and 96% (95% CI 91-100%) in pts with iPET+ and iPET-, respectively. In contrast, ∆SUV groups were significantly associated with PFS and OS (p=0.03 and p=0.002). Two-year estimates for PFS were 56% (95% CI 34-94%) and 87% (95% CI 79-95%) and 2-year estimates for OS were 56% (95% CI 34-94%) and 93% (95% CI 88-99%) in pts with ∆SUV &lt;66% and ∆SUV &gt;66%, respectively. Conclusion Agreement in visual 5-PS at iPET was moderate; most discrepancies arose from a local PET+ result when central review called PET-. Differences in maxSUV and ∆SUV tended to be small. Grouping ∆SUV resulted in only 4 discrepancies (4.6%). Similar to the previous analysis using central data, the separation in PFS and OS curves using local data for ∆SUV was greater than by visual 5-PS. Encouragingly, the agreement in ∆SUV of &lt;66% vs ≥66% was high between local and central review. Overall agreement however may be unduly influenced by the large proportion of pts with ∆SUV ≥66%, with less certainty in agreement for pts with ∆SUV &lt;66%. Larger prospective studies comparing local and central imaging data are warranted to best determine the utility of local imaging in clinical trials. Support: P30 CA008748, U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00118209 (CALGB 50303) Disclosures Kahl: Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Friedberg:Astellas: Consultancy; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy. Leonard:MEI Pharma: Consultancy; Sutro: Consultancy; Bayer: Consultancy; BMS/Celgene: Consultancy; GenMab: Consultancy; Roche/Genentech: Consultancy; Gilead/Kite: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy. Bartlett:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti–CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.