ABSTRACT"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identifi ed a novel cluster of extracellular domain (ECD) mutations in EGFR , mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profi ling can effectively defi ne the genomic landscape of cancer and yield important biological insights. SIGNIFICANCE:This study provides one of the fi rst examples of how large-scale genomic profi ling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identifi ed novel EGFR ectodomain mutations. Cancer Discov; 8(2);

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Purpose The phosphatidylinositol 3-kinase pathway (PI3K) is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B cell lymphomas. Experimental Design We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/MTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs. Results We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference mediated knock-down of the PAK1 gene, we demonstrated a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small molecule inhibitor of PAK1 and found significant synergy between PI3K inhibition and PAK1 inhibition. Conclusion Thus we demonstrate that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

Introduction: Up to 30% of patients (pts) aged ≥75 years do not receive standard chemoimmunotherapy (CIT) as first-line (1L) treatment for diffuse large B-cell lymphoma (DLBCL) due to concerns about frailty and comorbidities. Poor outcomes are commonly reported for elderly/unfit pts with 1L DLBCL who receive no treatment, reduced-dose R-CHOP or other therapies such as R-CVP and R-bendamustine (Morrison, et al. J Geriatr Oncol 2020); less toxic, efficacious alternatives to full-dose CIT are needed. Mosunetuzumab (Mosun) is a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Single-agent Mosun has shown promising efficacy (including durable complete responses [CRs]) and tolerable safety in relapsed/refractory DLBCL pts in an ongoing Phase I study (GO29781; NCT02500407; Bartlett, et al. ASCO 2019, Schuster, et al. ASH 2019). Here we present early clinical data with Mosun as 1L therapy for elderly/unfit pts with DLBCL. Methods: GO40554 (NCT03677154) is a Phase I/II, open-label, multicenter study. We report data from Cohort B, designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of Mosun in pts with 1L DLBCL who are unable to tolerate full-dose CIT. Two safety evaluation cohorts were planned to receive Mosun at 13.5mg and 30mg, followed by an expansion phase. No safety concerns emerged following evaluation of the two safety cohorts. Eligible pts were aged ≥80 years or 60-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL, or with impairment in cardiac, renal or liver function precluding the use of full-dose CIT. After optional pre-phase treatment with prednisone with or without vincristine, pts received Mosun intravenously with step-up dosing on Day (D) 1, 8 and 15 of Cycle (C) 1, followed by a fixed dose on D1 of each subsequent 21-day cycle. Interim response assessment (IRA) occurred after C4 and primary response assessment (PRA) occurred after C8, with an option to continue up to maximum 17 cycles in case of partial remission (PR) following PRA. Results: As of May 27, 2020, 19 pts in Cohort B had received Mosun (1mg [C1 D1]/2mg [C1 D8]/13.5mg [C1 D15 onwards], n=8; 1/2/30mg, n=11). Eight pts were enrolled in the 13.5mg safety evaluation cohort and 11 enrolled in the 30mg safety cohort and expansion (7+4 respectively). Median age was 84 (range: 67-100) years, 14 (74%) pts were women, 10 (53%) had Ann Arbor stage III-IV and 17 (90%) had an IPI score ≥2. Median Mosun cycles received was 6 (range: 2-9; one pt in PR continued treatment). Among 19 pts, 16 (84%) had ≥1 adverse event (AE), 13 (68%) had ≥1 AE related to Mosun and 7 (37%) experienced a Grade (Gr) 3-4 AE, of which 4 were related to Mosun. No fatal AEs were observed. The most common (>10%) treatment-emergent AEs were cytokine release syndrome (CRS; n=9, 47%), rash (n=4, 21%), neutropenia, nausea, decreased appetite, dry mouth, fatigue, pain and muscle spasms (all n=2, 11%). All CRS events were Gr 1 by ASTCT consensus criteria (Lee, et al. Biol Blood Marrow Transplant 2019); no pts experienced hypotension, hypoxia or required tocilizumab or steroid treatment. No severe (Gr ≥3) neurologic AEs were observed. Gr 2 (ICAN) neurotoxicity was observed in one (5%) pt on C1D2 with symptoms of inability to answer questions, drowsiness, weakness and somnolence, combined with Gr 1 CRS (fever and tachycardia). The event resolved after 2 days and was considered related to Mosun. Eight (42%) pts discontinued Mosun early due to progressive disease (PD) between C2-C6. No pts discontinued Mosun due to an AE. Among all treated pts, the overall response rate was 58% (11/19) and CR rate was 42% (8/19). At Mosun dose 13.5mg, 3/8 pts (38%) achieved a CR, 2 (25%) had a PR and 3 (38%) had PD at the PRA. At Mosun dose 30mg, response was available at IRA: 5/11 pts (45.5%) achieved a CR, 1 (9%) had a PR and 5 (45.5%) had PD. Of the 8 pts with PD (from both dosing cohorts), 5 have received salvage therapy post progression. Figure 1 shows a durable response of almost a year for the first responder. Correlative studies of T-cell response by flow cytometry and cytokine expression, and PK analyses are ongoing and will be provided. Conclusions: Early clinical data indicate that single-agent Mosun confers notable efficacy and remarkable tolerability for previously untreated elderly/unfit DLBCL pts. Mosun is a promising chemotherapy-free regimen for patients who otherwise have limited options. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Babu:Amgen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Sanofi: Research Funding; Janssen Oncology: Research Funding; Lutheran Hospital: Other; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; AstraZeneca/MedImmune: Research Funding; Boehringer Ingelheim: Consultancy; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Argenx: Consultancy, Research Funding; Novartis: Research Funding; Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Syndax: Research Funding; Nektar: Research Funding; Merck: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding. Levi:Abbvie Inc: Consultancy, Research Funding. Abadi:Abbvie Inc: Research Funding; Roche, Gilead, Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. McKinney:UNUM, Molecular Templates, Incyte, Beigene, Denovo Biopharma, Pharmacyclics, Nordic Nanovector, BMS, Genentech, Inc., Celgene: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Kite/Gilead, Seattle Genetics, Molecular Templates, BTG, Pharmacyclics, Verastem, Genentech, Inc., Celgene: Consultancy. McCord:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Xie:F. Hoffmann-La Roche: Current Employment. Chen:Janssen Pharmaceuticals: Current equity holder in publicly-traded company; Bristol-Myer Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sarouei:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Qayum:F. Hoffmann-La Roche: Current Employment. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Sellam:F. Hoffmann-La Roche: Current Employment. Eradat:UCLA Medical Center, David Geffen school of Medicine at UCLA: Current Employment; Genentech, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astrazeneca, Atara, Kite, Juno, Acerta, BeiGene, Celgene: Research Funding. OffLabel Disclosure: Mosunetuzumab (RG7828; CD20-TDB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Background: Marginal zone lymphoma (MZL) is a clinically heterogeneous, indolent, non-Hodgkin lymphoma (NHL) with 3 subtypes classified as extranodal, nodal, and splenic MZL. Parsaclisib, a potent, highly-selective, next-generation phosphatidylinositol 3 kinase (PI3K) δ inhibitor, has shown promising response rates in a phase 1/2 study in patients with previously treated B-cell malignancies. CITADEL-204 (NCT03144674) is a multicenter, open-label phase 2 study of parsaclisib in patients with relapsed or refractory (R/R) MZL. Here, we report preliminary results for patients who were not previously treated with a Bruton's tyrosine kinase inhibitor (BTKi-naïve). Methods: Eligible patients were ≥18 years of age with histologically confirmed MZL who received ≥1 prior line of systemic therapy, including anti-CD20 therapy, but were BTKi-naïve. Patients had documented disease progression or lack of response to the most recent regimen, had radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (or histologically confirmed bone marrow infiltration in cases of splenic MZL), and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were assessed by an independent review committee (IRC). Safety was evaluated in all treated patients, and efficacy was evaluated in all treated patients who had a follow-up of ≥9 weeks, had at least 1 post-baseline assessment, or discontinued study participation prematurely. Results: From December 2017 to January 17, 2020 (data cut-off), 99 patients (WG, n = 28; DG, n = 71) were treated. Median age was 71 years; 52.5% of the patients were male, 94.9% had an ECOG PS ≤1, and 31.3%, 33.3%, and 35.4% had nodal, extranodal, and splenic MZL, respectively. The median number of prior systemic therapies was 2. At cut-off, 40 (40.4%) patients had discontinued treatment, including 20 (20.2%) for disease progression. The median parsaclisib exposure (range) was 7.5 months (0.4−22.4). At the data cut-off, 94 patients were evaluable for response, including 66 in DG (Table). Median (range) follow-up for the efficacy evaluable population was 11.1 months (1.2−25.0) overall and 9.5 months (1.2−25.0) in DG. The ORR (95% confidence interval [CI]) was 54.3% (43.7−64.6) overall and 57.6% (44.8−69.7) in DG; the ORR (95% CI) was 48.3% (29.4−67.5), 50.0% (31.9−68.1), and 63.6% (45.1−79.6) for patients with nodal, extranodal, and splenic MZL, respectively (Table). The median time to response was 8 weeks. The median DOR (95% CI) was 9.3 months (6.2−not evaluable [NE]) among all responders and 9.4 months (6.0-NE) in DG. The median PFS (95% CI) was 13.8 months (8.8−NE) overall and 11.5 months (8.3-NE) in DG. Among the 99 treated patients, the most common treatment-emergent AEs (TEAEs) were diarrhea (36.4% of patients), cough (18.2%), and rash (14.1%). The most common TEAEs grade ≥3 were neutropenia and diarrhea (8.1%, each). The most common serious TEAEs were febrile neutropenia and pneumonia (5.1%, each). TEAEs leading to dose interruption or dose reduction occurred in 47.5% and 14.1% of patients, respectively. TEAEs leading to discontinuation occurred in 15.2% of patients; the most common events were diarrhea (5.1%) and colitis (3.0%). TEAEs leading to death occurred in 4 patients, with 2 events, febrile neutropenia (n = 1) and sepsis (n = 1), deemed treatment related. New or worsening grade ≥3 laboratory test values of clinical interest included increase in alanine/aspartate amino transferase (2.0%/1.0% of patients), and decrease in neutrophil count (13.1%), platelet count (3.0%), and hemoglobin (3.0%). Conclusion: BTKi-naïve patients with R/R MZL achieved rapid and durable responses with single-agent parsaclisib. Comparable efficacy was observed in patients diagnosed with nodal, extranodal, or splenic MZL. Treatment with parsaclisib was generally well tolerated without unexpected toxicities. Updated data will be presented. Disclosures Phillips: Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy; Cardinal Health: Consultancy. Corradini:KiowaKirin: Consultancy, Honoraria; Incyte: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Gurion:Medison: Consultancy; Gilead Sciences: Consultancy; Takeda Pharmaceuticals: Consultancy; JC Health CARE: Honoraria; Roche: Honoraria. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Jurczak:MorphoSys: Research Funding; European Medicines Agency,: Consultancy; Sandoz-Novartis: Consultancy; Takeda: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; MEI Pharma: Research Funding; Janssen China R&D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Research Funding; Afimed: Research Funding; Celgene: Research Funding; Epizyme: Consultancy; Gilead Sciences: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; TG Therapeutics, Inc.: Research Funding; Acerta: Consultancy, Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; AstraZeneca: Consultancy. Mehta:Affimed: Research Funding; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Innate Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; fortyseven Inc/Gilead: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Research Funding; Juno Parmaceuticals/BMS: Research Funding. Zinzani:Gilead: Consultancy, 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; Immune Design: Consultancy, 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; Kirin Kyowa: 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; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: 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; Merck: 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; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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; Sandoz: 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; BMS: Consultancy, 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; Verastem: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lossos:Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Scientific: Consultancy, Other; Verastem: Consultancy, Honoraria; Janssen Biotech: Honoraria. Thieblemont:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Incyte: Honoraria; Bayer: Honoraria; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. Rappold:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhao:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Johnson:Incyte: Honoraria; Kite Pharma: Honoraria; Kymera: Honoraria; Boehringer Ingelheim: Consultancy; MorphoSys: Honoraria; Oncimmune: Consultancy; Takeda: Honoraria; Novartis: Honoraria; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Honoraria; Bristol-Myers: Honoraria; Genmab: Honoraria; Epizyme: Consultancy, Research Funding; Janssen: Consultancy; Oncimmune: Consultancy.

Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL). Although most patients with FL respond well to first-line therapy, they will inevitably relapse, and the subsequent course is often characterized by a pattern of recurrent relapses with progressively shorter intervals between treatment lines. Moreover, the use of multiple consecutive therapies often leads to refractory disease with severely limited treatment options, demonstrating the need for new therapies for this patient population. Currently approved phosphoinositide 3-kinase (PI3K) inhibitors are often poorly tolerated. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, has shown promising activity in patients with previously treated B-cell malignancies. Here, we report preliminary results of CITADEL-203 (NCT03126019), a multicenter, open-label phase 2 study of parsaclisib in relapsed or refractory (R/R) FL. Methods: Key eligibility included, age ≥18 years, histologically confirmed R/R FL grade 1, 2, or 3a, ≥2 prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and ineligible for hematopoietic stem cell transplantation (HSCT). Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From March 2018 to 17January 2020 (data cut-off), 106 patients (WG, n = 22; DG, n = 84) were treated. Enrollment is ongoing (target: 120 patients). At cut-off, 39 (37%) patients had discontinued treatment, including 25 (24%) for disease progression. The median exposure (range) was 5.3 months (0.5-18.1). The median age was 67 years, and 54% of the patients were men. The median time since initial diagnosis was 6 years. At enrollment, most patients (92%) had an ECOG PS ≤1, and 43% had a Follicular Lymphoma International Prognostic Index score ≥3 (high risk). The median (range) number of prior systemic therapies was 2 (1−8); 20% of the patients had prior HSCT; 47% were refractory to and 41% had relapsed from their most recent therapy. At the data cut-off, 96 patients were evaluable for response, including 74 in DG (Table). The ORR and CRR were 69.8% (95% confidence interval [CI]: 59.6−78.7) and 13.5% respectively, in all evaluable patients, and 71.6% (95% CI: 59.9% - 81.5%) and 13.5%, respectively, in DG. The median time to response was 8 weeks. The median DOR (95% CI) was not reached among responders overall (9.2 months−not estimable) and those in DG (7.4 months−not estimable). The median PFS (95% CI) was 15.8 months (11.3−15.8) overall and 15.8 months (11.0−15.8) in DG. The median follow-up (range) for this population was 10.2 months (1.9−22.2) overall and 9.5 months (1.9−21.1) in DG. Among the 106 patients evaluable for safety, the most common treatment-emergent adverse events (TEAE) were diarrhea (27.4% of patients), nausea (22.6%), cough (18.9%), and fatigue (15.1%). The most common TEAEs grade ≥3 were diarrhea (9.4% of patients), neutropenia (6.6%), and colitis (3.8%). TEAEs leading to dose interruption or dose reduction occurred in 39.6% and 9.4% of patients, respectively. TEAEs leading to treatment discontinuation occurred in 16% of patients. Serious TEAEs observed in ≥2 patients included diarrhea (5.7% of patients), colitis (3.8%), and pleural effusion (1.9%). There were no fatal TEAEs. TEAEs of clinical interest included rash (12.3% of patients), exfoliative dermatitis (1.9%), pneumonia (0.9%), and PJP (0.9%). New or worsening grade ≥3 laboratory test values of clinical interest included increase in alanine/aspartate amino transferase (0.9%/0% of patients), and decrease in neutrophil count (8.5%), platelet count (0%), and hemoglobin (1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safety profile and was generally well tolerated. These results demonstrate a favorable benefit-risk profile in R/R FL. Updated data will be presented. Disclosures Lynch: Morphosys: Consultancy; Takeda: Research Funding; Incyte: Research Funding; TG therapeutics: Research Funding; Rhizen: Research Funding; Bayer: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding. Paneesha:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. McKinney:Verastem: Consultancy; Pharmacyclics: Consultancy; Kite/Gilead: Honoraria, Speakers Bureau; Beigene: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; BTG: Consultancy. Wahlin:Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Belada:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: 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, Other: Travel expenses, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Canales:Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, F. Hoffmann-La Roche, Sandoz: Honoraria; Janssen, F. Hoffmann-La Roche, Sandoz, Takeda: Speakers Bureau. Cunningham:Bayer: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Lilly: Research Funding; Janssen: Research Funding; Clovis Oncology: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Merck: Research Funding; Merrimack: Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; 4SC: Research Funding. Morley:Kite: Honoraria; Janssen: Honoraria; Abbvie: Other: Conference Support; Takeda: Other: Conference Support; Roche: Other: Conference Support; Advisory board. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Trněný:1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Incyte: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); MorphoSys: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy.

No abstract

Background: Allogeneic hematopoietic transplantation (HCT) is frequently considered for patients (pts) with relapsed T-cell lymphoma (TCL) and less often as consolidation of initial therapy. Outcomes from prior registry data show that only 31% of pts remain disease free 3 years after HCT (Smith et al. JCO 2013). However, several single institution studies have superior outcomes. We previously presented an analysis of allogeneic transplant in T-cell lymphoma but have expanded this effort to 12 academic centers with longer follow up (Mehta-Shah ASH 2017). Methods: We analyzed the patient characteristics at time of diagnosis and transplant, treatment history, overall (OS) and progression-free survival (PFS) in consecutive TCL pts who had an HCT from 1/1/2000-12/31/2019 at 12 academic institutions. Results: Patient characteristics are shown in Table 1. 508 pts were identified with median age 51 years (16 - 72). 452 (86.5%) had known remission status at the time of HCT: 245 (54.4%) complete remission (CR), 168 (37.2%) partial remission (PR), 23 (5.0%) stable disease (SD), 16 (3.2%) progressive disease (PD). Seventy-eight (15.5%) had a prior autologous HCT. Thirty-six (7%) pts underwent HCT in CR1, 352 (69%) for relapsed/refractory TCL, and was not specified in 120 pts (24%). The median HCT comorbidity index (HCT-CI) score was 1 (0-11). Conditioning regimens were myeloablative (n=180), reduced intensity/non-myeloablative (n=323), unknown (n=3). Donor type was known for 471 pts: 192 matched related (MRD), 183 matched unrelated (MUD), 53 mismatched (MMD), 18 haploidentical donors, 25 umbilical cord blood. In this series, the 2 year OS and PFS rate following HCT were 59.1% (95%CI: 54.6-63.3%) and 45.8% (95%CI: 41.3-50.2%) respectively. 5 year OS and PFS rate were 50.8% (95%CI: 46.1-55.3%) and 39.4% (95%CI: 34.9-43.9%) (Fig 1) For disease specific 2-year and 5-year PFS, see Table 1. At a median follow-up of 29.7 mo (0.1-263 mo), 163 pts had relapsed and 261 pts had died. The median time from relapse post HCT to death was 10.2 mo (0-158.4 mo). Of 261 deaths: 81 were due to transplant related mortality (TRM), 69 were confirmed to be from TCL, and 111 were from non-relapse mortality/unknown. There was not a significant difference in PFS for pts with AITL, PTCL-NOS, ALK positive ALCL or ALK negative ALCL, with median PFS of 23.2 mo (95%CI:15.3-64.2). However, when AITL was compared specifically to PTCL-NOS or ALCL, those with AITL had a trend towards improved median PFS (51.4 mo vs. 18.4 mo, p=0.14) and improved median OS (not reached vs. 73.1 mo, p=0.26). At 5 years, PFS was worse for CTCL (18.6%, 95% CI: 9.7%-30.0%) compared to PTCL subtypes (43.8%; 95% CI: 37.3%-50.0%)(p<0.001) . However, 5-year OS was similar for CTCL (44.0%, 95% CI: 30.1-56.4%) and PTCL (53.1%, 95% CI: 46.5-59.3%) (p=0.46). The rate of TRM at 1 year was 11.2% (95%CI:8.5%-14.0%). Of evaluable pts, 245/489 (46%) had acute GvHD and 192/473 (40.6%) had chronic GvHD. There were no differences in TRM according to recipient age (p=0.47). Higher HCT-CI was associated with an increased risk of TRM (HR 1.15, 95% CI: 1.031-1.286; p=0.012) Disease status at the time of HCT was associated with PFS (p<0.001). Median PFS for those with CR (n=239), PR (n=164), SD (n=22) or PD (n=14) were 44.6 mo, 8.6 mo, 21 mo, 3.5 mo respectively. Degree of donor match was associated with cumulative TRM (p=0.0241). For pts who underwent MRD, MUD, or MMD HCT, cumulative TRM at 12 months was 8% (95%CI: 5.5-12.2%), 13.1% (95%CI: 9.7-17.8%), 14.7% (95%CI: 8.7-24.6%). Conclusions: We present the largest series of HCT in TCL. In this dataset, HCT provided durable disease control for a significant portion of pts with relapsed or refractory or otherwise high risk TCL. Depth of response to therapy immediate prior to HCT was associated with PFS. Patients with AITL appeared to have a trend towards improved outcome with HCT compared to other common PTCL histologies. Patients with CTCL had a higher rate of relapse compared to PTCL subtypes, but OS was similar. MRD HCTs were associated with lower TRM. This data supports the curative potential of HCT in a patient group with otherwise poor survival and limited treatment options. Disclosures Mehta-Shah: Corvus: Research Funding; Genetech/Roche: Research Funding; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy; Innate Pharmaceuticals: Research Funding. Dahi:Kite: Consultancy. Sauter:Sanofi-Genzyme: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Spectrum Pharamaceuticals: Consultancy; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding. Jacobsen:Novartis: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Astra-Zeneca: Consultancy; Acerta: Consultancy; Merck: Consultancy. William:Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy; Seattle Genetics: Research Funding; Dova: Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria. Barta:Monsanto: Consultancy; Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Atara: Honoraria. Allen:Clinical Care Options: Speakers Bureau; Curio Sciences: Honoraria; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other; Bayer: Consultancy, Other. Song:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene,Takeda: Consultancy, Honoraria; Janssen: 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; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Otsuka: Honoraria. Ruan:Celgene: Consultancy, Research Funding; Seattle Genetics: Research Funding; Kite Pharma: Consultancy; Juno: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy, Research Funding. McKinney:Kite/Gilead: Honoraria, Speakers Bureau; Kite/Gilead, Seattle Genetics, Molecular Templates, BTG, Pharmacyclics, Verastem, Genentech, Inc., Celgene: Consultancy; UNUM, Molecular Templates, Incyte, Beigene, Denovo Biopharma, Pharmacyclics, Nordic Nanovector, BMS, Genentech, Inc., Celgene: Research Funding. Beaven:Tessa Therapeutics: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; MorphoSysAb: Research Funding; LoxoOncology: Research Funding; Celgene: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Porcu:Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Daiichi: Consultancy, Honoraria; Celgene: Research Funding; Cell Medica: Research Funding; Miragen: Research Funding; Verastem: Consultancy; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Horwitz:Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy.