Fowler, Nathan

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (> 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (<10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN &gt;7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

Abstract The ELARA trial indicates tisagenlecleucel (tisa-cel) is an effective anti-CD19 chimeric antigen receptor T-cell therapy for relapsed or refractory follicular lymphoma (r/r FL). As ELARA is a single-arm trial, this study compares tisa-cel outcomes from the ELARA trial with usual care from a real-world cohort. ELARA enrolled 98 patients as of 29 March 2021 (median follow-up: 15 months from enrollment). Usual care data were obtained from ReCORD-FL, a global retrospective study of patients with r/r FL, who met similar eligibility criteria to ELARA. With a data cutoff date of 31 December 2020, 187 patients with ≥2 preceding treatment lines were included in the ReCORD-FL (median follow-up: 57 months from third-line) study. An indirect treatment comparison was performed for 97 patients from the ELARA trial and 143 patients from the ReCORD-FL study with no missing data on baseline factors. The line of therapy for which outcomes were assessed was selected or matched between cohorts using propensity score modeling. After baseline factor adjustment via weighting by odds, complete response rate (CRR; 95% confidence interval) was 69.1% (59.8%-78.3%) for tisa-cel vs. 37.3% (26.4%-48.3%) for usual care; overall response rate was 85.6% (78.7%-92.5%) vs. 63.6% (52.5%-74.7%). Kaplan-Meier probability of being progression/event-free at 12 months was 70.5% (61.4%-79.7%) for tisa-cel vs. 51.9% (40.6%-63.3%) for usual care, with hazard ratio (HR)=0.60 (0.34-0.86); 12-month overall survival was 96.6% (92.9%-100%) vs. 71.7% (61.2%-82.2%), with HR=0.2 (0.02-0.38). In conclusion, tisa-cel was associated with a 1.9-fold higher complete response rate and a 1.4-fold higher rate of being progression or event free at 12 months vs usual care, as well as a death risk reduction of 80%. The findings provide additional evidence on the benefit of tisa-cel in patients with r/r FL after ≥2 treatment lines. This trial was registered at www.clinicaltrials.gov as NCT03568461

Abstract Background: In the ELARA (E2202) trial (NCT03568461), tisagenlecleucel (tisa-cel) demonstrated high response rates in patients with relapsed/refractory follicular lymphoma (r/r FL), including those with high-risk disease, with an overall response rate (ORR) of 86% and complete response rate (CRR) of 66%. As ELARA did not include a comparator arm, an adjusted indirect treatment comparison (ITC) using patient-level data from a global retrospective cohort study was conducted. This study aimed to provide comparative, contextual evidence to the efficacy outcomes of tisa-cel from ELARA relative to standard of care (SOC) in routine practice. Methods: ELARA is an ongoing, single-arm, global, multicenter, phase II trial which evaluates the efficacy and safety of tisa-cel in adult patients with r/r FL. As of March 29, 2021, 98 patients were enrolled with a median follow-up of 15 months. SOC data were obtained from ReCORD-FL, a global retrospective cohort study of clinical outcomes in patients with r/r FL meeting the ELARA eligibility criteria who were treated per routine practice at 10 academic centers across North America and Europe; 7 ReCORD-FL sites are also participating in ELARA, but no patients are enrolled in both studies. In ReCORD-FL, with a data cutoff date of December 31, 2020, a total of 187 patients with ≥2 lines of previous treatment were identified for inclusion, with a median follow-up from third-line of 57 months. A complete-case comparison analysis was performed for 97 ELARA apheresed patients and 143 ReCORD-FL patients with complete data on all baseline variables and prognostic factors used for adjustment. For the comparative analysis, one line of therapy (LoT) per patient was selected using a propensity score model to identify the LoT which had the highest chance of being enrolled in ELARA conditional on baseline characteristics and prognostic factors available at the start of the LoT (i.e., the selected LoT was the one with the highest propensity score to be in ELARA). After selection of LoT, an adjusted ITC was performed to assess the effect of tisa-cel versus SOC by measuring CRR, ORR, progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT). A subgroup analysis of SOC patients with ≥1 eligible LoT initiated from 2014 on (coinciding with the introduction of the Lugano response criteria as well as regulatory approval of idelalisib) was performed for all endpoints. Results: Baseline characteristics for the tisa-cel and SOC cohorts are described in Table 1; after weighting, baseline variables, including number of previous lines of systemic therapy (median: 4 lines) were well balanced between the tisa-cel and SOC cohorts. Treatment regimens observed for ReCORD-FL patients at LoT selection were: anti-CD20 antibody plus alkylator (31.5% of patients), anti-CD20 antibody without alkylator (25.9%), alkylator without anti-CD20 antibody (17.5%), and regimens other than anti-CD20 antibody and alkylator (25.2%). After LoT selection and adjusting for differences in baseline variables, tisa-cel was associated with improvement over SOC in CRR (69.1% vs. 37.3%), ORR (85.6% vs. 63.6%), as well as PFS, TTNT and OS (Table 2, Figures 1-2), with a numerically higher 6-month PFS rate vs. SOC (85.3% vs. 66.5%), as well as higher 24-month OS rate (87.8% vs. 64.8%). Further, there was an estimated 80% reduction in death risk in favor of tisa-cel over SOC, a 40% reduction in risk of progression in favor of tisa-cel over SOC and a 69% reduction in risk of death or requiring a new anticancer therapy (Table 1). In the sub-analysis of SOC patients with lines of therapy initiated in or after 2014, the superiority of tisa-cel over SOC was confirmed in all the efficacy outcomes (CRR: 69.1% vs. 30.5%; ORR: 85.6% vs. 58.8%; hazard ratios substantially &lt; 1 for OS, PFS, TTNT). Conclusion: The ITC results suggest that tisa-cel has superior efficacy over SOC in r/r FL for all evaluated endpoints. A key limitation of this study is that response assessment criteria and schedule was more heterogeneous in ReCORD-FL than in ELARA. However, the sub-analysis on SOC patients assessed with a LoT selected in 2014 or later (when more patients could have been assessed using the Lugano response criteria) showed similar favorability for tisa-cel over SOC in all the efficacy outcomes. Moreover, outcome parameters independent of response criteria, namely OS and TTNT, were also significantly better for tisa-cel vs. SOC. Figure 1 Figure 1. Disclosures Salles: Abbvie, Epizyme, Morphosys, Regeneron: Consultancy, Honoraria; Bayer: Honoraria; Beigene, BMS/Celgene, Debiopharm, Genentech/Roche, Genmab, Incyte, Ipsen, anssen, Novartis. Kite/Gilead, Loxo, Miltneiy, Rapt, TAKEDA, Velosbio, Allogene: Consultancy. Schuster: Acerta Pharma/AstraZeneca: Consultancy; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Dreyling: BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Kuruvilla: AbbVie: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria, Research Funding; Antengene: Honoraria; Roche: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria; Merck: Honoraria; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Novartis: Honoraria; Medison Ventures: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Seattle Genetics: Honoraria; TG Therapeutics: Honoraria. Patten: ROCHE: Research Funding; GILEAD SCIENCES: Honoraria, Research Funding; ABBVIE: Honoraria; NOVARTIS: Honoraria; ASTRA ZENECA: Honoraria; JANSSEN: Honoraria. Von Tresckow: AbbVie: Other: Congress and travel support; Amgen: Consultancy, Honoraria; AstraZeneca: Honoraria, Other: Congress and travel support; BMS-Celgene: Consultancy, Honoraria, Other: Congress and travel support; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Smith: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Celgene, Genetech, AbbVie: Consultancy. Davis: Novartis, Vertex Pharmaceuticals, Pfizer, Eisai, Eli Lilly, AstraZeneca: Research Funding. Anjos: Novartis: Current Employment. Chu: Novartis: Current Employment, Current equity holder in publicly-traded company. Zhang: Novartis: Current Employment, Current equity holder in publicly-traded company. Lobetti Bodoni: Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: Celgene: Honoraria; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: NHS: Ended employment in the past 24 months; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Novartis: Current Employment, Current equity holder in publicly-traded company. Thieblemont: Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dickinson: Janssen: Consultancy, Honoraria; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martinez-Lopez: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Link: Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy; Novartis, Jannsen: Research Funding.

8020 Background: Patients with R/R DLBCL ineligible for autologous stem cell transplant (ASCT) have a poor prognosis. In these patients, tafasitamab (anti-CD19 antibody) plus lenalidomide (LEN) has shown encouraging results in the open-label, single-arm, phase II L-MIND study (n = 81; NCT02399085). To evaluate the contribution of tafasitamab to the activity of this doublet, we conducted a global, real-world study of patients treated with LEN monotherapy (RE-MIND; NCT04150328). Here we present the primary analysis of a 1:1 patient-level matched comparison between the L-MIND and RE-MIND cohorts. Methods: Patients treated with LEN monotherapy for R/R DLBCL were enrolled in the observational, retrospective RE-MIND cohort. As in L-MIND, patients had 1–3 prior systemic therapies, including ≥1 CD20-targeting regimen; were aged ≥18 years; and were not eligible for ASCT. A 1:1 estimated propensity score (ePS) matching methodology ensured balancing of nine pre-specified baseline covariates. The primary analysis set, Matched Analysis Set 25 (MAS25), included patients who received a LEN starting dose of 25 mg/day. The primary endpoint was investigator-assessed best objective response rate (ORR). Key secondary endpoints included overall survival (OS) and complete response (CR) rate. Results: 490 patients were enrolled in RE-MIND across 58 centers in the US and Europe, of which 140 fulfilled the ePS matching criteria. The MAS25 included 76 patients each from the two cohorts. Baseline characteristics between cohorts were comparable. The primary endpoint was met with a significantly better ORR of 67.1% (95% CI: 55.4–77.5) for the L-MIND cohort versus 34.2% (95% CI: 23.7–46.0) for the RE-MIND cohort (odds ratio 3.89; 95% CI: 1.90–8.14; p < 0.0001). The CR rate was 39.5% (95% CI: 28.4–51.4) in the L-MIND cohort and 13.2% (95% CI: 6.5–22.9) in the RE-MIND cohort. A significant difference in OS favored the L-MIND cohort (HR = 0.499; 95% CI: 0.317–0.785). ORR and CR outcomes in the RE-MIND cohort were similar to the published literature for LEN monotherapy in R/R DLBCL. Conclusions: Significantly better ORR, CR and OS indicate potential synergistic effects of the tafasitamab + LEN combination in ASCT-ineligible R/R DLBCL. ePS-based 1:1 matching allows robust estimation of the treatment effect of tafasitamab when added to LEN. RE-MIND demonstrates the utility of real-world data in interpreting non-randomized trials. Clinical trial information: NCT04150328 .

7514 Background: Relapse is expected in treated indolent lymphoma patients, and an unmet need exists to prolong remission with effective therapies. Lenalidomide + rituximab (R2) may improve the efficacy of next treatment by their unique mechanisms. Methods: The AUGMENT phase III study evaluated patients with R/R FL gr 1-3a (82%) and MZL (18%) after ≥ 1 prior systemic therapy (not rituximab refractory). Randomization was 1:1 to R2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c] + rituximab [R] IV 375 mg/m2/wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). The primary endpoint was PFS by 2007 IWG; secondary/exploratory analyses were time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) and response to next treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment. Results: Median PFS was superior for R2 over R/placebo (39.4 vs 14.1 mo; HR = 0.46; P < 0.0001). As of 22June2018, median TTNLT, TTNCT, and PFS2 were not reached for R2, and were significantly longer than R/placebo (HR = 0.54, 0.50, and 0.52, respectively). For 49/178 (28%) R2 and 80/180 (44%) R/placebo patients receiving next antilymphoma therapy, response was generally higher with R2 (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table). Conclusions: These analyses suggest that R2 (vs R/placebo) prolonged time to subsequent treatment and is associated with longer PFS2, enabling greater response to next therapy. Although patient numbers were modest, it is hypothesized that patients who received R2 were generally more sensitive to subsequent therapy than those treated with R/placebo. Clinical trial information: NCT01938001. [Table: see text]

8523 Background: ISIS 481464 is a synthetic bicyclic nucleic acid-containing antisense oligonucleotide that is complementary to the mRNA for signal transducer and activator of transcription 3 (STAT3). Methods: Primary objective of the dose-escalation study (3+3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, tumor response, pharmacokinetics (PK), and pharmacodynamics (PD) using IL-6 and tumor markers. Patient (pt) eligibility included : >18 yrs old, solid tumors or lymphomas refractory to at least 1 prior systemic therapy. ISIS 481464 was administered IV as a loading dose on Days 1, 3, and 5 and then weekly. Results: 15 pts were dosed (4 at 2 mg/kg and 11 at 4 mg/kg). 6 pts had advanced lymphoma (3 DLBCL, 2 Hodgkin’s lymphoma, 1 mantle cell lymphoma) and 9 pts solid tumors. There was one dose limiting toxicity (DLT), a possibly related thrombotic microangiopathy at 4 mg/kg. Treatment emergent thrombocytopenia was observed with an average reduction of approximately 70% from baseline. Three pts, 1 at 2 mg/kg and 2 at 4 mg/kg, experienced nadirs in platelet count below 50x109/L (range 16 to 33x109/L). MTD was not reached; however, given the thrombocytopenia at 4mg/kg, the RP2D was 2mg/kg. Partial responses were observed in 2/3 DLBCL pts. The 1st DLBCL pt (2 mg/kg) with 10 prior treatments had a durable 55% reduction in tumor size and is ongoing treatment at 11 months. This pt had a 76% reduction in IL-6. The 2nd DLBCL pt (4 mg/kg) with 2 prior treatments had a 65% reduction for 4 months and was able to undergo autologous stem cell transplantation. There were no responses in the solid tumor pts. PKs revealed increased plasma trough levels (indicative of tissue concentrations) with increased dose. Conclusions: ISIS 481462 was well-tolerated and the RP2D was determined to be 2 mg/kg. Initial tumor activity was observed in DLBCL pts and a dose expansion in advanced lymphomas is ongoing. Clinical trial information: NCT01563302.

Background: The combination of lenalidomide+rituximab (R2) recently showed superior efficacy vs R-placebo in patients (pts) with R/R iNHL (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved by the US FDA for treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Advanced age at diagnosis is a risk factor in pts with iNHL. We performed post-hoc subgroup analyses by age from AUGMENT and data here focus on pts age ≥ 70 y. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs R-placebo in pts with FL grade 1-3a or MZL previously treated with ≥ 1 systemic therapy with R/R disease but not refractory to rituximab. Pts were randomized 1:1 to R2 or R-placebo. R2 was oral lenalidomide 20 mg/d, d1-21/28 for 12c plus rituximab IV 375 mg/m2 weekly in c1 and d1 of c2-5. R-placebo was rituximab+placebo on the same schedule. The primary endpoint was progression-free survival (PFS) per 2007 IWG response criteria (without PET) as assessed by IRC (central review). Secondary endpoints included overall response rate (ORR), complete response (CR), time to next anti-lymphoma treatment (TTNLT) and safety. Post-hoc analyses were performed by dividing pts into age &lt; 70 y and ≥ 70 y subgroups, the latter group considered unfit for chemotherapy. Results: Of 358 pts randomized (R2, n = 178; R-placebo, n = 180), 267 pts were age &lt; 70 y (R2, n = 131; R-placebo, n = 136), and 91 pts were age ≥ 70 y (R2, n = 47; R-placebo, n = 44). Baseline characteristics including histology, disease status, and prior treatments are shown in the table and were similar across treatment arms in pts ≥ 70 y. At a median follow-up of 28.3 mo, the study met its primary endpoint of PFS, with a hazard ratio (HR) of 0.46 (95% CI, 0.34-0.62; P &lt; 0.0001) in the overall population. R2 had superior PFS vs R-placebo in both &lt; 70 and ≥ 70 y subgroups, with HR of 0.41 (95% CI, 0.29-0.59) and HR of 0.66 (95% CI, 0.37-1.18), respectively. In pts ≥ 70 y, median PFS with R2 vs R-placebo was 24.9 vs 14.3 mo; ORR/CR was 81%/26% vs 59%/16%; and TTNLT was not reached in either arm. Efficacy results for all pts and those &lt; 70 y are reported in the table; notably in pts receiving R2, mPFS was longer in pts &lt; 70 y vs ≥ 70 y (39.4 mo [95% CI, 22.9-NE] vs 24.9 mo [95% CI, 16.4-NE]). In pts ≥ 70 y, any-grade adverse events (AEs) with a ≥ 10 % difference between R2 vs R-placebo included neutropenia (63% vs 11%), constipation (33% vs 16%), cough (33% vs 16%), leukopenia (26% vs 2%), anemia (24% vs 9%), pyrexia (24% vs 9%), pruritus/pruritus generalized (24% vs 2%), muscle spasms (22% vs 11%), rash/rash maculopapular (22% vs 5%), headache (20% vs 9%), thrombocytopenia (17% vs 2%), dyspepsia (13% vs 2%), influenza (13% vs 2%), back pain (7% vs 18%), and nasopharyngitis (4% vs 16%). Also, tumor flare was reported in 9% vs 0% of pts, respectively. In pts ≥ 70 y, 75% of R2 pts vs 36% of R-placebo pts had ≥ 1 grade 3/4 AE, mainly due to neutropenia (50% vs 7%). All other grade 3/4 AEs occurred in &lt; 10% of pts ≥ 70 y in both treatment arms. One grade 5 AE occurred in pts ≥ 70 y (R-placebo arm). In the R2 arm, the median number of treatment cycles was 12 for both the &lt; 70 y vs ≥ 70 y subgroups; however, fewer older pts completed 12 cycles of lenalidomide (76% vs 57%), and more started lenalidomide at the lower dose of 10 mg (6% vs 35%) because of low creatinine clearance, respectively. In the R2 &lt; 70 y and ≥ 70 y subgroups, the average daily dose of lenalidomide was 17.9 mg/d (range, 5.6-20.0) and 14.4 mg/d (range 4.2-20.0), and median relative dose intensity was 95% and 86%, respectively. Conclusions: Similar to the results in the original population, R2 showed superior efficacy vs rituximab monotherapy (plus placebo) as measured by the primary end point of PFS and secondary end points of ORR and CR in pts with R/R FL grade 1-3a and MZL irrespective of age. The efficacy and safety profiles of R2 and R-placebo in pts ≥ 70 y were similar to those reported in the overall population. Older pts treated with R2 vs R-placebo had superior mPFS (24.9 vs 14.3 mo). They were more likely to start lenalidomide at a lower dose and had lower median dose intensity which may have contributed to their shorter mPFS vs younger pts receiving R2. These data show that R2 maintained efficacy improvements vs R-placebo in pts ≥ 70 y, despite higher unfit status and lower overall lenalidomide treatment/exposure. Thus, R2 is an effective and available treatment option for pts with iNHL, including those with advanced age. Disclosures Trněný: Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Leonard:Nordic Nanovector: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Kalambakas:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Fustier:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Gribben:Janssen: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background: Indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is typically responsive to initial chemoimmunotherapy, but relapse is expected. Single-agent rituximab is FDA approved and frequently administered for patients with relapsed/refractory (R/R) low-grade or follicular CD20-positive B-cell NHL. Lenalidomide is an immunomodulatory agent with preclinical and clinical antilymphoma activity alone and in combination with rituximab. We compared the efficacy and safety of lenalidomide plus rituximab (R2) to rituximab (plus placebo) in patients with R/R iNHL. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs rituximab/placebo (control) in patients with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 months after last rituximab dose). Patients were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 years), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 year. R2 patients received oral lenalidomide 20 mg/day (d), d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control patients received rituximab and placebo on the same schedule. Dose modifications were pre-specified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). Secondary endpoints included overall response rate (ORR), complete response (CR), duration of response (DOR), time-to-next antilymphoma treatment (TTNLT), overall survival (OS), and safety. Results: A total of 358 patients were randomized (n = 178 R2; n = 180 control), median age was 63 years (range, 26 - 88), 34% FLIPI score ≥ 3, and histologies of 82% FL/18% MZL. Median number of prior systemic treatments was 1 (range, 1 - 12); 84% received prior rituximab and 51% had prior antilymphoma therapy within 2 years of enrollment. At median follow-up of 28.3 months, the study met its primary endpoint of PFS with HR = 0.46 (95% CI, 0.34 - 0.62; P < 0.0001) (Figure 1). Median PFS was 39.4 months for R2 vs 14.1 months for control. IRC-assessed ORR for R2 was 78% vs 53% for control (P < 0.0001). CR was 34% for R2 vs 18% for control (P = 0.001). Median DOR was 36.6 and 21.7 months for R2 and control arms, respectively. TTNLT was improved for R2 vs control with HR = 0.54 (95% CI, 0.38 - 0.78; P = 0.0007). OS data were not mature with 16 deaths reported in the R2 arm vs 26 deaths in control (HR = 0.61 [95% CI, 0.33 - 1.13]). Selected all-grade treatment-emergent adverse events (TEAEs) of interest more common in the R2 vs control arm (≥ 10% difference) were infections (63% vs 49%), cutaneous reactions (32% vs 12%), constipation (26% vs 14%), thrombocytopenia (15% vs 4%), and tumor flare reaction (11% vs 1%). Grade 3/4 TEAEs were reported in 69% R2 and 32% control patients. More frequent grade 3/4 TEAEs in the R2 vs control arm were primarily attributable to increased neutropenia (50% vs 13%) and leukopenia (7% vs 2%). Grade 5 TEAEs were reported in 2 patients in each arm. TEAEs leading to discontinuation of lenalidomide occurred in 9% of patients vs 5% for rituximab + placebo. Neutropenia was the only TEAE leading to discontinuation of lenalidomide in > 1 patient (n = 5). Seventy-one percent of R2 patients completed all 12 cycles of planned treatment vs 61% of control. Disease progression was the leading reason for discontinuation of lenalidomide/placebo (n = 21 R2, n = 54 control). Conclusions: R2 demonstrated superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of progression-free survival as well as secondary endpoints of ORR, CR, DOR, and TTNLT in patients with R/R FL grade 1-3a and MZL. At this early analysis, fewer deaths have been observed in the R2 arm. Despite additional hematologic toxicity, greater efficacy of the R2 regimen (and fewer early progressions) allowed more patients to complete the planned therapy and delayed the need for subsequent treatment. R2 represents an important new treatment option in patients with previously treated FL/MZL, with meaningful advantages over single-agent rituximab. Disclosures Leonard: Celgene: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; BMS: Consultancy. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria. Izutsu:Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Nihon Medi-Physics: Honoraria; Novartis: Honoraria; Mundhi: Honoraria; HUYA Bioscience International: Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Zenyaku: Research Funding; Celltrion: Research Funding; MSD: Honoraria; Ono: Honoraria, Research Funding; Symbio: Research Funding; Celgene: Consultancy, Research Funding; Solasia: Research Funding; Sanofi: Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Scheliga:INCA - Instituto Nacional Do Cancer, Brazil: Employment. Pinto:Servier: Consultancy; BMS: Honoraria, Research Funding; MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Scheinberg:Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Speakers Bureau. Flinn:Trillium: Research Funding; Takeda: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Verastem: Research Funding; ArQule: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Agios: Research Funding; BeiGene: Research Funding; Kite: Research Funding; Portola: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forma: Research Funding; Merck: Research Funding; Novartis: Research Funding; Constellation: Research Funding; Curis: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Moreira:Instituto Português de Oncologia do Porto FG, EPE, Porto, Portugal: Employment. Liu:Celgene: Employment, Equity Ownership. Kalambakas:Celgene: Employment, Equity Ownership. Fustier:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Gribben:Cancer Research UK: Research Funding; Unum: Equity Ownership; Novartis: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; NIH: Research Funding; Roche: Honoraria; Janssen: Honoraria, Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Honoraria.