PDF file - 528K, Supplementary Figure 1. BMS908662 enhances human T cell activation in vitro in a concentration-dependent manner. Supplementary Figure 2. BMS908662 inhibits the growth of BRAF mutant tumor cells in vitro. Supplementary Figure 3. BMS908662 enhances murine T cell activation in vitro in a concentration-dependent manner. Supplementary Figure 4. Detection of ERK phosphorylation in activated T cells. Supplementary Figure 5. Gating strategies for OT-1 and ex vivo phosphoflow. Supplementary Figure 6. PLX4720 enhances human T cell activation in vitro in a concentration-dependent manner.

9077 Background: NSCLC with EGFR ins20 represents a significant area of unmet need, with no approved targeted therapies. While several agents targeting EGFR ins20 are in development, wild-type (WT) EGFR-related adverse events (AEs) have been common and challenging to manage. CLN-081 is a novel oral EGFR TKI with broad activity against clinically relevant EGFR mutations, including ins20, and has attenuated activity against WT EGFR relative to EGFR ins20 in vitro, suggesting that CLN-081 may have a more favorable clinical therapeutic window. We present interim results of a multicenter, Phase (Ph) 1/2a trial evaluating CLN-081 in advanced, EGFR ins20 NSCLC (NCT04036682). Methods: Patients (pts) with EGFR ins20 previously treated with platinum-based therapy (tx) were eligible to enroll. Ph 1 dose escalation in this adaptive trial began with an accelerated titration (AT) design, and converted to a rolling six design based upon pre-specified safety criteria or at clinically active doses. Cohort expansion in Ph 1 occurred at any dose where responses were seen. Transition from Ph 1 to 2a was based on a Simon-Two Stage design. Prior tx with EGFR ins20-specific inhibitors was allowed in AT cohorts only. CLN-081 was dosed twice daily (BID) in 21-day cycles. Results: As of 10 November 2020, 37 pts [median age 64 years (44-82); median 2 (1-9) prior lines of tx] received CLN-081 at doses of 30 mg (n = 8), 45 mg (1), 65 mg (12), 100 mg (13), and 150 mg (3) BID. The most common all-grade (gr) treatment-related AEs (TRAEs) were rash (49%), diarrhea (24%), paronychia (16%), nausea (14%), stomatitis (14%), and dry skin (11%). Gr 3 TRAEs included anemia (5%), diarrhea (3%), and increased alkaline phosphatase (ALP) (3%). There was 1 DLT, gr 3 diarrhea at 150 mg BID. No gr ≥ 3 rash or gr 4/5 TRAEs were reported. Four pts (11%) required dose reductions for rash (2), diarrhea (1), and increased ALP (1). Two pts (5%) discontinued tx due to TRAEs of gr 2 hypersensitivity reaction (1) and gr 2 pneumonitis (1); the latter also experienced pneumonitis while receiving prior osimertinib. Among the 25 response evaluable pts (RECIST 1.1), 10 (40 %) had a partial response (PR) (6 confirmed, 2 pending confirmation, 2 unconfirmed), 14 (56%) had stable disease (SD), and 1 (4%) had progressive disease as best response. Of the 4 pts that received prior EGFR ins20 inhibitors, 2 had PR and 2 SD. Of pts with SD or PR as best response, 20/24 (83 %) experienced tumor regression [median regression: -18 % (-100 to +3)]. Enrollment is ongoing and updated data will be presented. Conclusions: CLN-081 has an acceptable safety profile, including diarrhea in < 25% of pts treated to date. CLN-081 has demonstrated encouraging preliminary anti-tumor activity across the full dose range tested, in multiple distinct EGFR ins20 variants, and in heavily pre-treated pts that are either naïve or refractory to other EGFR ins20 inhibitors. Since the time of the data cut, a Ph 2a expansion has been initiated at 100 mg BID. Clinical trial information: NCT04036682.

Introduction: B7-H3, a member of the B7 family of immunomodulatory molecules, is overexpressed in a wide range of solid tumors. B7-H3 tumor overexpression has been correlated with disease severity and poor outcome. MGC018 is a duocarmycin-based antibody-drug conjugate (ADC) targeting B7-H3. MGC018 exhibits a favorable preclinical profile, with strong reactivity toward tumor cells and tumor-associated vasculature, limited normal tissue reactivity, and potent antitumor activity toward B7-H3-expressing tumor xenografts. With the emergence of immune-checkpoint blockade as a promising treatment for cancer, interest has grown in understanding the potential of cytotoxic agents to promote immune surveillance or stimulate immune responses to dying cancer cells, leading to immunological memory. ADCs bearing tubulin and DNA modifying cytotoxic payloads have been reported to induce immunological cell death (ICD), mediate antitumor immunity in immunocompetent mouse models, and synergistically combine with checkpoint inhibitors to deliver enhanced antitumor responses. Based on those results, we investigated the immunomodulatory potential of MGC018 and the prospect to combine with checkpoint blockade to enhance antitumor responses. Methods: Syngeneic mouse models expressing human B7-H3 were employed to investigate the antitumor activity of MGC018 in an immune competent setting. Studies were conducted to assess the role of the immune system in the MGC018-mediated antitumor responses, whether MGC018 could impart antitumor memory responses in vivo, and the potential to enhance antitumor responses by combining MGC018 with PD-1 blockade. Results: MGC018 demonstrated specific, dose-dependent in vivo antitumor activity toward human B7-H3-bearing tumors in immunocompetent syngeneic mouse models. Depletion of CD8+ T cells led to reduced antitumor responses, indicating that CD8+ T cells contributed to MGC018-mediated antitumor activity. Antitumor activity in these models was enhanced when MGC018 was combined with anti-PD-1. Treatment with MGC018 alone, or in combination with anti-PD-1, led to complete antitumor responses, and the majority of mice rejected subsequent tumor rechallenge. Conclusion: MGC018, a clinical-stage therapeutic comprised of a humanized antibody targeting B7-H3, conjugated to a duocarmycin-based DNA alkylating payload, exhibits a favorable preclinical profile. Results from these syngeneic model studies support the hypothesis that the antitumor activity of the duocarmycin-based MGC018 ADC (1) mediates immunomodulatory activity, (2) is enhanced by combination with checkpoint blockade, and (3) induces immunological memory. Our findings support a clinical strategy that combines MGC018 with checkpoint blockade for the treatment of B7-H3-expressing solid cancers. Citation Format: Juniper A. Scribner, Michael Chiechi, Pam Li, Thomas Son, Jeff Hooley, Ying Li, Anushka De Costa, Peter Lung, Nicholas Yee-Toy, Francine Chen, Bhaswati Barat, Christina Wolff, Valentina Ciccarone, James Tamura, Scott Koenig, Chet Bohac, Jon Wigginton, Paul A. Moore, Ezio Bonvini, Deryk Loo. MGC018, a duocarmycin-based antibody-drug conjugate targeting B7-H3, exhibits immunomodulatory activity and enhanced antitumor activity in combination with checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5203.

Background Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. Methods CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. Findings Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19.9 months (IQR 10.7-23.1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18.48%; 95% CI 11.15-27.93) of 92 evaluable patients. Interpretation These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). Copyright (C) 2020 Elsevier Ltd. All rights reserved.

The hypoxia and profound inflammatory response associated with the pneumonitis observed with the severe acute respiratory virus coronavirus-2 (SARS-COV-2) virus responsible for the recent COVID-19 pandemic has overwhelmed intensive care facilities in the epicenters of infection including Wuhan,

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.

Approximately 40% of patients (pts) with newly diagnosed (AML) either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission duration (< 6 months). These pts, herein considered to have primary refractory disease, are an extremely challenging population to treat, with only 14% achieving remission following conventional chemotherapy and with subsequent salvage attempts being nearly universally ineffective (1). Increased immune infiltration of the tumor microenvironment (TME) and high CD123 expression on AML blasts have been associated with primary induction failure and poor prognosis (2, 3). Flotetuzumab (FLZ), a CD123 x CD3 bispecific DART molecule, is currently being tested in a phase 1/2 study in pts with either relapsed or refractory (R/R) AML. We have previously reported FLZ activity in primary refractory AML (4); herein, we provide additional scientific rationale supporting the investigation of FLZ in this patient population. The recommended Phase 2 dose (RP2D) of FLZ identified in an ongoing Phase 1/2 study is 500 ng/kg/day administered as a 7 -day/week continuous infusion. Pts receive a lead-in dose during week (W) 1, followed by 500 ng/kg/day during W2-4 of Cycle 1, and a 4-day on/3-day off schedule for Cycle 2 and beyond. Disease status was assessed by modified IWG criteria; bone marrow (BM) samples were collected to investigate biomarkers, including CD123 receptor density (RD), and gene expression profiling using the NanoString PanCancer IO 360™ panel, which measures the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures. Gene expression comparisons are presented at fold change (FC) and a t-test was used for statistical analysis. Fifty pts with R/R AML received FLZ at the RP2D. Thirty (60%) pts had primary refractory AML: 24 failed ≥2 induction attempts and 6 recurred after remission of <6 months (median duration of remission 32 [range: 29-45] days). This population was heavily pretreated (median 4 previous lines of therapy [range 2-9]), with 40% (12/30) having secondary AML and most having non-favorable cytogenetic risk (60% adverse and 23% intermediate by ELN 2017 risk category). Compared to relapsed pts, those with primary refractory disease had greater CD123 expression on AML blasts (11277±3246 vs 6254±1779 sites/cell), with baseline BM samples showing higher inflammatory chemokine signature scores (1.7x increase, p=0.018), and an enhanced interferon gamma (IFNγ) signaling gene expression score (1.85x increase, p=0.014), a signature associated with resistance to cytotoxic chemotherapy (2). Among 28 primary refractory pts evaluable for disease assessment, FLZ complete remission (CR) rate was 32.1% (3 CR, 3 CRh, 3 CRi). Four pts (1 CR, 1CRh, and 2 CRi) subsequently underwent allogeneic hematopoietic stem cell transplantation. For comparison, the expected CR rate to conventional salvage therapy in this population was calculated as <10%, estimated based on historical response rates of pts subjected to similar numbers and types of salvage therapies (1, 5). Pts with CR showed higher CD123 RD compared to pts with no response (15186.5 vs 10836.8 sites/cell). FLZ anti-leukemic activity (>30% decrease in BM blasts) was associated with increased baseline immune gene signatures, including significantly higher IFNγ scores (1.8 FC, p=0.0212; AUROC=0.74), and an increased tumor inflammation signature (TIS) score (1.658 FC, p=0.00827, AUROC=0.847 compared to non-responders. FLZ was well tolerated, with no increased cytokine release syndrome events in primary refractory pts (30% G1, 67% G2, 3% G3) compared to relapse pts (26% G1, 58% G2, 16% G3), notwithstanding the increased CD123 RD in the former. In conclusion, we show that FLZ elicits clinical response in heavily treated patients with poor response rates to primary therapy. We also show that increased IFNγ signaling gene expression scores in baseline BM appears to associate with response to FLZ therapy. Enrollment has been expanded to further define FLZ's activity specifically in pts with primary refractory AML, and candidate biomarkers to enable identification of pts more likely to respond to FLZ. Estey E, et al. Blood (1996), 88 (2) 756Vadakekolathu J, et al. Blood (2017) 130:3942Vergez F, et al. Haematologica (2011), 96(12):1792-8Uy GL, et al. Blood (2018) 132:764Duong V, et al. Leukemia (2013),13(6):711-5 Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Agios: Consultancy, Honoraria; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; Incyte: Research Funding. Rizzieri:AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; Stemline: Research Funding. Advani:Amgen: Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy. Emadi:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; Jazz Pharmaceuticals: Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Church:NanoString Technologies, Inc.: Employment, Equity Ownership. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Tran:MacroGenics: Employment. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:MacroGenics, Inc.: Employment, Equity Ownership; Western Oncolytics: Other: clinical advisory board. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding. Walter:Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Kite Pharma: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy.

TPS2661 Background: Immune checkpoint molecules, including CTLA-4 and PD-1, attenuate the duration and strength of adaptive immune responses to limit immune-mediated tissue damage. Tumors may inhibit cellular immune activation by expressing ligands that bind checkpoint molecules and inhibit T-cell function in the tumor microenvironment. Blockade of these inhibitory pathways is the primary mechanism of action of several novel cancer immunotherapy agents. Combined blockade of PD-1 and CTLA-4 with two checkpoint inhibitors, ipilimumab and nivolumab, increases antitumor activity beyond either single agent alone in patients with metastatic melanoma or other malignancies. MGD019, a novel bispecific molecule that co-engages and coordinately inhibits both PD-1 and CTLA-4 signaling, was developed to potentially improve antitumor activity and/or safety relative to the monoclonal antibody combination. MGD019 is an Fc-bearing tetravalent DART molecule (bivalent for each antigen) that can independently block either checkpoint molecule, with preferential co-blockade in cells co-expressing both molecules demonstrated in vitro. It is hypothesized that MGD019 might be clinically active in either checkpoint naïve or checkpoint experienced patients after prior PD-1/PD-L1 inhibitors. Methods: This Phase 1 study will characterize safety, dose limiting toxicities, and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD019. Dose Escalation will enroll patients with advanced solid tumors of any histology in sequential escalating doses in cohorts of 3 to 9 patients in a 3+3+3 design. Once the MTD/MAD is reached, a Cohort Expansion phase will characterize safety and initial antitumor activity per RECIST v1.1 and irRECIST in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade. Additional endpoints include pharmacokinetics; immunogenicity; impact of MGD019 on various measures of immune-regulatory effects in peripheral blood and biopsy specimens; and relationship between antitumor activity and gene profiles, tumor mutational burden, and PD-1, PD-L1, and CTLA-4 expression on tumor cells and immune cell infiltrates within biopsy specimens. Patients will be followed for survival approximately every 3 months for 2 years. Clinical trial information: NCT03761017.

Introduction The infiltration of immune cells into tumors has been associated with therapeutic effects in preclinical models and patients with cancer. In AML, we have previously reported that immune infiltrated TME is predictive of failure to cytotoxic chemotherapy, but associated with response to immunotherapy, specifically FLZ (Uy ASH 2018, Rutella ASH 2018). Furthermore, FLZ also affects immune infiltration in the TME (Rutella ASH 2018). NK cells play an important role in AML control (Ruggieri Science 2012). FLZ (MGD006/S80880) is a humanized DART® molecule that bridges CD123 on AML with CD3 on T cells and mediates anticancer activity via T-cell activation and cytolytic activity against the bound cancer cell. While this is well described in vitro, little evidence of this interaction is available in vivo. Methods Patients (pts) were treated on the recommended phase 2 dose (RP2D) of FLZ (multi-step lead-in dose followed by 500ng/kg/day, in 28-day cycles). We studied the bone marrow (BM) tissue samples for 6 primary refractory pts at baseline and after treatment. Response assessment was performed at day 25±3 days of each cycle. Serial BM samples were evaluated using 2 different staining panels (PD-L1, FoxP3, CD8, CD3, CD103 / CD123, CD3, CD57, CD16) on consecutive slides. Slides were stained using a Leica BondRx autostainer and fluorescence imaged using a Polaris Vectra 3 and analyzed using inForm software. A density-based clustering algorithm developed and run in QuPath was used to quantify CD3+ T cell clusters. Results Six pts with primary refractory AML were included in this report. Pts were heavily pretreated (median prior lines of therapy was 3, range 2-9), and had adverse cytogenetic risk (ELN 2017). Three pts had a complete remission (CR) after 1 cycle of therapy (CR, CRh, CRi), two went on the receive allogeneic stem cell transplant (HSCT). In baseline BM samples, CD3 and CD8 cell infiltrates were higher in CR vs non-responders (CD3+ 18.3% ±6.9 vs 9.3% ±1.8; CD8+ 9.4% ±3.5 vs 4.8% ±1.2; mean±SEM). Two of the three CR patients, who underwent HSCT, developed clusters (Figure 1) in their on-treatment biopsies with 65 and 22 clusters of an average of 34 and 17 T cells per cluster, respectively. All clusters in CR pts were found on or adjacent to CD123+ cells. The BM biopsy of the CR pt with no detected clusters had no unequivocal evidence of residual/recurrent leukemic blasts. This pt had their dose interrupted early due to non-treatment related AE (infectious complication) and did not receive a full cycle of treatment; the response was transient and the pt relapsed shortly thereafter. NK cells (CD57+CD16+) were increased in post treatment biopsies of CR vs non-responders (0.93 ±0.31 vs 0.27 ±0.13; mean±SEM) with the largest fold increase in CR (28 vs 9). Lastly, post treatment biopsy PD-L1 expression was higher in non-responders than CR (23% vs 16%) with non-responders exhibiting the largest fold change in total PD-L1+ cells (10.9 vs 2.2). Summary Consistent with its proposed mechanism of action, these data highlight for the first time, the dynamic induction of an increase in T-cell infiltration, and clustering around CD123 AML cells in the bone marrow microenvironment of two AML patients that responded to FLZ. In pts with resistance to FLZ (non-responders) PD-L1 induction was significantly higher indicating that in some pts treatment with sequential check point inhibitor could obviate this mechanism of resistance A trial combining FLZ with sequential administration of a PD-1 inhibitor (MGA012) is currently recruiting pts. Figure 1. Baseline and on-treatment IHC of BM biopsies of a FLZ-treated CR pt showing cluster formation following treatment. Disclosures Bifulco: Ventana: Other: advisory board; PrimeVax: Equity Ownership, Other: ScientificBoard; BMS: Other: Advisory Board; Providnece: Patents & Royalties: Imaging processing; Halio Dx: Other: advisory board. Wigginton:macrogenics: Employment, Equity Ownership; western oncolytics: Consultancy, Other: consultancy. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. Fox:Akoya: Research Funding; Bristol Myers Squibb: Research Funding; Definiens: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Research Funding; Ultivue: Membership on an entity's Board of Directors or advisory committees.

Background Acute myeloid leukemia (AML) blasts and leukemic stem and progenitor cells typically express higher levels of CD123 than their normal hematopoietic stem cell counterparts, making CD123 an attractive target. Leukemic CD123 expression is associated with poor prognosis, high-risk disease, and increased risk of induction failure (Vergez et al 2011). Single-agent flotetuzumab, an investigational CD123 x CD3 bispecific DART protein, has shown evidence of clinical activity in a Phase 1 study of relapsed/refractory (R/R) acute myeloid leukemia (AML). In this study, flotetuzumab led to T-cell activation which in turn was associated with PD-1 induction on T lymphocytes, enhanced IFNɣ secretion, and upregulation of PD-L1 expression by AML blasts (ASH 2018 Rutella, ASH 2018 Uy). In vitro studies have shown synergistic T-cell mediated cytotoxicity of an AML cell line (KG1A) with flotetuzumab in the presence of PD-1/PD-L1 axis blockade compared to flotetuzumab alone. MGA012, also known as INCMGA00012, is an investigational anti-PD-1 antibody that has shown clinical activity in a Phase 1 study (SITC 2018 Mehnert). We hypothesize that combined checkpoint inhibition with MGA012 together with redirected T‐cell killing of CD123+ cells with flotetuzumab may show enhanced activity over flotetuzumab alone. Methods This is a Phase 1 dose escalation study designed to characterize the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined), pharmacokinetics, and preliminary anti-leukemic activity of flotetuzumab in combination with MGA012, each administered intravenously (IV) in patients with R/R AML. Response evaluation will be determined by modified ELN 2017 criteria. Activity is measured by complete response (CR) (complete remission [CR], or CR with partial hematologic recovery [CRh], or CR with incomplete hematological recovery [CRi], or morphologic leukemia-free state [MLFS]) rate, relapse-free survival, or mortality rate at 1 and 3 months. The impact of flotetuzumab/MGA012 combination on overall survival and event-free survival will be explored. Eligible patients will consist of adults with relapsed or refractory AML (any subtype except acute promyelocytic leukemia) who have exhausted standard of care options. In Induction Cycle 1, patients will be treated with a step-up lead in dose of flotetuzumab, followed by continuous infusion flotetuzumab, starting at week 2 of Cycle 1 and continuing through each 28-day cycle. MGA012 will be administered every two weeks. Depending on response, patients will transition to either consolidation or second induction. Eligible patients who achieve CR/CRh/CRi can receive maintenance MGA012 alone for up to 12 months. Disclosures Wei: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. Fong:Novartis: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Gil:Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria; Daiichi-Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria. Perez De Oteyza:Celgene: Speakers Bureau. Rowe:BioSight: Consultancy. Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker. Sun:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. McNulty:MacroGenics, Inc.: Employment, Equity Ownership. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Wigginton:Western Oncolytics: Other: clinical advisory board; MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership.

TPS2601 Background: T cells naturally undergo activation-induced upregulation of co-inhibitory pathways, which may limit the antitumor immune response. Blocking these inhibitory pathways may enhance the antitumor activity of CD3 bispecifics. MGD009 is a clinical stage B7-H3 x CD3 DART protein designed to redirect T cells to kill B7-H3 expressing tumor cells. B7-H3, a member of B7 family of immune regulators, is overexpressed in a variety of solid tumors and has limited expression in normal tissues. In preclinical studies, MGD009 causes T-cell infiltration, activation and expansion in the tumors. It upregulates PD-1 on T cells and PD-L1 on tumor cells and immune cells in vitro. Preliminary observations in patients enrolled in the ongoing phase 1 dose escalation trial with MGD009 alone indicate evidence of PD-1 up-regulation on both peripheral CD4 and CD8 T-cells. MGA012 is an anti-PD-1 antibody under investigation in an ongoing Phase 1 clinical trial and has shown clinical responses. In vitro and in vivo studies have shown enhanced antitumor activity with the combination of MGD009 and MGA012 beyond that achieved with MGD009 alone. A combination approach that blocks checkpoint inhibition of T cells with MGA012, while recruiting cytotoxic and helper T cells to B7-H3-expressing tumors with MGD009, may show anti-tumor activity in a variety of tumors. Methods: This is a Phase 1, open-label, dose escalation, and cohort expansion study designed to characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary antitumor activity of MGD009 in combination with MGA012, both administered by IV infusion. Patients with B7-H3-expressing unresectable, locally advanced or metastatic solid tumors of any histology will be enrolled in the Dose Escalation Phase. Prior checkpoint inhibitor therapy is allowed. Dose escalation uses a 3+3+3 design, with patients treated every 2 weeks with escalating doses of IV MGD009 (starting dose 3µg/kg) and MGA012 at a dose of 3mg/kg in all cohorts. Cohort expansions will be limited to 6 tumor types (N = 20/cohort) treated at the maximum tolerated dose of the combination. Clinical trial information: NCT03406949.

Therapy-related acute myelogenous leukemia (t-AML) is associated with adverse genetic lesions, complex karyotype, and TP53 mutation; it is challenging to treat and confers a poor prognosis. We describe a 74-year-old female patient with AML that developed 9 years after receiving 6 cycles of cytotoxic (FOLFOX) chemotherapy as adjuvant treatment of colorectal carcinoma. At diagnosis, the bone marrow (BM) biopsy revealed blast count of 35%, with normal karyotype, 5q loss and AML1 (RUNX1) locus (21q22) amplification by fluorescence in situ hybridization (FISH). Initial treatment with 5 cycles of azacitidine (AZA) failed to induce a response. The patient was subsequently treated on a Phase 1 trial of flotetuzumab (MGD006/S80880) (FLZ), a novel T-cell redirecting (CD123 x CD3) DART protein [NCT02152956]. Prior to FLZ, BM blasts demonstrated clonal evolution with a complex karyotype (92,XXXX, t(14;21)(q22;q22)) and new IDH1, and TET2 mutations.

As healthcare costs continue to rise, there has been great interest in understanding and defining the value of current therapeutic strategies for the treatment of cancer. Cancer immunotherapy has emerged as a clinically beneficial alternative to conventional therapies for a variety of malignancies. Characterized by broad clinical activity, durable response rates, distinct side effects, and unique response kinetics, immune-based agents are vastly different compared with traditional cytotoxic or targeted therapies. To date, however, value assessments in oncology have not focused on the unique aspects of cancer immunotherapy, which has resulted in a lack of understanding of the true value of these therapies. Therefore, the Society for Immunotherapy of Cancer (SITC) convened key stakeholders to address the critical issues that define the value of cancer immunotherapy in National Harbor, Maryland on November 13, 2016. Organized in collaboration with the American Society for Clinical Oncology (ASCO) and with over 1500 registrants, this Value of Cancer Immunotherapy Summit united research scientists, academic physicians, industry professionals, health economists, third-party payers, and patients to discuss critical issues surrounding the value framework for cancer immunotherapy. This half-day summit addressed the current landscape of cancer therapy value models, economic outcomes, the current status of predictive biomarkers, as well as presentations from third-party payers, industry representatives, patient outcome experts, and patient advocacy groups to gain their perspectives on the value of cancer immunotherapy. Here, we summarize the presentations and the dominant themes from this symposium, with the intention of providing insight on future directions and to develop recommendations to better define the value of cancer immunotherapy for patients with cancer.

140 Background: Trastuzumab (T) + chemotherapy (ctx) is standard for 1st line advanced HER2+ GEA, yet subsequent targeted options are lacking. M is an anti-Her 2 monoclonal antibody with an optimized Fc domain to increase affinity for activating CD16A Fc-receptors (FcR) on NK cells. Outcomes for T-treated patients (pts) carrying the low-affinity CD16A-F allele are generally worse than pts homozygous for the high-affinity V allele. M is designed to be FcR genotype independent. Evidence of clinical activity of M alone has been seen in HER2+ GEA pts post T, while P has demonstrated durable activity. Loss of HER2 amplification may occur after T failure in a subset of initially HER2+ GEA pts. Preclinical studies suggest that engagement of innate and adaptive immunity with the combination of anti-HER-2 antibodies and T-cell checkpoint inhibition could achieve greater antitumor activity than either agent alone. Methods: Advanced HER2+, PD-L1-unselected GEA pts post T failure were eligible. Dose escalation evaluated 10 and 15 mg/kg M and 200 mg P for 2nd line or higher pts. Cohort expansion evaluates safety and objective response rate (ORR) by RECIST v1.1 in 2nd line pts. M + P is given every 21 days; response assessed every 6 weeks. HER2 amplification status was assessed in a subset of pts by plasma circulating tumor (ct) DNA analysis prior to Cycle 1 of M+P. Results: Dose escalation enrolled 9 pts; cohort expansion 48 pts at 15 mg/kg M: 30 in North America (NA) and 18 in Asia (A). Treatment was well tolerated, with 1 drug-related serious adverse event. Of 38 evaluable pts to date in expansion (24 NA and 14 A), the best overall responses include 7 pts (18.4%) with PR (4 confirmed and 3 unconfirmed) and 11 (28.9%) with SD. Higher ORR trends were observed in A vs NA (35.7% vs 8.3%) and G vs GEJ (31.6% vs 5.3%). Of 25 pts with ctDNA results, HER2 amplification detection was higher in GC than GEJ (80% vs 53%). Responses were independent of FcR genotype; CD16A genotype for evaluable pts with PR: 1 V/V, 2 V/F, 2 F/F with similar allelic distribution among non-responders. Conclusions: M+P is a well-tolerated ctx-free regimen that has shown preliminary antitumor activity in 2nd line pts with advanced/metastatic GEA. Clinical trial information: NCT02689284.