own shares of Faron Pharmaceuticals. M Hollmén reports receiving funding from Faron for the preclinical development of anti-Clever-1 mAbs. S Shetty, P Bono and M Hollmén have received consultancy fees from Faron. P Bono reports (outside the submitted work) honoraria from Bristol-Myers Squibb, MSD, Pfizer, Novartis, Oncorena, TILT Biotherapeutics, Ipsen, EUSA and Herantis Pharma, and stock ownership: TILT Biotherapeutics and Terveystalo. Translational Relevance: Successfully overcoming innate immune checkpoints remains elusive in cancer therapy. We demonstrate that adaptive immune activation in advanced cancer can be achieved by modulating endo-lysosomal acidification and antigen degradation in macrophages. Thus, targeting scavenger receptors may provide an attractive immunotherapeutic strategy in cancer.Research.

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3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.

3097 Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8 T cell responses with robust anti-tumor activity. Targeting CLEVER-1 could therefore overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. Methods: The MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced cancers including immunotherapy-refractory melanoma, cholangiocarcinoma, hepatocellular carcinoma, ovarian cancer, colorectal (CRC), and pancreatic ductal adenocarcinoma. Part 1 consisted of a dose escalation phase; 30 pts (median age 65, range 30-81) were enrolled to examine 5 dose levels (0.1, 0.3, 1.0, 3.0, 10 mg/kg), to determine the optimal dose of FP-1305 for Parts 2 and 3. Two-stage time-to-event continual reassessment method (TITE-CRM) was utilized for the dose escalation in Part 1. Pts received 1-8 cycles (median 3) of FP-1305 Q3w. FP-1305 was well tolerated without dose-limiting toxicities. A consistent increase in blood NK cells, CD8/CD4 T cell ratio, B cells and a decrease in regulatory T cells was demonstrated. FP-1305 dosing led to the activation (CD25+) and Th1 skewing (CXCR3+) of T cell populations including increase in effector CD8 T-cells with downregulation of several inhibitory immune checkpoint molecules (PD-1, PD-L1, CTLA-4, and LAG3). Increased circulating IFNɣ levels were detected, with the highest levels in a heavily pretreated metastatic, microsatellite stable (MSS) colorectal cancer patient leading to a partial tumor response (-52%). FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response especially in non-inflamed tumors. Full safety, pharmacokinetic and efficacy results of MATINS trial (Part 1) will be presented for the first time in a final late breaking abstract. Clinical trial information: 2018-002732-24 .