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Figure 1 Mean ({plus minus}SD) serum lumretuzumab profiles following multiple ascending doses from 100 mg up to 2000 mg Figure 2 Percentage change in standardized uptake value maximum from baseline as assessed by FDG-PET at (a) Cycle 1 Day 14 and (b) Cycle 4 Day 14 Table 1 Summary of baseline and change in HER3 expression measured by IHC in skin and tumor biopsy samples pre and post treatment with lumretuzumab Table 2 Summary of change in expression of HER3, HER2, EGFR and cMET in fresh tumor biopsies compared to primary archival samples Table 3 Peripheral blood immunophenotyping (T, B and NK cells and NK subsets) from patients dosed with 2000 mg lumretuzumab Table 4 Ex-vivo activation potential of peripheral NK lymphocytes for all patients at ba seline and following exposure to lumretuzumab in the 2000 mg dose cohort Table 5 Summary of tumor immune effector cell infiltration Table 6 Tumor response to treatment (RECIST)

Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration–time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80–225 days).Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards. Clin Cancer Res; 22(4); 877–85. ©2015 AACR.

Figure 1 Mean ({plus minus}SD) serum lumretuzumab profiles following multiple ascending doses from 100 mg up to 2000 mg Figure 2 Percentage change in standardized uptake value maximum from baseline as assessed by FDG-PET at (a) Cycle 1 Day 14 and (b) Cycle 4 Day 14 Table 1 Summary of baseline and change in HER3 expression measured by IHC in skin and tumor biopsy samples pre and post treatment with lumretuzumab Table 2 Summary of change in expression of HER3, HER2, EGFR and cMET in fresh tumor biopsies compared to primary archival samples Table 3 Peripheral blood immunophenotyping (T, B and NK cells and NK subsets) from patients dosed with 2000 mg lumretuzumab Table 4 Ex-vivo activation potential of peripheral NK lymphocytes for all patients at ba seline and following exposure to lumretuzumab in the 2000 mg dose cohort Table 5 Summary of tumor immune effector cell infiltration Table 6 Tumor response to treatment (RECIST)

Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy +/- pembrolizumab is a standard first-line option but only provides an incremental overall survival (OS) benefit vs chemotherapy. Anticalin® proteins are recombinant human proteins based on lipocalins. Cinrebafusp alfa, a first-in-class bispecific antibody-Anticalin fusion protein, targets HER2 and the co-stimulatory immune receptor 4-1BB on T cells. In a previous Phase 1 study cinrebafusp alfa monotherapy was generally well tolerated and showed deep and durable responses in patients with HER2-positive gastrointestinal malignancies at doses of 8mg/kg Q2W and 18mg/kg Q2W. Significant induction of plasma 4-1BB as well as increase of CD8+ cells was observed in on-treatment tumor biopsies at active dose levels (Piha-Paul, SITC 2020). Based on pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy data, a phase 2 dose of 18mg/kg Q2W in C1 followed by 8mg/kg Q2W maintenance was chosen. Methods: This is a global, open-label, multicenter, two-arm phase 2 trial of cinrebafusp alfa in patients with metastatic gastric or gastroesophageal junction cancer. Arm 1 is enrolling patients with HER2 high (Immunohistochemistry (ICH) 3+ or IHC 2+ with HER2/neu gene amplification) disease. Pts who have received one prior treatment regimen for metastatic disease, including HER2-directed therapy such as trastuzumab are eligible. Pts will receive cinrebafusp alfa in combination with ramucirumab and paclitaxel. Arm 2 is enrolling patients with HER2 low (IHC 1+ or 2+ without HER2/neu gene amplification) disease. Pts who have received at least one prior treatment regimen for metastatic disease are eligible. Pts will receive cinrebafusp alfa in combination with tucatinib. After a run-in consisting of 3 pts in each arm, an additional 17 patients will be enrolled in each arm. For Arm 1, an additional 40 patients may be enrolled after a futility analysis has been conducted. Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is confirmed overall response rate per RECIST 1.1 and key secondary endpoints are duration of response, progression free survival, overall survival, safety, PK, and immunogenicity. Recruitment is ongoing. Approximately 10 sites in 3 countries in US, Asia and Europe are expected to participate. Citation Format: Sarina A. Piha-Paul, Mukul Gupta, Do-Youn Oh, Yeul Hong Kim, Sun Young Rha, Yoon-Koo Kang, Marc Diez Garcia, Tania Fleitas Kanonnikoff, Virginia Arrazubi Arrula, Kayti Aviano, Tim Demuth, Geoffrey Ku. A phase 2, multi-center, open-label study of cinrebafusp alfa (PRS-343) in combination with ramucirumab and paclitaxel in patients with HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma and in combination with tucatinib in patients with HER2 low gastric or gastroesophageal junction (GEJ) adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT122.