Maurizio Ceppi

First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors.

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.

Phase Ib study of lumretuzumab plus cetuximab or erlotinib in solid tumor patients and evaluation of HER3 and heregulin as potential biomarkers of clinical activity

Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non–small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR. Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406–15. ©2017 AACR.

Direct estrogen receptor (ER) / HER family crosstalk mediating sensitivity to lumretuzumab and pertuzumab in ER+ breast cancer

Bidirectional cross talk between members of the human epidermal growth factor family of receptors (HER) and the estrogen receptor (ER) is believed to underlie resistance mechanisms that develop in response to treatment with anti-HER agents and endocrine therapy. We investigated the interaction between HER2, HER3 and the ER in vitro using human embryonic kidney cells transfected with human HER2, HER3, and ERα. We also investigated the additive efficacy of combination regimens consisting of anti-HER3 (lumretuzumab), anti-HER2 (pertuzumab), and endocrine (fulvestrant) therapy in vivo. Our data show that both HER2 and HER3 can directly complex with the ER and can mediate phosphorylation of the ER. Phosphorylation of the ER was only observed in cells that expressed both HER2 and ERα or in heregulin-stimulated cells that expressed both HER3 and ERα. Using a mouse xenograft model of ER+/HER2-low (HER2 immunohistochemistry 1+ or 2+ without gene amplification) human breast cancer we show that the combination of lumretuzumab and pertuzumab is highly efficacious and induces long-lasting tumor regression in vivo and adding endocrine therapy (fulvestrant) to this combination further improved efficacy. In addition, a prolonged clinical response was observed with the combination of lumretuzumab and pertuzumab in a patient with ER+/HER2-low breast cancer who had failed endocrine therapy. These preclinical data confirm that direct cross talk exists between HER2/HER3 and ER which may explain the resistance mechanisms to endocrine therapy and monoclonal antibodies that target HER2 and HER3. Our data also indicate that the triplet of anti-HER2, anti-HER3, and endocrine therapy might be an efficacious combination for treating patients with ER+/HER2-low breast cancer, which is an area of significant unmet medical need.

Abstract LB-085: RG70099: A novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment

IDO1/TDO* mediate substantial immunosuppressive effects through the metabolism of tryptophan (Trp) to kynurenine (Kyn). The consequent decrease in Trp suppresses T cell activity by multiple mechanisms, including the activation of GCN2 and mTOR pathways. Additionally, increased levels of Kyn further enhance the effect of Trp metabolism by engagement of aryl hydrocarbon receptor and potentially enhancing the number and activity of regulatory T cells. Taken together, expression of IDO1 and TDO in the tumor micro-environment dampens tumor-specific effector T cell response, and elevated expression of IDO1/TDO correlates with reduced survival of cancer patients. IDO1 selective inhibitors have already demonstrated clinical anti-tumor activity for certain tumor types. Therefore, targeting the Trp/Kyn pathway via simultaneous inhibition of IDO1 and TDO enzymes has the potential to bring enhanced benefit to cancer patients by relieving immunosuppression in a wide variety of tumor types. We have discovered a novel, highly potent, small molecule IDO1/TDO dual inhibitor, RG70099, with favorable preclinical oral bioavailability and safety profile. RG70099 potently inhibits both enzymes in cell based assays (IDO1 IC50: Our data show for the first time that a dual inhibition of IDO1 and TDO significantly reduces Kyn levels in preclinical tumor models. RG70099 is a potent, dual-selective IDO1 and TDO small molecule inhibitor with favorable pharmaceutical and pharmacokinetic properties that has the potential to relieve immunosuppression by both IDO1 and TDO and activate anti-tumor immune responses for a broad range of cancer types. *IDO1: Indoleamine 2,3-Dioxygenase 1; TDO: Tryptophan 2,3-Dioxygenase Citation Format: Gabor Gyulveszi, Christine Fischer, Massimiliano Mirolo, Martin Stern, Luke Green, Maurizio Ceppi, Haiyan Wang, Beatrice Burgi, Andreas Staempfli, Wolfgang Muster, Robert van Waterschoot, Andreas Gloge, Hadassah Sade, Irina Klaman, Gabriele Hoelzlvimmer, Arjun Surya, Monali Banerjee, Ritesh Shrivastava, Sandip Middya, Dharmendra Yadav, Sourav Basu, Gonzalo Acuna. RG70099: A novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-085.

EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion

Rearrangements of NRG1 have been identified in invasive mucinous adenocarcinoma of the lung (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma. NRG1 ligand signals through induction of HER2-HER3 heterodimers, thus leading to PI3K-AKT pathway activation. Therefore, targeting HER2, HER3 and the downstream pathway may be a hypothesis-driven strategy for IMA with NRG1 fusion. Herein we reported two patients who benefited from lumretuzumab, a monoclonal anti-HER3 antibody, in combination of erlotinib during a clinical trial (NCT01482377). At least sixteen weeks of progression-free survival were achieved without any unacceptable toxicity.

Abstract A092: Phase 1 trial of RO6874813, a novel bispecific FAP-DR5 antibody, in patients with solid tumors

Introduction: FAP-DR5 (RO6874813) is a novel bispecific antibody that binds with high and low affinity to fibroblast activation protein (FAP) and death receptor 5 (DR5), respectively. FAP-driven binding of RO6874813 mediates the high levels of DR5 clustering that are required for triggering cell death. Here, we present ongoing phase 1 data in patients with advanced solid tumors who were treated with escalating doses of single agent RO6874813 and assessed for tolerability. Methods: Study endpoints are safety and tolerability (primary) and antitumor activity (secondary). The study uses a continuous reassessment method (CRM) design for dose escalation. Patients received drug (IV ≤ 90 min) weekly (QW) or every other week (Q2W), starting with a run-in dose on Cycle 0/Day 1 (C0/D1) of 0.5 mg/kg for all cohorts to characterize linear and nonlinear pharmacokinetics (PK) . Doses administered at C1/D1 ranged from 1.0 to 45 mg/kg (3 or more patients per cohort). Dosing continued until progression of disease (PD) or toxicity occurred. Plasma biomarkers (BM) of DR5 binding (TRAIL, the DR5 ligand) and apoptosis (ccCK18) were measured at multiple timepoints. Archival or fresh tumor samples collected prior to RO6874813 treatment were analyzed for target expression by IHC and mRNA (qRT-PCR), cellular infiltrates, and apoptosis. Results: As of 26 April 2017, 32 patients have been treated with RO6874813. Patients had a median of 3.5 prior regimens (range 1-11) and received a median of 4 (range 2-21) doses of RO6874813. One patient (NSCLC) remains on treatment; 31 discontinued treatment (30 for PD; 1 for subject decision). A maximum tolerated dose has not been reached. The most common treatment-related adverse events (TR-AEs) were: fatigue (21.9%); nausea (15.6%), and infusion-related reactions (9.4%). Grade (Gr) ≥3 TR-AEs occurred in 2 patients (6.25%): anemia and asthenia (both Gr 3, occurring in 1 patient each). No Gr 4/5 TR-AEs and no protocol-defined DLTs were reported. No AE led to permanent study drug withdrawal; 5 patients died from PD, one within 30 days of their last dose. Thirty-one patients were evaluated for antitumor activity: using RECIST criteria, 1 PR (NSCLC; time on treatment = 324 days, ongoing) and 6 stable diseases (SD; median duration 42 days) were observed. 28 patients were evaluated by PET, with 2 (7%) FDG partial metabolic responses (EORTC criteria) seen. No difference was found between QW (used with select doses) and Q2W schedules for safety, antitumor activity, and PK/PD parameters. RO6874813 serum concentrations increased linearly with dose and revealed saturation of TMDD at ≥ 5 mg/kg (Q2W). For the single patient with a PR (30 mg/kg; Q2W), the Cmax at C1 exceeded that of other patients and showed accumulation over time, despite two dose interruptions for Gr 2 neutropenia. Blood BM analyses revealed a significant upregulation of TRAIL and ccCK18 after dosing in this and other patients, suggesting apoptotic activity. FAP and DR5 were expressed in tumor tissue of all patients. Conclusions: RO6874813 demonstrated a favorable safety profile in patients with multiple solid tumor types, and dose escalation and regimen optimization continue. Preliminary antitumor activity was observed in a patient with heavily pretreated NSCLC. Analyses required to support the hypothesis that FAP-binding mediates sufficiently high levels of DR5 clustering for apoptosis induction are ongoing. Citation Format: Johanna Bendell, Jean-Yves Blay, Philippe Cassier, Todd Bauer, Catherine Terret, Claudia Mueller, Anthony Morel, Evelyne Chesne, Zhi-xin Xu, Jean Tessier, Maurizio Ceppi, Ian James, Sabine Wilson, Elizabeth Quackenbush, Maria Ochoa de Olza, Josep Tabernero, Maria De Miguel, Emiliano Calvo. Phase 1 trial of RO6874813, a novel bispecific FAP-DR5 antibody, in patients with solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A092.