Volker Wacheck

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab. Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non–small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. Clin Cancer Res; 23(8); 1910–9. ©2016 AACR.

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2–7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drugs half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344–56. ©2016 AACR.

Abstract A55: Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma

Background: Activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor receptor (MET) pathway promotes tumor growth, invasion and dissemination. Emibetuzumab is a humanized IgG4 monoclonal antibody that binds to and inhibits ligand-dependent and ligand-independent activation of MET. In the first-in-human dose escalation study NCT0128756, emibetuzumab demonstrated favorable tolerability when administered up to 2000mg Q2W IV in unselected patients. The study was expanded to evaluate emibetuzumab in expansion cohorts for patients with tumors positive for MET expression. Methods: Patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC) with bone metastasis, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) received 2000 mg emibetuzumab Q2W IV on a 28-day cycle. RCC, NSCLC, and HCC patients were required to have measurable disease as defined by RECIST v1.1 and have MET positive tumors (≥50% of cells to be ≥2+ for MET expression) as determined by a MET IHC assay (Ventana). The objectives were to evaluate the safety and activity of emibetuzumab in patients with MET positive tumors. Additional objectives included pharmacokinetics (PK) and pharmacodynamics (PD). Results: A total of 62 patients received emibetuzumab across the 4 cohorts: CRPC n = 15, RCC n = 19, NSCLC n = 19,and HCC n = 9, with a median of prior systemic oncology therapies of 6, 3, 5, and 3, respectively. Common possibly related treatment-emergent adverse events included fatigue (29% all grades, 3% Gr3/4), nausea (13% all grades, no Gr3/4), edema of limbs (8% all grades, 2% Gr3/4), and anorexia (8%, no Gr3/4) and were similar among cohorts. No evidence of clinical activity was observed in CRPC patients. For RCC, NSCLC, and HCC patients with MET positive tumors, an overall disease control rate (DCR = partial response [PR] + stable disease [SD]) of 32% (15/47) was observed. In the individual cohorts, DCR was 26% (5/19) in RCC, 26% (5/19) in NSCLC, and 56% (5/9) in HCC. The median duration of disease stabilization in the 3 cohorts was: 4.2 months (range 1.6-24.6) in RCC, 3.9 months (range 2.5-6.4) in NSCLC, and 3.7 months (range 1.2-6.6) in HCC. One PR was observed in an HCC patient with MET amplification. After a single dose of 2000 mg emibetuzumab, PK parameters were similar among these cohorts and also comparable to patients treated at this dose during dose escalation. Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted. Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A55.

MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping

SummaryPurpose Approximately 3% of lung cancer bears mutations leading to MET exon 14 skipping, an oncogenic driver which is further evidenced by case reports of patient response to MET kinase inhibitor treatment. Approximately 15% of tumors harboring MET exon14 skipping have concurrent MET amplification. Experimental Design Merestinib is a type II MET kinase inhibitor. Emibetuzumab, a bivalent anti-MET antibody, internalizes MET receptor. Each single agent and the combination were evaluated in the Hs746t gastric cancer line bearing MET exon14 skipping and MET amplification. Results Merestinib inhibited Hs746t cell proliferation (IC50=34 nM) and totally eliminated pMET at 100nM. Emibetuzumab showed little anti-proliferative activity against Hs746t cells (IC50>100nM), did not reduce pMET, and slightly reduced cell surface MET. In the Hs746t xenograft model, dose dependent differences in durability of response were seen with merestinib including durable tumor regression (91.8%) at 12 mg/kg qd. Emibetuzumab treatment (10mg/kg qw) provided transient tumor regression (37.7%), but tumors re-grew while on treatment. Concurrent combination of merestinib (6 mg/kg qd) and emibetuzumab resulted in 85% tumor regression, while a sequential combination (initiating merestinib first) resulted in longer duration of treatment response. Conclusions Data in this study support a clinical evaluation of merestinib in patients with MET exon 14 skipping (NCT02920996). As a type II MET kinase inhibitor, merestinib may provide a therapeutic option to treatment naïve patients or to patients who progress on type I MET inhibitor treatment. Data also support clinical evaluation of the sequential combination of merestinib with emibetuzumab when patients progress on single agent merestinib.

MET in gastric cancer with liver metastasis: The relationship between MET amplification and Met overexpression in primary stomach tumors and liver metastasis

Although MET amplification/overexpression was observed in a subset of gastric cancer (GC) patients, the relationship between MET amplification/overexpression in primary GC and liver metastasis was unclear.

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. Patients and Methods: A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug–drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20–450 mg) or twice-daily dosing (150–250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. Clin Cancer Res; 24(14); 3253–62. ©2018 AACR.

Abstract 3259: LY3127804, a novel anti-Angiopoietin-2 antibody in combination with an anti-VEGFR2 antibody potently inhibits angiogenesis, tumor growth and metastasis

Angiopoeitin-2 (Ang2) is released from endothelial cells only in response to stimulus (e.g. wound healing, tumor growth) and facilitates blood vessel sprouting and inhibits pericyte-endothelial cell interaction via Tie2 signaling. Combination of an anti-Ang2 antibody and aflibercept, a VEGF trap, has been shown to inhibit tumor growth and decrease tumor vascularity in mouse xenograft tumor models (Daly et al., Cancer Res (2013) 73(1):108). Multiple investigational anti-Ang2 antibody therapies are currently in clinical trials. LY3127804 is a humanized and engineered IgG4 isotype antibody that selectively binds to Ang2 with high affinity and neutralizes Ang2 induced phospho-Tie2. LY3127804 inhibits sprouting angiogenesis and increases pericyte coverage in a mouse developmental retinal angiogenesis model and in mice bearing PC3 xenograft tumors. Combination of LY3127804 and DC101, a potent anti-VEGFR2 antibody, exhibits enhanced efficacy when compared to monotherapy in multiple patient derived xenograft models including NSCLC and ovarian cancers. Anti-Ang2 antibody monotherapy alone resulted in marginal reduction of tumor growth and improved overall survival, while DC101monotherapy had greater reduction in tumor volume with no survival benefit in MDA-MB-231 breast orthotopic model. Combination of anti-Ang2 antibody with anti-VEGFR2 antibody shows reduction in tumor volume and improved overall survival. This robust pre-clinical evidence supports testing the combination of anti-Ang2 and anti-VEGFR2 antibodies in the clinic. LY3127804 is currently in Phase 1 clinical trials (NCT02597036) Citation Format: Sudhakar R. Chintharlapalli, Johnny E. Croy, Donmienne Leung, Damien Gerald, Jirong Lu, Philip W. Iversen, Linda N. Lee, Lysiane Huber, Jonathan Tetreault, Rowena Almonte-Baldonado, Jianghuai Xu, Bharathi Ramamurthy, Jennifer A. Pereira, Chi-Kin Chow, Axel-Rainer Hanauske, Volker Wacheck, Laura Benjamin, Ling Liu. LY3127804, a novel anti-Angiopoietin-2 antibody in combination with an anti-VEGFR2 antibody potently inhibits angiogenesis, tumor growth and metastasis. [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 3259.

Abstract C121: A non-randomized, open-label, single-arm, phase 2 study of LY2875358 in Asian patients with MET diagnostic positive, advanced gastric cancer

Introduction: MET is expressed in gastric cancer and associated with poor clinical outcome. LY2875358 (LY) is a humanized immunoglobin G4 (IgG4) monoclonal bivalent antibody blocking ligand-dependent and independent MET signaling. In preclinical studies, LY showed single agent anti-tumor activity for MET amplified gastric cancer in xenograft models. Based on these results, a non-randomized, multicenter, single-arm, open-label, Phase 2 study was conducted to evaluate the antitumor activity of LY in patients (pts) with MET diagnostic positive (+), advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Pts with MET diagnostic (+), advanced gastric or GEJ adenocarcinoma, who had received 2 prior chemotherapies, were administered LY 2000 mg as flat dose intravenously every 2 weeks (Q2W) on a 28 day cycle. MET diagnostic (+) tumor status was determined by immunohistochemistry (IHC). The primary objective was to evaluate the activity of LY in terms of progression-free survival (PFS) rate at 8 weeks (+ 3 days). Secondary objectives were to assess other efficacy variables (eg overall response rate, disease control rate [DCR], PFS, overall survival [OS]), toxicity and safety profile of LY, and pharmacokinetics (PK). The exploratory objectives included evaluation of pharmacodynamics, pharmacogenomics, and exploratory biomarkers. Results: Tumor samples of 65 pts were screened for MET expression by IHC and 15 pts (23.1%) with MET diagnostic (+) were enrolled in this study. Fifteen pts (5 female, 10 male) from Asia (Japan 8, Korea 7) with a median age of 63 years (range 39-74) were enrolled. PFS rate at 8 weeks was 47% (70% Confidence Interval [CI]: 33%, 59%). There was no partial response according to RECIST, while shrinkage of tumor size was observed in 3 out of 15 pts. DCR was 40.0%, with stable disease shown in 6 out of 15 pts. Median PFS was 8.3 weeks (95% CI: 4.1, 12.1) with stable disease for up to a maximum of 37.1 weeks. Median OS was 17.1 weeks (95% CI: 6.3, Not Available). A total of 12 pts (80%) experienced at least 1 LY-related treatment-emergent adverse event (TEAE). Common LY-related TEAE (all grades) included constipation and hypoalbuminemia (3 pts [20%] each). LY-related TEAEs with Grade ≥ 3 were hyponatremia and hyperuricemia (2 events in 1 patient), and hyperkalemia (1 patient). Serious adverse events were reported in 6 patients, none of which was related to LY. There was no TEAE leading to death or study treatment discontinuation. PK profiles were similar to those observed in previous studies of LY monotherapy, which were conducted in the United States, and the majority of patients were Caucasian. Exploratory biomarker analysis (IHC data) will be presented at the venue. Conclusion: LY 2000 mg Q2W showed a well-tolerated safety profile with a limited single agent activity in heavily pretreated patients with MET diagnostic (+), advanced gastric or GEJ adenocarcinoma. Citation Format: Hyun Cheol Chung, Taroh Satoh, Do-Youn Oh, Se Hoon Park, Shigenori Kadowaki, Volker Wacheck, Ayuko Yamamura, Kazunori Uenaka, Xuejing Aimee Wang, Sameera R. Wijayawardana, Toshihiko Doi. A non-randomized, open-label, single-arm, phase 2 study of LY2875358 in Asian patients with MET diagnostic positive, advanced gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C121.