Abstract OT1-08-04: A first-in-human phase Ia dose escalation study of GDC-0077, a p110a-selective and mutant-degrading PI3K inhibitor, in patients with PIK3CA-mutant solid tumors

Abstract Background: Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K), are highly prevalent in breast cancer and solid tumor malignancies. GDC-0077 is a potent p110α-selective inhibitor with a novel mechanism of action that degrades mutant p110α and anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with anti-estrogens with or without a CDK4/6 inhibitor. An open-label, Phase I dose-escalation study of GDC-0077 monotherapy and GDC-0077 combined with endocrine therapies and palbociclib is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from th…

Abstract PD1-02: A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background GDC-0077 is a PI3Kα-selective inhibitor and mutant PI3Kα degrader that demonstrates antitumor activity in PIK3CAmut BC xenograft models. A phase I/Ib study of GDC-0077 alone and combined with endocrine therapy ± the CDK4/6 inhibitor (i) palbo is ongoing (NCT03006172). Data from GDC-0077 + palbo + fulvestrant in pts with PIK3CAmut, HR+/HER2- mBC are presented herein. Methods Safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥ 24 weeks, partial response [PR], or complete response) of 9 mg oral once daily GDC-0077 + 125 mg palbo 21/28 days + 500 mg intramuscular fulvestrant on day 1 …

Abstract PD3-06: Neratinib + fulvestrant for HER2-mutant, HR-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT trial

Abstract Background: HER2 mutations define a rare subset of metastatic breast cancer (MBC) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated single-agent clinical activity in HER2-mutant MBC. In HER2-mutant, HR+ MBC, neratinib + fulvestrant (N+F) appears synergistic vs single-agent neratinib, possibly due to more complete inhibition of bi-directional signaling between HER2 and estrogen receptors. Here we describe interim efficacy results of the expanded HER2-mutant, HR+ MBC cohort treated with N+F from SUMMIT (NCT01953926). Methods: HR+ MBC patients (pts) with HER2 mutations documented by local te…

A phase I/Ib study evaluating GDC-0077 (inavolisib) + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract 3363: Pharmacodynamic (PD) assessment of drug activity in tumor tissue from patients (pts) enrolled in a Phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual action antibody, in pts with locally advanced or metastatic epithelial tumors.

Abstract Background Members of the human epidermal growth factor receptor (HER) family of oncogenes are often co-expressed and heterodimerized, suggesting that simultaneous blockade of multiple HER family receptors may be more effective than targeting single receptors. MEHD is a dual-action human IgG1 antibody that can bivalently bind to HER3 and EGFR and block ligand binding to either. FDG-PET imaging is a recognized method of assessing PD modulation with EGFR inhibitors in the clinic. HER3 and EGFR signaling via the MAPK and PI3K pathways can be monitored in tissue by examining phosphorylation of downstream markers. Methods A Phase 1, multicenter, open-label study was conducted to evaluat…

Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors.

Abstract Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1–30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. …

Abstract CT-08: A Phase 1 study of MEHD7945A (MEHD), a first-in-class EGFR/HER3 dual action antibody, in patients (pts) with locally advanced or metastatic epithelial tumors

Abstract Background Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive HER RTK co-expression and heterodimerization suggest that simultaneous blockade of multiple RTKs may be more effective than targeting individual RTKs, and may help prevent or delay development of resistance mechanisms. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to both EGFR and HER3, which is meant to inhibit the activity of the major ligand-dependent HER dimers in cancer. MEHD also elicits antibody-dependent cell-mediated cytotoxicity, and has single-a…

Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

Abstract HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of m…

Abstract CT046: A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors

Abstract Background: PIK3CA, a gene that encodes the α-isoform of the catalytic subunit of Class I PI3K (PI3Kα), is frequently mutated or amplified in solid tumors. Taselisib is an oral, potent, selective inhibitor of Class I PI3Kα, γ, and δ isoforms with enhanced activity against PIK3CA-mutated cancer models. Preclinical and clinical data demonstrated that single-agent taselisib has activity in multiple PIK3CA-mutated tumor types. Methods: This open-label phase I study (Cohort X of PMT4979g; NCT01296555) enrolled patients (pts) with PIK3CA-mutated tumors who had progressed after, or failed to respond to, at least one prior treatment regimen and were not candidates for regimens known to pro…

Abstract PS5-12: Preliminary correlative analysis of clinical outcomes with PIK3CA mutation (mut) status from a phase I/Ib study of GDC-0077 in patients (pts) with hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background Mutations in p110α, encoded by PIK3CA, are present in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, elicits antitumor activity in PIK3CAmut preclinical models as a single agent and when combined with endocrine therapy (ET). New evidence suggests BCs harboring multiple PIK3CAmut exhibit increased signaling through the PI3K/AKT pathway and are more sensitive to PI3Kα inhibitors compared with BCs with a single PIK3CAmut. We report a preliminary analysis of PIK3CAmut status with clinical outcomes from an ongoing study of GDC-0077 alone or with ET (letrozole/fulvestrant) ± palbociclib (palbo) in pts with PIK3CAmut HR+/HER2- mBC (NCT03…

Abstract P1-19-46: A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer

Abstract Background: Dysregulation of the PI3K/AKT/mTOR signaling pathway occurs in solid tumor malignancies. GDC-0077 (G) is a potent p110α-selective, p110α-mutant degrading inhibitor with anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with endocrine therapies (ET) with or without a CDK4/6 inhibitor (i). An open-label, Phase I dose escalation study of Galone and in combination with ET and P is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the combinations of G and L with and without P in pts with PIK3CA-mutant HR+/HER2- breast cancer are presented herein. Methods: This study (NC…

Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, …

Abstract PS11-11: Targeted safety events from a phase I/Ib study evaluating GDC-0077 alone and in combination with endocrine therapy (ET) ± palbociclib (palbo) in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K) occur in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, is being developed as an anticancer agent. A phase I/Ib study of GDC-0077 alone and combined with other therapies is ongoing in pts with locally advanced or metastatic PIK3CAmut, HR+/HER2- mBC (NCT03006172). Targeted safety events are presented here. Methods Safety was assessed via NCI-CTCAE v4 for GDC-0077 administered alone (Arm A), with letrozole and palbo (Arm B), with letrozole (Arm C), with fulvestrant (Arm D), or with fulvestrant and palbo (Arm E, plus metformin in Arm F …

A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual-action antibody, in patients (pts) with refractory/recurrent epithelial tumors: Expansion cohorts.

2568 Background: Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive co-expression and heterodimerization suggest that simultaneous blockade of multiple HER RTKs may be more effective than blockade of a single RTK. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to HER3 or EGFR, and intended to inhibit signaling from all major ligand-dependent HER dimers. MEHD has single-agent activity in multiple tumor models including models resistant to anti-HER3 or anti-EGFR. Methods: This Phase I study evaluated safety, tolerability, pharm…

Abstract PD5-2: Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer

Abstract Background: Taselisib (GDC-0032) is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant (MT) cancers. Taselisib is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PI3K alpha isoform (PIK3CA) MT breast cancer cell lines and enhanced antitumor activity when combined with letrozole. Clinical data with single-agent taselisib also showed increased tumor shrinkage in patients with PIK3CA MT breast cancer as compared to patients with PIK3CA…

336P PI3K pathway biomarkers and clinical response in a phase I/Ib study of GDC-0077 in hormone receptor-positive/HER2-negative breast cancer (HR+/HER2– BC)

Abstract CT109: A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer

Abstract Background: PIK3CA encodes the PI3K p110α subunit, and dysregulating mutations are widely seen in breast cancer (BC) and other solid tumors. GDC-0077 (G) is a potent p110α-selective inhibitor that degrades mutant p110α and demonstrates antitumor activity in PIK3CA-mutant BC xenograft models, either as a single agent, or combined with anti-estrogen therapy. From an ongoing, open-label, phase I/Ib dose-escalation study of G alone and combined with endocrine + targeted therapies (NCT03006172), we present data of G + fulvestrant (F) in postmenopausal patients (pts) with PIK3CA-mutant, hormone receptor-positive/HER2-negative BC, including a food-effect assessment on the pharmacokinetics…