William Kubasek

Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer

Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.

246PA META-ANALYSIS OF BIOMARKERS IN THREE RANDOMIZED, PHASE 2 STUDIES OF MM-121, A LIGAND-BLOCKING ANTI-ERBB3 ANTIBODY, IN PATIENTS WITH OVARIAN, LUNG, AND BREAST CANCERS

ABSTRACT Aim: Heregulin (HRG)-driven ErbB3 signaling mediates resistance to standard-of-care (SOC) cancer therapy in a variety of preclinical models. MM-121, a HRG-blocking anti-ErbB3 antibody, underwent clinical evaluation to determine if patients with advanced malignancies would derive benefit from the addition of MM-121 to their standard therapy. Potential predictive biomarkers were identified from a pre-specified set of mechanistic markers. Study BM+ n/N* BM+ Prevalence PFS HR in study PFS HR in measured BM PFS HR in BM+ PFS HR in BM- Ovarian 69/150 46% 1.03 [0.74-1.42] 1.10 [0.74-1.63] 0.40 [0.21-0.76] 2.02 [1.17-3.50] Lung 36/67 54% 0.82 [0.55-1.21] 0.91 [0.51-1.61] 0.39 [0.18-0.82] 2.43 [1.07-5.55] Breast 21/57 37% 0.75 [0.48-1.15] 0.68 [0.38-1.23] 0.35 [0.13-0.94] 0.99 [0.47-2.08] *n = BM + , N = patients with measured biomarkers Methods: Randomized Phase 2 studies were conducted in: i) platinum-resistant ovarian cancer, ii) EGFR wt NSCLC, and iii) ER/PR + , HER2- mBC. Patients were randomized to SOC therapy, with or without MM-121. Safety and clinical activity data from these studies have previously been presented. Tumor tissue was acquired from each patient and five pre-specified biomarkers were measured and correlated with clinical benefit: HRG, betacellulin, EGFR, HER2, and ErbB3. Protein levels were determined by quantitative IHC (qIHC) and mRNA levels by RT-PCR and RNA in-situ hybridization (RNA-ISH). Results: Among 464 patients (220 ovarian, 115 breast, 129 lung), RNA-ISH data were available from 224 patients (157 ovarian, 67 lung), qIHC from 252 (174 ovarian, 78 lung), and RT-PCR from 175 (105 ovarian, 57 breast, 13 lung). Of the five biomarkers, the most predictive of response was HRG mRNA: patients with detectable HRG in pre-treatment biopsies or high HRG in archived tissue blocks responded poorly to SOC therapy and benefited most from MM-121. In addition, benefit was largely restricted to patients with low ErbB2. Hazard ratios for PFS were calculated, defining biomarker positive (BM+) patients: Ovarian cancer, detectable HRG and low ErbB2; Lung cancer, detectable HRG; and, Breast cancer, high HRG. PFS hazard ratios with 95% CI and prevalence of the BM+ and BM- subpopulations are provided below. Conclusions: Heregulin is a potential biomarker for poor response to SOC therapy and a potential predictor of clinical benefit from MM-121 in late-stage ovarian, lung, and breast cancers. Disclosure: G. MacBeath is an employee of Merrimack Pharmaceuticals and holds stock in the company; B. Adiwijaya is an employee of Merrimack Pharmaceuticals, the sponsor of this clinical research, and holds stock in the company; J. Liu is an unpaid advisor for Merrimack Pharmaceuticals and was a Principal Investigator for one of the clinical studies included in this analysis; L.V. Sequist is an upaid advisor for Merrimack Pharmaceuticals and was a Principal Investigator of one of the clinical studies included in this analysis; E. Pujade-Lauraine serves as an upaid advisor to Merrimack Pharmaceuticals and Sanofi. He was also a lead investigator for one of the clinical studies included in this analysis; M. Higgins is an unpaid advisor to Merrimack Pharmaceuticals and Sanofi. She was a Principal Investigator of one of the clinical studies included in this analysis; I. Tabah-Fisch is an employee of Sanofi, a sponsor of the clinical studies summarized in this abstract, and holds stock in the company; J. Pearlberg is an employee of Sanofi, a sponsor of this clinical research, and holds stock in the company; V. Moyo, W. Kubasek, R. Nering and A. Czibere: Is an employee of Merrimack Pharmaceuticals, a sponsor of the clinical research, and holds stock in the company.

Heregulin-ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

PI3K is frequently mutated in cancer and plays an important role in cell growth and survival. Heregulin (HRG)-mediated autocrine or paracrine signaling through the receptor tyrosine kinase ErbB3 potently activates the PI3K/AKT pathway and has been shown to mediate resistance to a wide variety of anticancer agents. Although PI3K functions downstream of HRG–ErbB3, it is unknown whether activating mutations in PI3K render HRG ineffective. If so, patients with PI3K mutations would not be expected to benefit from ErbB3-directed therapies. Here, we find that a subset of cell lines harboring activating PI3K mutations can be further growth-stimulated by HRG, and this effect is blocked by incubation with seribantumab (MM-121), a monoclonal anti-ErbB3 antibody. Although expression of mutant PI3K in wild-type PI3K cells frequently results in loss of HRG-stimulated growth, some cell lines continue to respond to HRG. In cell lines where HRG-stimulated growth is lost, this loss is invariably accompanied by a reduction in ErbB3 levels, a corresponding increase in basal phosphorylation levels of FOXO-family transcription factors, and a reduction in HRG-induced downstream signaling. Importantly, HRG-stimulated growth is partially rescued by re-expressing ErbB3. This response is blocked by seribantumab, indicating that ErbB3 levels rather than downstream signaling proteins limit HRG-stimulated growth in PI3K mutant cells. Overall, these results suggest that activating mutations in PI3K do not preclude potential benefit from ErbB3-directed therapy, but that it may be important to measure ErbB3 levels in patients with PI3K mutant cancers to determine if they would benefit. Mol Cancer Ther; 14(9); 2072–80. ©2015 AACR.

Abstract LB-410: Phase I dose escalation study of MM-121, a fully human monoclonal antibody to ErbB3, in patients with advanced solid tumors

Introduction: ErbB3 has been identified as a key driver of the PI3K/AKT signaling pathway, resulting in cell growth and survival. MM-121 is a fully human monoclonal antibody targeting ErbB3. By binding to ErbB3, MM-121 blocks heregulin, thereby inhibiting ligand-induced ErbB3 heterodimerization and activation of receptors. Binding of MM-121 also induces downregulation of ErbB3 from the cell surface. Methods: Patients ≥ 18 years with refractory advanced solid tumors were given MM-121 weekly in 4-week cycles at 6 dose levels. Dose escalation was based on dose limiting toxicities (DLTs) during cycle 1. Primary objectives were to determine the maximum tolerated dose (MTD) of MM-121 and describe any objective response and progression free survival. Secondary objectives were to describe the safety, pharmacokinetic (PK), and pharmacodynamic profile of MM-121. A dose expansion cohort at the highest dose cohort was also included for selected tumor types, with required pre- and post-treatment biopsies to assess MM-121 target effects, ErbB3 pathway markers, and guide dose schedule decisions. Results: Between July 2008 to January 2011, 38 patients have been enrolled in the study. Twenty-five patients were enrolled in the dose escalation part of the study and treated until unacceptable toxicity or progression. Six cohorts were completed and an MTD was not reached. Grade 1/2 nausea, diarrhea, fatigue and rash were the most commonly observed adverse events. Grade 1 hypomagnesemia was observed in 4 patients at different doses. One patient experienced a DLT of confusion at the lowest dose, considered possibly related to MM-121 treatment but confounded by other comorbidities. No other treatment related serious AEs were reported. An additional 13 patients have been enrolled to date in an expansion cohort. The overall safety profile for patients in the expansion cohort is similar to that observed for the dose escalation cohorts. Conclusion: In this single agent, first in human, dose escalation phase I study MM-121 was well tolerated with a favorable safety profile. Enrollment in the dose expansion cohort is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-410. doi:10.1158/1538-7445.AM2011-LB-410

Abstract P3-11-03: A randomized, phase 2 trial of preoperative MM-121 with paclitaxel in triple negative (TN) and hormone receptor (HR) positive, HER2-negative breast cancer

Background: MM-121 is a fully human monoclonal antibody that targets ErbB3 and blocks heregulin (HRG), the principal ligand for ErbB3, from binding. HRG-driven ErbB3 signaling has been widely implicated in the development of resistance to conventional chemotherapies and targeted agents. Recently, as part of a broader Phase 2 program designed to identify responders to MM-121, HRG was identified as a key biomarker that correlates with poor response to standard-of-care therapies and benefit from co-treatment with MM-121 in the metastatic setting in patients with NSCLC, ovarian cancer and breast cancer. Here we present data on the impact of HRG and MM-121 co-treatment in the pre-operative setting in HER2- breast cancer. Methods: Patients enrolled had locally advanced HR+, HER2-negative invasive breast cancer (Group 1) or TN (Group 2), no distant metastatic disease, no prior treatment for the disease under study, and ≥T2. Patients were randomized in a 2:1 fashion to receive MM-121 plus paclitaxel or paclitaxel alone followed by doxorubicin and cyclophosphamide, followed by surgery. The primary endpoint of this study was to describe pCR rates, defined as the absence of invasive cancer in the breast and lymph nodes (i.e. ypT0, ypN0). Residual cancer burden index (RCBI) was also recorded for each patient. Pre- and post-treatment tumor biopsies were collected in order to assess the levels of HRG and other potential biomarkers. Results: 200 patients (101 HR+, 99 TN) entered the study. For Group 1 (HR+), 96 of the 101 patients were Efficacy Evaluable (EE) and the pCR rate in the MM-121 treatment arm was 7/66 (10.6%, 95% CI [5.2%, 20.3%]) compared to 1/30 (3.3%, 95% CI [0.6%, 16.7%]) on the control arm. For Group 2 (TN), 85 of the 99 patients were Efficacy Evaluable (EE) and the pCR rate in the MM-121 treatment arm was 23/56 (41.1%, 95% CI [29.2%, 54.1%]) compared to 14/29 (48.3%, 95% CI [31.4%, 65.6%]) on the control arm. Preliminary analysis of pretreatment biopsies (52% of samples analyzed) suggests a potential link between HRG levels and both pCR rates and RCBI. For both groups, the overall incidence of adverse events, regardless of relationship, was comparable between the two arms. A higher frequency of any grade AEs (Treatment vs. Control) was reported for diarrhea, rash, stomatitis, fatigue, epistaxis, nail disorder and dysgeusia. A higher frequency of Grade 3 or higher AEs (Treatment vs. Control) was reported for febrile neutropenia (HR+: 10.4% vs. 3.0%), diarrhea (HR+: 7.5% vs. 0%, TN: 7.8% vs. 0%), fatigue (HR+: 6.0% vs. 3.0%), anemia (HR+: 7.5% vs. 3.0%, TN: 7.8% vs. 3.1%), hypokalemia (HR+: 7.5% vs. 3.0%), infusion-related reactions (TN: 4.7% vs. 0%), pulmonary embolisms (TN: 4.7% vs. 0%), and hyperglycemia (TN: 4.7% vs. 0%). Conclusion: Although a potential signal of benefit from MM-121 was observed in the HR+ group, the same was not observed in the TN group, and overall the results are inconclusive. Biomarker analyses, including pharmacodynamics studies, are ongoing. The observed safety profile is consistent with the expected toxicities associated with ErbB inhibitors and weekly paclitaxel, and did not impact exposure or compliance on treatment. Citation Format: Frankie A Holmes, Kristi J McIntyre, Ian E Krop, Cynthia R Osborne, John W Smith II, Manuel R Modiano, Manish Gupta, Leona B Downey, Rita Nanda, Mansoor N Saleh, Jonathan R Young, Kerry E Horgan, William Kubasek, Gavin MacBeath, Michael A Danso, Joyce A O9Shaughnessy. A randomized, phase 2 trial of preoperative MM-121 with paclitaxel in triple negative (TN) and hormone receptor (HR) positive, HER2-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-03.

Abstract 5464: In-vitro studies of MM-121/SAR 256212, an anti-ErbB-3 antibody, in combination with erlotinib in EGFR-wild-type NSCLC.

MM-121/SAR 256212 is a fully human anti ErbB3/HER3 antibody that blocks ligand-induced receptor activation. Formation of EGFR/ErbB3 (ErbB1-3) heterodimers has been implicated as a major driver of tumor growth and survival in non-small cell lung cancer (NSCLC). Although erlotinib remains the standard-of-care treatment for patients with EGFR-wild-type NSCLC who have failed platinum combination chemotherapy, clinical benefit is typically modest. To address this unmet medical need, we investigated the combination of erlotinib with MM-121 in pre-clinical models of NSCLC. We initially assembled a panel of 25 EGFR-WT NSCLC cell lines spanning the most common histological subtypes (adenocarcinoma, squamous and large-cell carcinoma). Clinical studies show that tumors harboring activating Ras mutations less commonly respond to ErbB-directed therapies. To explore the effect of Ras mutations on responsiveness to MM‐121, we also selected our cell lines to include a variety of H-/K-/N-Ras genotypes. Using a carefully optimized in-vitro 3D culture system, we then measured cell viability in response to MM-121, erlotinib or a combination of the drugs in the presence or absence of exogenously added epidermal growth factor (EGF) and/or heregulin-β1 (HRG). Our results indicate that MM-121 inhibits HRG-driven cell proliferation in the studied cell lines. In the five cell lines exhibiting dual-EGF-HRG-driven cell proliferation, the combination of MM-121 with erlotinib demonstrated superior inhibition of cell viability over erlotinib alone.To assess the ability of MM-121 to inhibit tumor cell growth independent of exogenously supplied HRG, we established mouse xenografts from three of the cell lines and treated mice with erlotinib, MM-121, or a combination of the two. All three in-vivo models showed greatly enhanced inhibition of tumor cell growth compared to erlotinib alone in a manner consistent with our in-vitro results. Analyzing our in vitro data we found that mutations in Ras genes (HRAS, KRAS, NRAS) do not preclude response to MM-121 or incremental benefit from the combination of MM-121 with erlotinib over erlotinib alone. Non-adenocarcinoma origin likewise did not preclude response to MM-121, although a weak trend towards diminished activity in the ten non-adenocarcinoma NSCLC cell lines was apparent. Merrimack Pharmaceuticals and Sanofi are co-developing MM-121 and a Phase 1-2 study of MM-121 in combination with erlotinib is currently enrolling patients with EGFR-wild-type NSCLC. Citation Format: Marisa J. Wainszelbaum, Mark S. Sevecka, Olga Burenkova, Gabriela Garcia, William Kubasek, Gavin MacBeath. In-vitro studies of MM-121/SAR 256212, an anti-ErbB-3 antibody, in combination with erlotinib in EGFR-wild-type NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2013-5464

Abstract C27: Targeting ErbB3 and EGFR in lung cancer patients: A phase I trial of MM-121 in combination with erlotinib in patients with non-small cell lung cancer (NSCLC).

Background: The benefit of EGFR tyrosine kinase inhibitors (TKIs) is largely restricted to EGFR mutation-positive cancers and resistance invariably develops. A central theme of acquired resistance is persistent ErbB3 signaling, resulting in activation of the PI3K/AKT survival pathway. MM-121 is a fully human IgG1 monoclonal antibody (mAb) to ErbB3 with pre-clinical activity as a single agent and in combination with erlotinib in NSCLC, particularly in cancers with ligand-dependent activation of EGFR. This phase 1 study evaluated the safety and tolerability of MM-121 and erlotinib in NSCLC, as well as PK, immunogenicity, efficacy endpoints and exploratory biomarker evaluation. Methods: Patients with advanced NSCLC, good performance status and adequate organ function were enrolled. Patients were EGFR TKI-naive, unless they were EGFR mutant, in which case acquired resistance was allowed. MM-121 was administered weekly and erlotinib was administered daily. Seven cohorts were enrolled, evaluating varying dose levels of the combination, as well as alternate MM-121 infusion schedules. Dose levels were determined by safety and pharmacokinetic (PK) data. Results: Between February 2010 and July 2011, 33 patients were enrolled. Median age was 64 years and there were 19 (57.5%) women. Twenty-four patients were erlotinib-naive and 1 patient was an EGFR mutant. The most frequent adverse events were rash, diarrhea, nausea and fatigue. As of 31 July 2001, 16 patients remain on study. Full results will be presented at the meeting. Conclusions: In this phase 1 dose escalation study, MM-121 plus erlotinib was well tolerated by the majority of patients. A phase 2 study is planned. Reference:NCT00994123 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C27.