Amy Peterson

Randomized Phase II Trial of Onartuzumab in Combination With Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) -targeted drugs in patients with non-small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. PATIENTS AND METHODS Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. RESULTS There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. CONCLUSION Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

Biomarker Analyses from a Placebo-Controlled Phase II Study Evaluating Erlotinib ± Onartuzumab in Advanced Non-Small-Cell Lung Cancer: MET Expression Levels Are Predictive of Patient Benefit

Purpose: In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. Experimental Design: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. Results: A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment. Conclusions: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers. Clin Cancer Res; 20(17); 4488–98. ©2014 AACR.

Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, onartuzumab (MetMAb), in patients with advanced solid tumors

Onartuzumab is a unique, humanized, monovalent (one‐armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non‐small cell lung cancer (NSCLC) patients. The potential for drug–drug interaction (DDI) was assessed during co‐administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration–time profiles of onartuzumab were adequately described using a two‐compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1), and median terminal half‐life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1, and weight on peripheral compartment volume (V2), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.

Enzalutamide for the Treatment of Androgen Receptor–Expressing Triple-Negative Breast Cancer

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study. Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PgR+) breast cancer. Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone. Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046–54. ©2017 AACR.

Abstract PD3-6: A phase 1 open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of enzalutamide (previously MDV3100) alone or in combination with an aromatase inhibitor in women with advanced breast cancer

Background: Enzalutamide (ENZA) is a potent novel oral inhibitor of androgen receptor (AR) signaling. AR expression is observed in ∼70% of breast cancers (BC) and across the 3 major histologic subtypes (ER+, HER2+ and triple negative) [Collins LC et al. Mod Pathol 2011; 24:924-31]. Based on findings in preclinical models of AR+ BC, the potential therapeutic effect of ENZA in AR+ BC is being evaluated. This is the first trial of ENZA in women with advanced BC (aBC). Methods : This Phase 1 study in patients (pts) with aBC comprised a dose-escalation stage evaluating ENZA 80 mg/d or 160 mg/d (3+3 design) to determine the Phase 2 dose, and a dose-expansion stage evaluating the Phase 2 dose alone (C1) or in combination with the aromatase inhibitors (AI), anastrozole (C2) or exemestane (EXE; C3). Pts on single-agent ENZA must have received ≥2 treatment regimens for aBC. Tumor tissue was collected at screening for central analysis of AR expression. In the dose-escalation stage, single-dose ENZA was given on Day 1 with pharmacokinetic (PK) sampling through Day 8, followed by ENZA daily until discontinuation criteria were met, dose-limiting toxicities (DLTs) were recorded through Day 35. In C2 and C3, pts received ≥14 days of AI before starting ENZA, and AI PK sampling occurred on Days -1 and 29 of ENZA dosing to assess PK interactions. Blood for central assessment of estrogens was collected at Days 1, 29 and with tumor assessments performed at 2 months then ∼every 3 months thereafter. Results : The dose-escalation stage (n = 15) defined the Phase 2 dose as 160 mg/d. A single DLT (adrenal insufficiency) occurred in a pt at the 80 mg/d dose. This pt had pre-existing history of adrenal insufficiency and a PK interaction with her daily steroids could not be excluded. As of 1 May 2013, the dose-expansion stage has enrolled 3 pts in C1, 10 in C2, and 16 in C3. For pts receiving single-agent ENZA (n = 18) median age/ECOG was 58/1 and median prior therapies for aBC was 5; these values were 55/0 and 3 for combination cohorts (n = 26). Common (>15%) treatment-related adverse events (AEs) in the single-agent ENZA cohorts included nausea and nasal congestion and in C2 and C3 included nausea, fatigue, back pain, decreased appetite, and hot flush. To date, no serious treatment-related AEs have been reported for single-agent ENZA (other than the DLT) or in C2; in C3 back pain, hypercalcemia and nausea were observed. For single-agent ENZA, a preliminary PK analysis indicates that the apparent clearance and volume of distribution are approximately 0.4 L/h and 120 L, respectively, and steady-state trough concentration is approximately 13 μg/mL. ENZA + EXE resulted in ∼50% reduction in exposure to EXE (AUC pre vs post ENZA: 134±65 vs 70±39 ng.h/mL). PK, tolerability, estrogen levels and anti tumor activity in all cohorts will be presented. Conclusions : The PK and tolerability of single-agent ENZA appear similar in women with aBC vs. data reported in men. As ENZA reduced exposure to EXE, effects on estrogens (i.e., EXE pharmacodynamics) are being assessed and will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-6.

Abstract OT3-2-01: A phase 2 randomized, double-blind, placebo-controlled multicenter trial evaluating the efficacy and safety of enzalutamide in combination with exemestane in estrogen or progesterone receptor-positive and HER2 non-amplified advanced breast cancer

Background Androgen receptor (AR) is expressed in 75% of patients (pts) with ER/PgR+ breast cancer (BC). In some studies, AR expression has been associated with lack of response to endocrine therapies, and forced overexpression in ER+ cell lines can lead to hormone-resistance. Androgens can stimulate in vitro and in vivo growth of ER+/AR+ cells lines which can be blocked by enzalutamide (ENZA), a potent inhibitor of AR. Furthermore, ENZA can block in vitro and in vivo estradiol-mediated growth in MCF7 cells. Treatment with aromatase inhibitors (AIs) increases androgen levels, which in turn could stimulate growth of AR+ ER+ tumors. Trial design This phase 2 trial will evaluate ENZA 160mg/day vs placebo in 240 pts with advanced BC treated concurrently with exemestane (EXE). AR expression will be assessed centrally. Two cohorts will each enroll 120 patients (pts) who have received no (Cohort 1: C1) or one (Cohort 2: C2) prior hormone treatment for advanced BC. Randomization is stratified 1:1 by prior hormone (Y/N: C1 only), prior AI (Y/N), and hormone resistance (disease recurrence within 24 mo of initiating hormone treatment in the adjuvant setting [C1]; and, disease progression within 24 wks of initiating hormone treatment in the advanced setting [C2]). The primary endpoint is progression-free survival (PFS) in C1, C2 and the subgroups with AR+ disease. Upon disease progression, eligible pts may choose to receive open-label ENZA in addition to continuing EXE. This trial will be enrolling at time of presentation. Eligibility criteria Women with advanced ER+ or PgR+ and HER2-non-amplified (HER2-) BC; 0-1 prior chemotherapy regimens for advanced disease; ECOG performance status ≤1 with measurable or bone-only nonmeasurable disease. Advanced BC is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. ER/PgR+ disease is defined as ≥1% tumor cell staining by IHC; HER2- disease is defined as 0 or 1+ IHC staining or FISH HER2 negative. Pts with current or previously treated brain metastases or history of seizure are excluded. Prior therapy (>28 days) with EXE for advanced disease is not permitted. Study endpoints The primary objective is PFS by cohort and in subgroups with AR+ disease. Secondary endpoints include clinical benefit rate (complete/partial response or stable disease at ≥24 weeks); best objective response per RECIST 1.1, duration and time to response, and safety and tolerability of ENZA. Statistical methods Efficacy analyses will be conducted on all randomized pts. Primary analyses for each cohort will be identical and performed separately depending on data maturity for PFS. Primary analysis will use a minimum of 90 PFS events per cohort. The 95% confidence interval (CI) of the PFS hazard ratio (HR) will be reported. For all secondary endpoints, unadjusted P-values will be used to make inferences as appropriate. For a target HR of PFS = 0.67 for each cohort, at least 55 PFS observed events in the AR+ subset (60% of study population) provides an 85% CI that the HR will exclude 1. Contact information amy.peterson@medivation.com. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-01.

Abstract OT3-2-08: A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer

Background: Androgen receptor (AR) expression by IHC is observed in 10-30% of patients (pts) with triple-negative breast cancer (TNBC). Molecular profiling of TNBC has identified a subtype, luminal AR, so called as it clusters with luminal A or B on PAM50 profiling. This AR positive (AR+) subtype of TNBC expresses high levels of AR mRNA and is heavily enriched in hormone-regulated pathways, yet lacks expression of estrogen and progesterone receptors. Experiments using AR+ TNBC cell lines have demonstrated enhanced growth, both in vitro and in vivo , in response to androgen stimulation that can be inhibited by enzalutamide (ENZA), a potent inhibitor of AR signaling that lacks the agonist activity observed with bicalutamide. AR+ TNBC may represent a novel clinical subtype of breast cancer, driven by AR signaling and which may respond to ENZA. Trial design: ENZA will be administered orally at 160mg daily to pts with AR+ TNBC until disease progression or intolerability. The primary endpoint is clinical benefit rate (CBR), defined as the proportion of pts with complete response (CR), partial response (PR), or stable disease (SD) at ≥16 weeks (wks). A Simon 2-stage design is used to ensure that a minimum threshold for activity is met. If the CBR at 16 wks exceeds 2 in 26 pts, the sample size will increase to enroll 62 evaluable pts. AR testing may be performed locally for eligibility, but central testing is required in all pts. This trial is currently enrolling pts. Eligibility criteria: Eligible pts are adult women with advanced AR+ (any nuclear staining by IHC) TNBC. TNBC is determined locally and defined as <1% IHC staining for both ER and PgR and 0 or 1+ IHC staining for Her2 or negative for Her2 amplification in IHC 2+ disease. Advanced is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. Bone-only non-measurable disease is permitted. Pts must have adequate organ and bone marrow function and ECOG status ≤1. Pts with current or previously treated brain metastases or a history of seizure are excluded, as are pts who received prior AR targeted agents for 28 or more days. Specific aims: The primary objective is to determine CBR at ≥16 wks. Secondary objectives include CBR at ≥24 wks, response rates and duration of response, progression-free survival, pharmacokinetics of ENZA, and safety and tolerability. Exploratory endpoints include overall survival and evaluation of the relationship between AR expression and signaling in breast tissue and ENZA activity. Statistical methods: Efficacy analyses will be conducted on all enrolled pts with centrally defined AR+ TNBC and at least 1 available post-baseline tumor assessment. Efficacy analyses will use investigator-assessed outcomes according to RECIST 1.1. The null hypothesis (H), that the true CBR is 8%, will be tested against a 1-sided alternative; if CBR is <3 in 26 pts in Stage 1, enrollment will stop. If CBR exceeds 9 in 62 pts in Stage 2, H will be rejected. This design yields a 1-sided type 1 error rate of 5% and 85% power when the true response rate is 20%. Contact information: For more information on this trial, please contact Amy Peterson at Medivation (amy.peterson@medivation.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-08.

Abstract OT3-1-06: A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (HER2)-positive breast cancer

Background Androgen receptor (AR) expression is observed in ∼60% of patients (pts) with HER2+ breast cancer1. In vitro, ENZA inhibits proliferation of AR+/HER2+ cell lines and enhances the activity of trastuzumab. ENZA also inhibits proliferation of trastuzumab resistant HER2 positive cells2. Methods Any amount of AR expression (local or central) is allowed, submission of tissue is mandatory. Patients must have measurable disease per RECIST 1.1, and have received 1 to 4 prior lines of anti-HER2 therapy in the advanced / metastatic setting. Brain imaging is required to exclude patients with CNS metastases. Pts with a seizure history are excluded. Women with metastatic or locally advanced HER2+, AR+, and ER-/PgR- breast cancer will receive daily ENZA (160 mg) continuously and trastuzumab (6 mg/kg) administered every 21 days, until disease progression (NCT02091960). The primary endpoint (EP) is clinical benefit rate (CBR) where benefit is defined as complete or partial response (CR or PR) or stable disease (SD) ≥24 weeks according to RECIST 1.1 criteria. Additional EPs include safety and tolerability, and the relationship between AR expression and ENZA activity. If the CBR is ≥3 in 21 evaluable pts, the sample size will increase to 66 pts. The primary EP will be analyzed in pts with centrally confirmed AR expression (≥10% nuclear staining by IHC), who have received at least one dose of ENZA, and have ≥1 post-baseline tumor assessment. The null hypothesis (H0), that the true CBR is 10%, will be tested against a 1-sided alternative. This Simon’s two-stage design yields 90% power when the true response rate is 25% with a 1-sided type 1 error rate of 5%. Enrollment is expected to continue through 2016. References: 1. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses9 Health Study. Mod Pathol. 2011;24(7):924-31. 2. J. Richer, AACR Advances in Breast Cancer, San Diego, CA, October 2013. Citation Format: Maureen E Trudeau, Eric Winer, Joyce L Steinberg, Maggie Liosatos, Srinivasu Poondru, Michael Dydo, Yun Zhou, Michael Westphal, Amy C Peterson, William Gradishar. A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (HER2)-positive 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 OT3-1-06.