Michael A. Danso

Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer

Purpose: Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%–39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer. Clin Cancer Res; 19(19); 5505–12. ©2013 AACR.

Phase III Study of Iniparib Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple-Negative Breast Cancer

PURPOSE There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. PATIENTS AND METHODS Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. RESULTS Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. CONCLUSION The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation.

Chemotherapy and Targeted Therapy for Women With Human Epidermal Growth Factor Receptor 2–Negative (or unknown) Advanced Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)- negative (or unknown) advanced breast cancer. METHODS A systematic review of randomized evidence (including systematic reviews and meta-analyses) from 1993 through to current was completed. Outcomes of interest included survival, progression-free survival, response, quality of life, and adverse effects. Guideline recommendations were evidence based and were agreed on by the Expert Panel via consensus. RESULTS Seventy-nine studies met the inclusion criteria, comprising 20 systematic reviews and/or meta-analyses, 30 trials on first-line treatment, and 29 trials on second-line and subsequent treatment. These trials form the evidence base for the guideline recommendations. RECOMMENDATIONS Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor-positive metastatic breast cancer unless improvement is medically necessary (eg, immediately life-threatening disease). Single agent is preferable to combination chemotherapy, and longer planned duration improves outcome but must be balanced against toxicity. There is no single optimal first-line or subsequent line chemotherapy, and choice of treatment will be determined by multiple factors including prior therapy, toxicity, performance status, comorbid conditions, and patient preference. The role of bevacizumab remains controversial. Other targeted therapies have not so far been shown to enhance chemotherapy outcome in HER2-negative breast cancer.

Antiemetics: American Society of Clinical Oncology Focused Guideline Update

PURPOSE To update a key recommendation of the American Society of Clinical Oncology antiemetic guideline. This update addresses the use of the oral combination of netupitant (a neurokinin 1 [NK1] receptor antagonist) and palonosetron (a 5-hydroxytryptamine-3 [5-HT3] receptor antagonist) for the prevention of acute and delayed nausea and vomiting in patients receiving chemotherapy. METHODS An update committee conducted a targeted systematic literature review and identified two phase III clinical trials and a randomized phase II dose-ranging study. RESULTS In one phase III trial, the oral combination of netupitant and palonosetron was associated with higher complete response rates (no emesis and no rescue medications) compared with palonosetron alone in patients treated with anthracycline plus cyclophosphamide chemotherapy (74% v 67% overall; P = .001). In another phase III trial, the oral combination of netupitant and palonosetron was safe and effective across multiple cycles of moderately or highly emetogenic chemotherapies. In the phase II dose-ranging study, each dose of netupitant (coadministered with palonosetron 0.50 mg) produced higher complete response rates than palonosetron alone among patients receiving cisplatin-based chemotherapy. The highest dose of netupitant (ie, 300 mg) was most effective. RECOMMENDATIONS All patients who receive highly emetogenic chemotherapy regimens (including anthracycline plus cyclophosphamide) should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone. The oral combination of netupitant and palonosetron plus dexamethasone is an additional treatment option in this setting. The remaining recommendations from the 2011 ASCO guideline are unchanged pending a full update. Additional information is available at www.asco.org/guidelines/antiemetics and www.asco.org/guidelineswiki.

Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer

PURPOSE This multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC). PATIENTS AND METHODS We treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m2 and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6-8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles. RESULTS The overall response rate (ORR) was 62.5% (95% CI, 45.7%-79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD > 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%). CONCLUSION Weekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.

Chemotherapy and Targeted Therapy for Women With Human Epidermal Growth Factor Receptor 2-Negative (or unknown) Advanced Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

Breast cancer is the most prevalent cancer in women in the developed world and is the second most common cause of cancer-related death for women in the United States. It is estimated that in 2014 more than 232,000 women in the United States will be diagnosed with the disease, and 40,000 will die from it. Long-term survival outcomes are related to disease stage at presentation. Currently, the majority of patients who present with localized disease will experience long-term disease-free survival, whereas those who present with metastatic disease have a 5-year relative survival of only 24%, and almost none are cured. The prognosis for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has improved significantly with the emergence of trastuzumab and other anti-HER2 agents (see companion ASCO guideline 1-07:

Interim safety results of eribulin (E) combined with ramucirumab (RAM) in patients (pts) with advanced metastatic breast cancer (MBC).

110 Background: VEGF-mediated angiogenesis contributes to breast cancer (BC) pathogenesis. RAM (IMC-1121B), a fully human IgG1 monoclonal antibody (MAb), targets VEGFR-2, blocking the interaction of VEGF ligands and VEGFR‑2. DC101 (murine anti-VEGFR-2 MAb) impairs vascular function and increases tumor hypoxia in xenograft BC models and inhibits tumor growth in cytotoxic-resistant models. E is a novel non-taxane microtubule inhibitor indicated in MBC pts who have received ≥2 prior chemotherapy regimens, including an anthracycline and a taxane. It is hypothesized that addition of RAM to E as 3rd-5th line therapy in MBC will result in an improvement of median PFS in this ongoing, multicenter, US study. A planned safety analysis of an initial cohort is reported. METHODS Pts with locally recurrent or MBC (HER2+ or HER2-) and 2-4 prior chemotherapy regimens are randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 Days 1, 8; RAM 10 mg/kg Day 1; q21 days). Pts are stratified by TNBC and prior antiangiogenic therapy status and must have ECOG PS 0-1 and normal LVEF. Planned accrual: 134 pts. RESULTS Evaluable pts (n=13, 8 RAM+E) received ≥1 dose of RAM+E or E and completed 2 cycles of therapy (or discontinued prior to completing the initial 2 cycles). Median age is 55 yrs. Assessment of adverse events (all cause) revealed nausea, fatigue, headache, and neutropenia were more frequent for RAM+E; anemia was more frequent for E. G1 sensory neuropathy was reported for 1 pt in each arm. One RAM+E pt experienced G3 febrile neutropenia and odynophagia, recovered within a week, and subsequently received reduced dosage (E = 1.1 mg/m2; RAM = 8 mg/kg). No deaths are reported. The safety assessment committee recommended to continue the trial unmodified. CONCLUSIONS Based on preliminary data, the combination of RAM+E demonstrates an acceptable toxicity profile. Accrual continues, with planned updated safety and dose intensity data to be presented at the meeting. [Table: see text].

Abstract P2-08-04: Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC)

Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon9s 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs > 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi9s unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

The prevalence and pattern of chemotherapy-induced peripheral neuropathy (CIPN) among women with breast cancer receiving care in a large community oncology practice.

80 Background: CIPN is a common side effect of taxane-based chemotherapy agents. This study examined the prevalence, severity, and risk factors of CIPN and its impact on quality of life (QOL) among women treated for breast cancer in a large U.S. community oncology practice. METHODS In this cross-sectional survey study, women previously treated with taxane-based chemotherapy for early stage breast cancer completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), breast cancer module (QLQ-BR23) and CIPN module (QLQ-CIPN20). Each subscale is scored 0-100 where higher scores indicate better function or greater symptom severity. Clinical data were abstracted from the medical record. Bivariate analyses were conducted to test pre- specified hypotheses. RESULTS 126 women with mean age 56.7 years (SD = 11.8) were stage I-II (79.4%) or stage III (20.6%) at the time of the survey; 65.1% were White and 27.8% were Black or African American. 73.0% of women reported they had CIPN. The mean time since last taxane chemotherapy cycle was 144.9 weeks (SD = 112.9). The mean (SD) score of QLQ-C30 global health status/QOL was 77.0 (20.3) and physical function was 85.7 (17.1). QLQ-CIPN20 mean scores for the sensory, motor, and autonomic subscales were 18.9 (23.1), 18.6 (18.7), and 17.1 (21.8), respectively. Presence of CIPN was associated with patient referral and visitation to a neurologist or pain specialist (p < 0.05). CIPN symptom severity was negatively correlated with global health status/QOL and physical and role functioning (range of r= -0.46 to -0.72). Further, it was not associated with age, body mass index, diabetes, or cumulative taxane dosage, but was greater for Black or African American patients versus White patients (e.g., sensory: 28.6 vs 14.5, p < 0.002). CIPN sensory impairment was marginally greater for patients treated with paclitaxel compared to docetaxel (23.3 vs 15.6, p < 0.06). CONCLUSIONS CIPN was prevalent in this community oncology practice and significantly impacts function and QOL. These data highlight the importance of developing methods to mitigate CIPN.

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.