Pruritus related to trastuzumab and pertuzumab in HER2 + breast cancer patients.

PURPOSE: The combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2 + breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported. METHODS: A retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2 + breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis. RESULTS: Of 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation. CONCLUSIONS: Pruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.

Pruritus Related to Trastuzumab and Pertuzumab in HER2+ Breast Cancer Patients.

Purpose: The combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2+ breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported. Methods: A retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2+ breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis. Results: Of 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation. Conclusions: Pruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.

Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03).

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

Dermatologic adverse events related to the PI3Kα inhibitor alpelisib (BYL719) in patients with breast cancer.

PURPOSE: Rash develops in approximately 50% of patients receiving alpelisib for breast cancer, often requiring dose modifications. Here, we describe the clinicopathologic, laboratory, and management characteristics of alpelisib-related dermatologic adverse events (dAEs). METHODS: A single center-retrospective analysis was conducted. Data were abstracted from electronic medical records. RESULTS: A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash distributed primarily along the trunk (78%) and extremities (70%) that developed approximately within two weeks of treatment initiation (mean 12.8 ± 1.5 days) and lasted one-week (mean duration 7.1 ± 0.8 days). Of 29 patients with documented morphology of alpelisib-related dAEs, 26 (89.7%) had maculopapular rash. Histology showed perivascular and interface lymphocytic dermatitis. All-grade rash correlated with an increase in serum eosinophils from 2.7 to 4.4%, p < 0.05, and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs resulted in interruption of alpelisib, which were managed with antihistamines, topical and systemic corticosteroids. We did not observe rash recurrence in 12 (75%) patients who were re-challenged. CONCLUSIONS: A maculopapular rash associated with increased blood eosinophils occurs frequently with alpelisib. While grade 3 rash leads to alpelisib therapy interruption, dermatologic improvement is evident with systemic corticosteroids; and most patients can continue oncologic treatment at a maintained or reduced dose upon re-challenge with alpelisib.

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial.

Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown. Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019. Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks. Main Outcomes and Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival. Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusions and Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit. Trial Registration: ClinicalTrials.gov identifier: NCT02252887.

First-in-Human Human Epidermal Growth Factor Receptor 2-Targeted Imaging Using 89Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer.

In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of 89Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)-targeted imaging in patients with HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with 89Zr. Patients underwent PET/CT with 74 MBq of 89Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered 89Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean ± SD) were the liver (1.75 ± 0.21 mGy/MBq), the kidneys (1.27 ± 0.28 mGy/MBq), and the heart wall (1.22 ± 0.16 mGy/MBq), with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 d after administration. 89Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases, 89Zr-pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the 89Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with 89Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity.

Feasibility Assessment of Patient Reporting of Symptomatic Adverse Events in Multicenter Cancer Clinical Trials.

IMPORTANCE: In cancer clinical trials, symptomatic adverse events (AEs), such as nausea, are reported by investigators rather than by patients. There is increasing interest to collect symptomatic AE data via patient-reported outcome (PRO) questionnaires, but it is unclear whether it is feasible to implement this approach in multicenter trials. OBJECTIVE: To examine whether patients are willing and able to report their symptomatic AEs in multicenter trials. DESIGN, SETTING, AND PARTICIPANTS: A total of 361 consecutive patients enrolled in any 1 of 9 US multicenter cancer treatment trials were invited to self-report 13 common symptomatic AEs using a PRO adaptation of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) via tablet computers at 5 successive clinic visits. Patient adherence was tracked with reasons for missed self-reports. Agreement with clinician AE reports was analyzed with weighted κ statistics. Patient and investigator perspectives were elicited by survey. The study was conducted from March 15, 2007, to August 11, 2011. Data analysis was performed from August 9, 2013, to March 21, 2014. RESULTS: Of the 361 patients invited to participate, 285 individuals enrolled, with a median age of 57 years (range, 24-88), 202 (74.3%) female, 241 (85.5%) white, 73 (26.8%) with a high school education or less, and 176 (64.7%) who reported regular internet use (denominators varied owing to missing data). Across all patients and trials, there were 1280 visits during which patients had an opportunity to self-report (ie, patients were alive and enrolled in a treatment trial at the time of the visit). Self-reports were completed at 1202 visits (93.9% overall adherence). Adherence was highest at baseline and declined over time (visit 1, 100%; visit 2, 96%; visit 3, 95%; visit 4, 91%; and visit 5, 85%). Reasons for missing PROs included institutional errors in 27 of 48 (56.3%) of the cases (eg, staff forgetting to bring computers to patients at visits), patients feeling "too ill" in 8 (16.7%), patient refusal in 8 (16.7%), and internet connectivity problems in 5 (10.4%). Patient-investigator CTCAE agreement was moderate or worse for most symptoms (most κ < 0.05), with investigators reporting fewer AEs than patients across symptoms. Most patients believed that the system was easy to use (234 [93.2%]) and useful (230 [93.1%]), and investigators thought that the patient-reported AEs were useful (133 [94.3%]) and accurate (119 [83.2%]). CONCLUSIONS AND RELEVANCE: Participants in multicenter cancer trials are willing and able to report their own symptomatic AEs at most clinic visits and report more AEs than investigators. This approach may improve the precision of AE reporting in cancer trials.

Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance).

PURPOSE: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned. RESULTS: From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%). CONCLUSION: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.

A Pilot Study of Dose-Dense Paclitaxel With Trastuzumab and Lapatinib for Node-negative HER2-Overexpressed Breast Cancer.

BACKGROUND: Dual anti-HER2 therapy is effective for HER2-amplified breast cancer. Weekly paclitaxel, trastuzumab, and full-dose lapatinib (PTL) is not feasible because of grade 3 diarrhea. We conducted a phase II feasibility study of dose-dense (DD; every other week) PTL (ClinicalTrials.gov identifier, NCT01827163). PATIENTS AND METHODS: Eligible patients had HER2-positive breast cancer, tumor size ≤ 3 cm, and negative nodes. Treatment included paclitaxel (175 mg/m(2) × 4, every 2 weeks with pegfilgrastim), trastuzumab (4 mg/kg load and then 2 mg/kg weekly), and lapatinib (1000 mg daily). After paclitaxel × 4, trastuzumab (6 mg/kg every 3 weeks) plus lapatinib were continued for 1 year. The primary endpoint was feasibility, defined as (1) > 80% of patients completing PTL without a dose delay or reduction, (2) grade 3 diarrhea rate < 20%, and (3) cardiac event rate < 4%. RESULTS: From May 2013 to November 2013, we enrolled 20 of 55 planned patients. The median age was 49 years (range, 34-74 years). One patient had immediate paclitaxel hypersensitivity and was deemed inevaluable. Only 13 of 19 evaluable patients (68%) completed PTL without a dose delay or reduction or unacceptable toxicities. Only 3 of 19 (16%) had grade 3 diarrhea. Rash was frequent, with all grades in 18 of 19 (95%) and grade 3 in 2 of 19 (11%). The study was stopped early because of excess toxicity. CONCLUSION: The discontinuation rate during DD PTL was high, owing, in part, to an unexpectedly high incidence of rash. The trial was halted, because the initial discontinuation rate from overall toxicity made it unlikely that full accrual would demonstrate feasibility.

Do MRI and mammography reliably identify candidates for breast conservation after neoadjuvant chemotherapy?

BACKGROUND: Neoadjuvant chemotherapy (NAC) may allow breast-conserving therapy (BCT) in patients who require mastectomy at presentation. Breast MRI is more accurate than mammography in assessing treatment response, but combined test reliability in identifying BCT candidates after NAC is not well described. We evaluated whether post-NAC breast MRI alone and with mammography accurately identifies BCT candidates. METHODS: In this retrospective study of 111 consecutive breast cancer patients receiving NAC, all had pre- and postchemotherapy MRI, followed by surgery. Posttreatment MRI and mammography results were correlated with surgical outcomes and pathologic response. RESULTS: Fifty-one of 111 (46 %) patients presented with multicentric or inflammatory breast cancer and were not BCT candidates. The remaining 60 (54 %) were considered BCT candidates after downstaging (mean age: 47 years). All 60 had at least a partial response to NAC and were suitable for BCT on MRI after NAC. Forty-five of 60 (75 %) underwent lumpectomy; 15 of 60 (25 %) chose mastectomy. Forty-one of 45 (91 %) of lumpectomies were successful; 4 of 45 (9 %) required mastectomy. Twelve of 15 (80 %) patients choosing mastectomy could have undergone BCT based on pathology; 3 of 15 (20 %) did require mastectomy. Two of these three patients had extensive microcalcifications on mammogram, indicating the need for mastectomy despite MRI suitability for BCS. MRI alone correctly predicted BCS in 53 of 60 (88 %) patients. MRI plus mammography was correct in 55 of 60 (92 %), although only 9 of 45 (20 %) BCT patients and 4 of 15 (27 %) potentially conservable mastectomy patients had complete pathologic responses. CONCLUSIONS: Posttreatment MRI plus mammography is an accurate method to determine whether BCT is possible after NAC is given to downstage disease.

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS: From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION: Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance).

PURPOSE: CALGB 40302 sought to determine whether lapatinib would improve progression-free survival (PFS) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant. PATIENTS AND METHODS: Eligible women had estrogen receptor-positive and/or progesterone receptor-positive tumors, regardless of human epidermal growth factor receptor 2 (HER2) status, and prior aromatase inhibitor treatment. Patients received fulvestrant 500 mg intramuscularly on day 1, followed by 250 mg on days 15 and 28 and every 4 weeks thereafter, and either lapatinib 1,500 mg or placebo daily. The study planned to accrue 324 patients and was powered for a 50% improvement in PFS with lapatinib from 5 to 7.5 months. RESULTS: At the third planned interim analysis, the futility boundary was crossed, and the data and safety monitoring board recommend study closure, having accrued 295 patients. At the final analysis, there was no difference in PFS (hazard ratio [HR] of placebo to lapatinib, 1.04; 95% CI, 0.82 to 1.33; P = .37); median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo. There was no difference in overall survival (OS) (HR, 0.91; 95% CI, 0.68 to 1.21; P = .25). For HER2-normal tumors, median PFS did not differ by treatment arm (4.1 v 3.8 months). For HER2-positive tumors, lapatinib was associated with longer median PFS (5.9 v 3.3 months), but the differential treatment effect by HER2 status was not significant (P = .53). The most frequent toxicities were diarrhea, fatigue, and rash associated with lapatinib. CONCLUSION: Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic.

A phase II open-label study of ganetespib, a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer.

BACKGROUND: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. PATIENTS AND METHODS: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). CONCLUSION: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.

Randomized phase II trial of weekly vs. every 2 weeks vs. every 3 weeks nanoparticle albumin-bound paclitaxel with bevacizumab as first-line chemotherapy for metastatic breast cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-P) and bevacizumab have each demonstrated efficacy in patients with MBC. This trial was designed to further develop nab-P by evaluating its efficacy and safety using every 3 weeks (q3w), every 2 weeks (q2w), or weekly scheduling in combination with bevacizumab as first-line treatment of MBC. PATIENTS AND METHODS: This open-label phase II study randomized patients to nab-P 260 mg/m(2) q3w (arm A) vs. 260 mg/m(2) q2w with filgrastim (arm B) vs. 130 mg/m(2) weekly uninterrupted, all with bevacizumab (15 mg/kg q3w arm A, 10 mg/kg q2w arms B and C). The primary endpoints were overall response rate (ORR) and toxicity. Time to tumor progression (TTP) and overall survival were secondary endpoints. RESULTS: Of 212 patients randomized, 208 (arm A, 75; arm B, 54; arm C, 79) were treated. Arm B was closed early due to toxicity, with more grade ≥ 2 fatigue (arm A, 46%; arm B, 62%; arm C, 62%) and bone pain (arm A, 11%; arm B, 23%; arm C, 5%). Neurotoxicity grade ≥ 2 was equivalent across the arms (> 50%) and reversible for most patients. Febrile neutropenia occurred in ≤ 3% of patients in all arms. ORR was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median TTP was slightly longer in arm C (9.0 months) vs. arms A (8.0 months) and B (5.8 months) (overall, P = .105). CONCLUSIONS: Significant antitumor activity was observed in all the arms. Weekly nab-P with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment limiting, which suggests that a 3 weeks on and 1 week off schedule should be explored.

Phase II trial of a novel capecitabine dosing schedule in combination with lapatinib for the treatment of patients with HER2-positive metastatic breast cancer.

Our group applied mathematical modeling to capecitabine dosing and predicted 7 days of treatment followed by 7 days of rest (7-7) would improve efficacy and minimize toxicity. The conventional schedule of capecitabine limits full dosing in combination with other agents due to toxicity. Lapatinib inhibits the tyrosine kinase of HER2 and has activity when added to conventionally scheduled capecitabine for the treatment of patients with trastuzumab-refractory, HER2-positive, metastatic breast cancer (MBC). We performed this study to evaluate the activity and tolerability of capecitabine 7-7 with lapatinib in patients with trastuzumab-refractory MBC. Eligible patients had measurable, HER2-positive, MBC that progressed following exposure to trastuzumab. Treatment consisted of capecitabine 2,000 mg orally twice daily, 7-7 and lapatinib 1,250 mg orally daily. The primary endpoint was response rate. Secondary endpoints included toxicity, progression-free survival, and stable disease ≥ 6 months. Twenty-three patients were treated on study. More than 60% had prior chemotherapy for MBC and all had prior trastuzumab. After a median of 23 weeks (range 2-96+), five patients had partial responses (23; 95 CI, 7-44%) and six (27; 95 CI, 10-48%) had stable disease ≥ 6 months. Median progression-free survival was 9.4 months. The most common treatment-related toxicities ≥ grade (gr) 2 were hand-foot syndrome (gr 2 43%; gr 3 4% gr 4 0%), diarrhea (gr 2 26%; gr 3/4 0%), elevated liver chemistries (gr 2 17%; gr 3/4 0%), and anemia (gr 2 13%; gr 3 4%; gr 4 4%). No grade ≥ 3 nausea, vomiting, or diarrhea events occurred. This study demonstrated feasibility and after meeting biostatistical requirements for continued accrual was terminated in anticipation of slow enrollment. Capecitabine 7-7 with lapatinib was well tolerated with minimal gastrointestinal toxicity. Antitumor activity was observed in patients with trastuzumab-refractory MBC.

A feasibility study of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (AC) followed by nanoparticle albumin-bound paclitaxel in early-stage breast cancer.

PURPOSE: Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (ddAC) → nanoparticle albumin-bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer. EXPERIMENTAL DESIGN: Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC → nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted. RESULTS: The median age was 48 years (range, 27-75 years), and baseline LVEF was 68% (53%-82%). After 39 months' median follow-up (5-45 months): median LVEF was 68% (53%-80%) at 2 months (n = 78), 64% (51%-77%) at 6 months (n = 66), 63% (48%-77%) at 9 months (n = 61), and 66% (42%-76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively. CONCLUSIONS: Bevacizumab with ddAC → nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials.

Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer.

PURPOSE: Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule. PATIENTS AND METHODS: Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon's 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%. RESULTS: The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals. CONCLUSION: Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.