Treatment Of HER2-positive Metastatic Breast Cancer Research Articles

Real-world outcomes of long-term efficacy of T-DM1 after discontinuation due to limiting toxicity in patients with HER2-positive metastatic breast cancer.

e13034 Background: Antibody-drug conjugates (ADC) are widely used in the treatment of breast cancer (BC). In our service, we observed that a significant number of patients (pts) with HER2-positive metastatic breast cancer (MBC) treated with T-DM1 had long-lasting response and survival rates, even after discontinuing T-DM1 due to limiting toxicity. However, data are scarce regarding its long-term benefit. We performed a retrospective study to evaluate the long-term efficacy of T-DM1 in the treatment of HER2-positive MBC. Methods: Medical records of pts with HER2-positive MBC treated with T-DM1 between September 2013 and January 2023 were reviewed. We analyzed data in the overall population and in the subgroup of pts who discontinued T-DM1 due to only limiting toxicity and did not have disease progression or death for at least 12 months, without receiving other subsequent lines of treatment. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from the start of the treatment with T-DM1 to disease progression or death for the overall population, and from the time of T-DM1 discontinuation to disease progression or death for the aforementioned subgroup. Secondary endpoints were objective response rate (ORR) and toxicity. Results: A total of 73 pts were included. In the overall population, ORR was 82.6%, median PFS was 12.7 months (CI95% 8-16) and median OS was 53.9 months (CI95% 34-73). 10 (13.6%) pts had T-DM1 discontinued due to only limiting toxicity and had no disease progression or death for at least 12 months. In this specific subgroup, 2 pts received T-DM1 as first line, 6 pts as second line, and 2 as third or more lines. At the start of T-DM1, 5 pts had visceral metastasis (3 liver, 2 lung), and 2 had only leptomeningeal involvement. Median age was 57 years (IQR 49-70) and median T-DM1 duration was 30 months (IQR 12-45). At the time of T-DM1 discontinuation, 9 pts presented complete response (CR) and 1 presented partial response (PR). 5 pts maintained CR, with no evidence of disease progression or death throughout the analyzed period. The PFS of these 5 pts, from the time of T-DM1 discontinuation to the last evaluation, was 35.6, 37.9, 40.5, 42.7 and 68.5 months. In the entire subgroup, median PFS was 22.5 months, 5-year OS was 66.7% and median OS was not reached. The adverse events that led to the T-DM1 discontinuation were thrombocytopenia (10%), nausea, vomiting and fatigue (10%), pneumonitis (20%), hepatic pseudocirrhosis (20%) and peripheral neuropathy (40%). Conclusions: Our experience suggests that pts with HER2-positive MBC who had T-DM1 discontinued due to limiting toxicity may derive long-term benefit. Further prospective studies are warranted to evaluate our findings, also including other ADC.

Abstract P2-11-07: Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis

Abstract BACKGROUND: PIK3CA mutations have been shown to be associated with poor prognosis in HER2-positive breast cancer (BC). We combined data from three completed Phase III Roche-sponsored randomized trials of HER2-targeted therapy for the first-line treatment of HER2-positive metastatic BC (MBC); this allowed for exploration of the prognostic impact of PIK3CA mutations observed in the three individual trials across subgroups of interest. METHODS: Data from CLEOPATRA (pertuzumab + trastuzumab + docetaxel [PHD] vs. placebo [Pla] + HD; NCT00567190; N = 808), MARIANNE (HD vs. ado-trastuzumab emtansine [K] + Pla vs. K + P; NCT01120184; N = 1095), and PUFFIN (PHD vs. Pla + HD; NCT02896855; N = 243) were included. An individual patient data (IPD) meta-analysis was performed to test the association between PIK3CA mutation status in tumor tissue (mutated vs. wild type [WT]) and efficacy (progression-free and overall survival [PFS/OS]) in different biomarker and clinical subgroups. Confounder adjustment was conducted for age, Eastern Cooperative Oncology Group Performance Status, body mass index, treatment, disease type, and number of metastases (all at baseline). “Study” was included as a random effect in the IPD meta-analysis model to account for variability between studies. A landmark analysis was conducted on fast and non-fast progressors (cutoff of >137 days [i.e., after six chemotherapy cycles]) from CLEOPATRA and PUFFIN only, since they include the current standard-of-care regimens (PHD), by using Day 137 as the landmark time with separate Cox proportional hazards models. RESULTS: PIK3CA mutation data were available for 1905/2146 patients (89%; ~80% from primary tissue); mutation prevalence was 27% (n = 521). PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms is shown in the table. OS data were consistent. CONCLUSIONS: PIK3CA mutations were associated with a worse prognosis across subgroups of interest, including in fast and non-fast progressors, in the two PHD-containing studies as compared with the overall ITT population. Table: PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms Citation Format: Sandra Swain, Javier Cortés, Binghe Xu, Chiara Lambertini, Laurent Essioux, Adam Knott, Eleonora Restuccia, Katrin Madjar, Sanne Lysbet De Haas. Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-07.

Computed tomography based analyses of body mass composition in HER2 positive metastatic breast cancer patients undergoing first line treatment with pertuzumab and trastuzumab

Body composition parameters (BCp) have been associated with outcome in different tumor types. However, their prognostic value in patients with HER2-positive metastatic breast cancer (BC) receiving first line treatment with dual anti-HER2 antibody blockade is unknown. Preclinical evidences suggest that adipocytes adjacent to BC cells can influence response to anti-HER2 treatments. We retrospectively analyzed Computed Tomography (CT)-based BCp from 43 patients with HER2-positive metastatic BC who received first line pertuzumab/trastuzumab-based treatment between May 2009 and March 2020. The impact of baseline CT-based BCp on progression-free survival (PFS) was tested using Kaplan–Meier estimates and univariate and multivariate Cox regression models. We found a significantly worse PFS for patients with high baseline subcutaneous fat index (median 7.9 vs 16.1 months, p = 0.047, HR = 2.04, 95%CI 1–4.17) and for those with high total abdominal fat index (8.1 vs 18.8 months, p = 0.030, HR = 2.17, 95%CI 1.06–4.46). Patients with baseline sarcopenia did not show shorter PFS compared to those without sarcopenia (10.4 vs 9.2 months, p = 0.960, HR = 0.98, 95%CI 0.47–2.03). Total abdominal fat index remained a significant predictor of PFS at multivariate analysis. Our findings suggest that a high quantity of total abdominal fat tissue is a poor prognostic factor in patients receiving trastuzumab/pertuzumab-based first-line treatment for HER2-positive metastatic BC.

280P Intracranial activity of trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: Results from the first stage of the phase II TUXEDO-1 trial

Brain metastases (BM) are frequently diagnosed in HER2-positive breast cancer (BC) and add to morbidity and mortality. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate approved for the treatment of HER2-positive metastatic BC but has not been specifically investigated in the context of BM. Here, we present preliminary results of the prospective, single-centre, single-arm, phase II TUXEDO-1 trial investigating T-DXd in HER2-positive BC patients (pts) with active BM.

Phase II study of gemcitabine (G), trastuzumab (H), and pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) after prior pertuzumab-based therapy.

1037 Background: The combination of taxanes with HP for first line treatment of HER2-positive MBC is associated with improved progression-free (PFS) and overall survival (OS). Treatment per physician’s choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is standard, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of G with HP. Eligible patients (pts) had HER2-positive (IHC 3+ or FISH > 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Pts received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of 1-27-17, 41 of 45 pts are enrolled; 34 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 26/34 (76%) are progression free (1 CR, 8 PR, 17 SD); 8 pts progressed. There are no cardiac or febrile neutropenic events to date. 4 pts required G dose reduction (3 grade 3 neutropenia and 1 grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% in evaluable pts (95% CI 60% to 88%). The updated 3 month-PFS results will be presented. Continuation of P beyond progression is associated with apparent clinical benefit. A randomized trial is justified to confirm this clinically important observation. Clinical trial information: NCT02252887.

First-line therapy in HER2 positive metastatic breast cancer: is the mosaic fully completed or are we missing additional pieces?

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC).HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC.This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles.There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective.

Phase II study of gemcitabine (G), trastuzumab (H), and pertuzumab (P) for HER2-Positive metastatic breast cancer (MBC) after prior HP- or TDM/P-based therapy.

611Background: The combination of taxanes with HP for first line treatment of HER2-positive MBC is associated with improved progression-free (PFS) and overall survival (OS). Previous data demonstra...

Therapeutic Considerations in Treating HER2-Positive Metastatic Breast Cancer.

Despite advances in detection and treatment, metastatic breast cancer (MBC) remains the second highest cause of cancer-related death for women in the United States. Human epidermal growth factor receptor-2 (HER2) is amplified in 25-30% of breast cancers and is associated with aggressive disease and, historically, with poorer outcomes. The advent of trastuzumab, a monoclonal antibody to HER2, revolutionized the management of HER2-positive breast cancer (BC) in the metastatic and adjuvant settings. However, relapse despite adjuvant trastuzumab and resistance to trastuzumab in the metastatic setting remain substantial clinical problems for many patients with HER2-positive BC. As such, analyzing the mechanisms of trastuzumab resistance and developing new therapy to overcome trastuzumab resistance are research priorities. There has been progress, with the approval of three additional HER2-targeted agents in the last six years: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Other HER2-targeted therapies, including neratinib and afatinib, are in clinical development, and trials of novel agents such as heat shock protein-90 (HSP90) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and HER2-targeted vaccines are ongoing. In addition to developing new therapy, research is addressing several unique challenges in the management of HER2-positive MBC. In this article, we discuss advances in the treatment of HER2-positive MBC, with a focus on novel HER2-targeted therapy and HER2-targeted agents recently approved by the United States Food and Drug Administration (FDA). Additionally, we also address the management of brain metastases (BM) and hormone receptor (HR) - positive, HER2-positive MBC.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment

Background:The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC).Methods:One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively.Results:Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ⩽20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ⩽20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS.Conclusion:HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.

Abstract P2-16-10: Safety of pertuzumab plus trastuzumab plus vinorelbine for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer

Abstract Background: HER2 overexpression or amplification, occuring in ∼15-20% of breast cancers (BC), is associated with a poor prognosis. Trastuzumab (T) and pertuzumab (P) are humanized monoclonal antibodies that bind to different HER2 epitopes, inhibiting HER2 signaling. It was previously shown that first-line (1L) treatment of patients (pts) with HER2-positive metastatic breast cancer (MBC) with vinorelbine (V)+T had similar efficacy to docetaxel+T, but with fewer adverse events (AEs) (HERNATA). In a recent study, P+T+docetaxel significantly improved progression-free survival (PFS) and overall survival (OS) compared with T+docetaxel in pts with HER2-positive 1L MBC (CLEOPATRA). The objective of the VELVET study is to investigate the efficacy and safety of P+T+V for 1L treatment of HER2-positive MBC. Methods: This is a multicenter, open-label, single-arm, two-cohort, Phase II study. The recruitment target is 105 pts per cohort. Pts in Cohort 1 receive P+T+V as separate infusions. Pts in Cohort 2 receive P+T from a single infusion bag followed by V. The initial dose of P is 840 mg, followed by 420 mg q3w; the initial dose of T is 8 mg/kg, followed by 6 mg/kg q3w; V is administered at 25 mg/m2 in Cycle 1, followed by 30-35 mg/m2, on Days 1 and 8 of each cycle, q3w. Pts must have HER2-positive MBC or locally advanced BC (LABC) and a baseline left ventricular ejection fraction (LVEF) of ≥55%. Previous treatment with systemic nonhormonal anticancer therapy in the metastatic setting is not allowed. The primary endpoint is independently assessed overall response rate. Secondary endpoints include PFS, OS, and safety. Results: Interim safety data are presented for Cohort 1; 106 pts were enrolled. Median age at screening was 56 years. Median interval between initial BC diagnosis and enrollment was 2.6 years. 33% of pts had Stage IV BC at initial BC diagnosis. At diagnosis of advanced disease, 13% and 87% of pts had LABC and MBC, respectively. 54% of pts had previously received chemotherapy, including taxane (38%) and anthracycline (36%). 41% had prior T exposure. A median of 6 cycles of P, T, and V was received at the time of this analysis. An AE overview is shown in the table. Pts, n(%)N = 106Any AE102(96)Grade 338(36)Grade 417(16)Grade 52(2)aAny serious AE25(24)Most frequent (≥4 pts) grade ≥3 AEs Neutropeniab21(20)Febrile neutropenia6(6)Leukopenia5(5)Asthenia4(4)Constipation4(4)Diarrhea4(4)a Myocardial infarction and septic shock; b Covers ‘neutropenia’ and ‘neutrophil count decreased’ Grade ≥3 neutropenia/febrile neutropenia was experienced by 8% of pts in Cycle 1 and by 14% of pts in Cycle 2; this proportion decreased during subsequent cycles. There was no overall decrease in mean LVEF from baseline. Conclusions: The combination of P+T+V was well tolerated; no new safety signals were observed. The incidences of grade ≥3 neutropenia, febrile neutropenia, and leukopenia were lower than those previously observed in pts with HER2-positive MBC treated with 1L P+T+docetaxel in CLEOPATRA or those treated with T+V in HERNATA; however, it should be noted that the treatment period in these two studies was longer. Efficacy data for Cohorts 1 and 2 will be reported at the end of the study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-10.

Lapatinib in combination with paclitaxel for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2

SUMMARY Metastatic breast cancer (MBC) is the leading cause of cancer death for women worldwide. Amplification of the HER2 gene has been observed in approximately 20–25% of human breast cancers, and is associated with aggressive disease and a poor prognosis, and reduced progression-free survival and overall survival. Inhibition of HER2 activity has been an effective strategy against HER2-positive breast cancers. In the first-line metastatic setting, the combination of trastuzumab with paclitaxel is well-tolerated, offering significant clinical benefit to patients with HER2-positive MBC. It has also been shown that lapatinib combined with paclitaxel offers a significant survival benefit over paclitaxel alone in first-line treatment of HER2-positive MBC, especially when trastuzumab is not available.

Clinical value of trastuzumab in the treatment of lapatinib-resistant HER2-positive metastatic breast cancer

Retrospective and prospective studies have shown that continuous administration of trastuzumab with different chemotherapy regimens resulted in better clinical outcomes than the administration of chemotherapy alone in women with HER2-positive, trastuzumab-refractory metastatic breast cancer (MBC). However, there are limited data to evaluate the activity of trastuzumab in patients progressed after other anti-HER2 therapies, e.g. lapatinib. The aim of the present study was to evaluate retrospectively the clinical value of trastuzumab in patients with lapatinib-resistant HER2-positive advanced breast cancer treated in our center. Patients with HER2-positive MBC who experienced progression after first-line lapatinib-based regimens were assigned to receive either conventional treatment without trastuzumab or in combination with trastuzumab as second-line therapy. The efficacy end points included progression-free survival (PFS) and overall survival (OS). Thirty-five eligible patients progressed after treatment with lapatinib-based regimens were collected. None of the patients had received prior trastuzumab in either the adjuvant or metastatic setting. Twenty-two patients were assigned to receive conventional treatment without trastuzumab as second-line therapy (non-T arm) and 13 patients received conventional treatment combined with trastuzumab (T arm). There were no significant differences in the main clinical factors between the two arms, such as age, PS status, ER/PR, metastatic status, etc. Both the two cases with no disease progression after the second-line therapy were trastuzumab-treated patients, and all the other 33 cases were patients with progression despite the second-line therapy. Twenty-seven patients died due to disease progression, and eight survived (six cases of the T-arm and two cases of the non-T arm). The median PFS was 3.3 months in the non-T arm and 10.0 months in the T arm (P = 0.001). The median OS was 7.0 months in the non-T arm and 31.1 months in the T arm (P = 0.015). Trastuzumab plus conventional treatment is superior to conventional treatment in women with lapatinib-resistant HER2-positive metastatic breast cancer. Continuous anti-HER2 management can provide survival benefit to patients with HER2-positive breast cancer.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) patients who received taxane plus trastuzumab treatment.

637 Background: The HER3 receptor is a key member of ErbB family and preferentially signals through the PI3K pathway. Formation of dimers between HER3 and HER2 seems to be crucial for HER2-driven signals in HER2 overexpressing tumors. Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 activity may contribute to the resistance of trastuzumab. PTEN plays a well-established role in the negative regulation of the PI3K pathway. Our aim of this study was to investigate the role of HER3 and PTEN expression in patients with HER2 overexpressed MBC. Methods: One-hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as the first line therapy were included in this analysis. Immunohistochemical stainings (IHC) with HER3 and PTEN antibody were conducted retrospectively. Results: Median age was 48 years. HER3 IHC was graded from 0 to 3. PTEN IHC was scored as multiplication of intensity and proportion from 0 to 300. The patients who had negative HER3 stain showed better progression free survival (PFS) to taxane plus trastuzumab chemotherapy than those positive HER3 stain (p=0.001, median PFS 21 vs. 11 mo.). The patients who had PTEN score of more than 20 showed longer PFS than those PTEN score of 20 or less than 20 (p=0.006, median PFS 13 vs. 9 mo.). The patients who had PTEN score of more than 20 showed longer overall survival (OS) than those PTEN score of 20 or less than 20 (p=0.005, median OS 48 vs. 25 mo.). HER3 negativity and PTEN loss were identified as independent risk factors for PFS [Hazard Ratio (HR) 0.4 (95% CI 0.3-0.8 for HER3 negativity; HR 2.1 (95% CI 1.2-3.7) for PTEN loss]. However, PTEN loss (HR 3.1 [95% CI 1.6-6.3]) was identified as an independent risk factor for OS. Conclusions: HER3 and PTEN expression may be predictive markers for trastuzumab treatment in HER2-positive MBCs. PTEN expression may have a potential predictive and prognostic biomarker for trastuzumab treatment.

Abstract S5-1: Biomarker analyses in CLEOPATRA: A phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC)

Abstract Background: The anti-HER2 humanized monoclonal antibodies trastuzumab (T) and pertuzumab (P) have complementary mechanisms of action. CLEOPATRA showed that P+T+docetaxel (D) significantly improved progression-free survival (PFS) compared with placebo (Pla)+T+D in the first-line treatment of HER2-positive MBC (HR = 0.62, 95% CI 0.51–0.75; p < 0.001), with a similar safety profile. A panel of biomarkers (BMs) was assessed in tumor tissue and in serum samples to explore their potential predictive and/or prognostic value. Methods: Samples were collected at baseline prior to the first dose of study drug (N = 808; 58–99% of which were assessable for BMs due to tissue availability/technical reasons). HER2, HER3, IGF1R, PTEN, and pAKT were assessed by immunohistochemistry and a modified H-score was derived for each. HER1, HER2, HER3, AREG, and betacellulin tumor mRNA levels were assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and c-myc by fluorescence in situ hybridization. PCR-based methods were used for mutational analyses of 8 hotspots within PIK3CA on tumor DNA, and for assessments of FCγR polymorphisms in DNA extracted from whole blood. Serum HER2 extracellular domain, AREG, EGF, and TGFα were detected by ELISA. Exploratory subgroup analyses of PFS by BM level were performed for each BM. Median values were used as cutoffs for high vs low levels, except for PTEN, PIK3CA mutation, and c-myc amplification, where cutoffs were applied following a biologic rationale. Univariate Cox regression analyses assessed the prognostic value on a background of HER2-targeted treatment (relationship of each BM to clinical outcome, both arms pooled) and predictive value (association of BMs with treatment benefit) of each BM. Analyses were exploratory; therefore no adjustment for multiplicity was made. Results: Significant prognostic variables identified were: HER2 protein (p = 0.05), HER2 mRNA (p = 0.008), HER3 mRNA (p = 0.03), and PI3KCA mutation (p = 0.0001). The HR was <1 for each, indicating that patients with high levels of HER2 protein, HER2 mRNA, HER3 mRNA, or wild type PIK3CA had a better prognosis. Irrespective of prognostic impact, the PFS benefit of P+T+D, as observed in the overall study population, was maintained following individual adjustment for each BM (HR range=0.61–0.66), including PIK3CA (HR = 0.66). Analyses exploring the predictive value showed that all patients derived a benefit from P+T+D treatment compared with Pla+T+D, regardless of the expression of any assessed candidate BMs. HR point estimates were <1.0 for all BM subgroups assessed. Summary: The BM analysis from CLEOPATRA is consistent with results from previous phase II studies: HER2 remains the only marker suitable for use when selecting patients for anti-HER2 therapy. The current analyses did not identify any additional predictive markers that would allow refinement of the HER2-positive target population treated with P+T+D. The lack of a HER2 treatment-naive control group may partly explain the lack of a signal. The PI3K mutational status may identify a poor prognostic group within the HER2-positive population that could be appropriate for clinical trials of HER2-targeted molecules in combination with PI3K pathway-targeted agents. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-1.

Multicenter international phase II study of oral vinorelbine (NVBo), capecitabine (X) and trastuzumab (H) triple combination in HER2-positive metastatic breast cancer (MBC): updated results with a longer follow-up.

Abstract Abstract #3151 Background: CT plus H is the standard treatment for HER2-positive MBC. Combination therapy of H plus vinorelbine is an active and safe regimen in this setting. The all-oral combination of NVBo and X has been reported as an active and safe regimen in many different trials in MBC. We report efficacy and safety information from an updated analysis of all 50 patients (pts) included in this trial, with a median follow-up of 28.5 months.
 Methods: Main eligibility criteria included: HER2-positive disease (defined as IHC 3+ or FISH+), documented measurable metastatic disease previously untreated by CT, relapse ≥ 6 months after the end of neoadjuvant or adjuvant CT, Karnofsky PS ≥ 70. NVBo was given as at a dose of 80 mg/m2 (after a first cycle at 60) D1 and D8 every 3 weeks, X at 1000 (750 if ≥ 65 years) mg/m2 bid D1-D14 every 3 weeks, H at 4 mg/kg on D1 as a loading dose then 2 mg/kg i.v. weekly starting on D8. Treatment was continued until progression.
 Results: Median age: 53.5years (18% ≥ 65); prior (neo)adjuvant CT 27 pts (54%); visceral involvement 41 pts (82%), > 2 metastatic sites 17 pts (34%); Median number of cycles: 10 (range 1-56); Median relative dose intensity: NVBo 75%, X 77%, H 96%; NVBo escalated to the recommended dose of 80 mg/m2 in 84% of pts; G3/4 NCI CTC v2 adverse events per pt: (n=49) neutropenia 69%, (n=50) febrile neutropenia 8%, infection without neutropenia 4%, stomatitis 4%, nausea 4%, vomiting 12%, diarrhea 16%, hand-foot syndrome 20%, asthenia 8%, LVEF decline 6%, alopecia (grade 2) 14%; Efficacy (n=44 evaluable patients): objective response rate (RECIST) 77% (95% CI [62-89]), CR 18%, PR 59%, SD 18%, PD 5%, disease control (CR+PR+ SD ≥6 months) 93% (95% CI [81-99]), median duration of response was 14.3 months (95% CI [9.8-16.8]), median progression-free survival was 12.8 months (95% CI [10.8-16.9]), overall survival results are not mature yet. Treatment is ongoing in 5 pts.
 Conclusion: The combination of NVBo and X + H has shown high antitumoral efficacy in pts with HER2-positive MBC. Toxicity profile was acceptable with, in particular, a very low rate of alopecia. An efficacy and safety analysis in pts aged < vs ≥ 65 years will be performed and presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3151.

Efficacy of oral vinorelbine (NVBo), capecitabine (X) and trastuzumab (H) triple combination (NVBoXH) in HER2-positive metastatic breast cancer (MBC): First results of an international phase II trial

1052 Background: Chemotherapy (CT) plus H is the standard first-line treatment for HER2-positive MBC. H plus vinorelbine is an active and well-tolerated regimen in this setting. The all-oral combination of NVBo and X also appears active and well-tolerated in MBC. We report efficacy and safety results from the first 34 patients (pts) included in an international trial evaluating NVBoXH in HER2-positive MBC. Methods: In this multicenter trial, main eligibility criteria included: HER2-positive disease (IHC 3+ or FISH+), documented measurable MBC previously untreated by CT, relapse 6 months after completing neoadjuvant or adjuvant CT, Karnofsky PS = 70, age =18 years. Pts received 3-weekly cycles of NVBo 60 mg/m2 (cycle 1) escalating to 80 mg/m2 (from cycle 2) days 1 and 8; × 1,000 mg/m2 bid (750 if = 65 years) days 1–14; H 4 mg/kg day 1 as a loading dose then 2 mg/kg i.v. weekly starting on day 8. Treatment was continued until progression or unacceptable toxicity. Primary endpoint is overall response rate. Results: Baseline characteristics: median age 54 years (20% = 65); prior (neo)adjuvant CT 21 pts (62%); type of CT: anthracycline 52%, anthracycline + taxane 29%, CMF 14%, taxane 5%; visceral involvement 29 pts (85%), >2 metastatic sites 13 pts (38%). Treatment administered: median 8 cycles, median relative dose intensity: NVBo 77%, X 81%, H 95%; NVBo dose escalation to 80 mg/m2 in 91% of pts. Safety (n=34, G3/4 NCI CTC v2 adverse events): neutropenia 22 pts (65%), diarrhea 4 pts (12%), febrile neutropenia 3 pts (9%), vomiting 3 pts (9%), hand-foot syndrome 3 pts (9%), asthenia 3 pts (9%), infection without neutropenia 2 pts (6%), LVEF decline 2 pts (6%), stomatitis 1 pt (3%), nausea 1 pt (3%), constipation 1 pt (3%). Efficacy (n=31 evaluable pts): objective response rate (RECIST) 71% (95% CI [52–86]), CR 13%, PR 58%, SD 23%, PD 6%, disease control (CR+PR+ SD for =6 months) 84%. Progression-free survival, overall survival and duration of response data are not yet mature. Conclusions: This is the first trial, in pts with HER2-positive MBC, to show high efficacy with first-line NVBoXH therapy. This regimen can be safely administered in this pt population. No significant financial relationships to disclose.

A phase II trial of trastuzumab (H) + capecitabine (X) as first-line treatment in patients (pts) with HER2-positive metastatic breast cancer (MBC)

10615 Background: The addition of H to a taxane provides significant clinical benefit, including prolonged survival, in HER2-positive MBC. H adds little to the toxicity of taxanes alone. As monotherapy, X has consistently high activity and favorable safety. The addition of X to docetaxel extends survival in MBC. Preliminary data [Bangemann et al. 2000] indicated that the combination of H + X is effective and well-tolerated for intensively pretreated HER2-positive MBC (ORR 47%). The current study evaluated the efficacy and safety of H + X in first-line MBC. Methods: 72 pts of a planned population of 100 pts were enrolled between Mar03 and Dec05. All pts had measurable (WHO criteria), HER2-positive (IHC 3+ or IHC 2+/FISH positive) and untreated MBC, KPS ≥60, and adequate organ function. H was administered as a 4mg/kg loading dose followed by 2mg/kg i.v. weekly (until disease progression) and X 1250mg/m2 bid d1–14 q3w (max 6 cycles). The primary endpoint was progression-free survival (PFS). Results: Baseline characteristics: median age 49 years (range 27–74), median KPS 90 (range 60–100). Principal tumor sites: lymph nodes (49%), lung (33%), liver (28%), breast (14%), thoracic wall (9%), chest (9%), other (12%). Prior treatment: surgery (77%), radiotherapy (21%), and adjuvant chemotherapy (58%), including anthracycline (35%), paclitaxel (7%), docetaxel (7%) and other (21%). 43 pts are evaluable for safety and efficacy. The remaining 29 pts are being analyzed. 6 pts received 3 cycles of H + X; the other 37 pts completed 6 cycles of treatment. 16 pts received H monotherapy after completing 6 cycles of H + X. 3 pts discontinued H due to disease progression. The most common grade 1/2 adverse events (AEs) were HFS (14%), neutropenia (14%), SGOT abnormality (16%), and SGPT abnormality (14%). Grade 3 HFS occurred in 4 pts (10%) with grade 3 myelosuppression in 1 pt (2%). AEs were mild and resolved in all pts. The overall response rate was 63%, including 5 CRs and 22 PRs. At a median follow-up of 6 months, median PFS has not been reached. Conclusions: The combination of H and X is a highly active and well-tolerated regimen for first-line treatment of HER2-positive MBC. Updated data will be presented. No significant financial relationships to disclose.