HER2-overexpressing Metastatic Breast Cancer Research Articles

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 OT1-1-03: A phase 3 randomized, double-blind trial comparing PF-05280014 + paclitaxel vs. trastuzumab + paclitaxel for treatment of HER2+ metastatic breast cancer patients

Abstract Background: PF05280014 is being developed as a potential biosimilar to trastuzumab. PF-05280014 demonstrated similarity to trastuzumab in nonclinical evaluations. In a Phase I trial in healthy volunteers, PF-05280014 pharmacokinetic characteristics and safety profile were shown to be similar to those of trastuzumab. The goal of this Phase 3 trial is to demonstrate that the efficacy and safety of PF-05280014 + paclitaxel are similar to those of trastuzumab sourced from the EU (trastuzumab-EU) + paclitaxel in women with HER2-positive metastatic breast cancer. Trial design: In this randomized, double-blind trial, patients will be randomized 1:1 into 2 arms: PF-05280014 + paclitaxel and trastuzumab-EU + paclitaxel. Randomization will be stratified by prior adjuvant trastuzumab exposure and estrogen receptor status. The order of infusion will be PF-05280014 or trastuzumab (4 mg/kg in Cycle 1; 2 mg/kg thereafter over 90 min) first followed by paclitaxel (80 mg/m2). Eligibility: Female patients, aged ≥18 y with confirmed HER-2 overexpressing metastatic breast cancer, ≥1measurable lesion (RECIST), Eastern Cooperative Oncology Group status 0–2, normal left ventricular ejection fraction, and normal laboratory values are eligible. Key exclusion criteria are prior systemic therapy for metastatic disease, prior cumulative dose of anthracyclines >400 mg/m2, and major surgery, radiotherapy or investigational agents within 4 weeks. All subjects must provide informed consent. Aims: The primary objective is to demonstrate the similarity in objective response rate (ORR) of PF-05280014 + paclitaxel treatment to that of trastuzumab-EU + paclitaxel. Secondary objectives include evaluating 1-year progression-free survival, safety, pharmacokinetics, and immunogenicity of these combination treatments. Statistical methods: This study tests whether the ORR of PF-05280014 is similar to that of trastuzumab-EU, using a margin of 13%, i.e., 5% alpha for non-inferiority. Assuming 60% ORR in both arms, 600 patients (300/arm) will be needed to achieve 90% power. Assuming 10% attrition, a total of 660 patients will be randomized. The intent-to-treat (ITT) population is defined as all subjects who are randomized to receive treatment. The per-protocol population is defined as all subjects who are randomized to and receive treatment and do not have any major protocol violations and will be used for evaluation efficacy endpoints. Accrual: The target accrual of this global trial is 660 patients. Contact information: For further information, please contact the Director, Clinical Trials Disclosure Group, Pfizer Inc. (marla.brickman@pfizer.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-03.

O2–047 - The Role of HER3 Expression and PTEN Loss in Patients with HER2-Overexpressing Metastatic Breast Cancer (MBC)

Background: Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 may contribute actively 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.

Overcoming therapeutic MAb resistance in agressive HER2 positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells

Herceptin (Trastuzumab), a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, half of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse after one year of treatment despite Herceptin-based therapy. Alteration of Antibodies Dependant Cellular Cytotoxicity (ADCC) is one of the rational mechanisms for resistance to therapeutic Mab. The goal of this project is to overcome this resistance by adoptive transfer using genetically engineered optimized NK cells. We thus compare efficacy of two different approaches : (i) NK cells armed with a high affinity Fc domain (FcγRIIIα, CD16) linked to its transduction chain FCeRIγ (CD16/γ) to allow recognition and interaction with Mab, inducing ADCC and (ii) NK cells expressing Herceptin sequence fused to the transduction chain FCeRIγ(CD16/γ) to directly kill the HER2 positively cells. Results obtained in vitro demonstrated higher direct killing efficacy of NK expressing Herceptin/γ against HER2 amplified breast carcinoma cells. However, abnormal reactivity against cells with undetectable HER2 expression by FACS analysis was observed. This last point might represent an important limitation point for clinical use. On the other hand, “two step killing by ADCC” with NK-CD16/γ demonstrated a very specific cytotoxicity against HER2 positive cells through ADCC only in the presence of antibody. We demonstrated that efficacy of specific lysis is linked (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression but not level on target cells In Herceptin resistant HER2+ xenograft immunodeficient NSG mice model, complete regression was obtained only with NK- CD16/γ in the presence of Herceptin. Our last results will be discussed. Restoration or improvement of effectors cells might be considerate as an issue in therapeutic humanized Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs, in order to maximize their antitumor activity.

PCN30 - Trastuzumabe No Câncer De Mama Metastático: Uma Revisão Sistemática De Análises Custo-Efetividade

Breast cancer is the type that affects more women worldwide. Approximately 30-50 % of patients diagnosed in the early stages will develop metastatic disease, which is considered incurable. At this stage of the disease, therapies aimed prolong survival and provide palliative symptom control. Trastuzumab, a monoclonal antibody targeted to the receptor of the human epidermal growth factor (HER2), has increased response rates, progression-free survival and/or overall survival in breast cancer and has recently been incorporated by the Sistema Unico de Saude (SUS) for treatment of early and locally advanced breast cancer. The aim of this study was to conduct a systematic review of the cost-effectiveness analyses of trastuzumab in patients with metastatic breast cancer overexpressing HER2. Searches were conducted between the period 1998-2013, on six electronic databases, two generic searches on the Internet, as well as manual search of references. We considered articles in English, Spanish and Portuguese, being excluded reviews, editorials, letters, case studies, review articles, systematic reviews and meta-analyses. The stages of study selection and data extraction were performed by two independent reviewers, and doubts were resolved by one third reviewer. Studies were assessed for quality according to approaches employed by Teerawattananon et al (2007). Data analysis was performed from the conversion of the costs and comments of the incremental cost-effectiveness ratios of trastuzumab were made. A quantity of 521 studies, all in English, was identified. Of these, we discarded 455 (294 did not meet the criteria for review and 161 duplicates). Sixty-six studies were included for reading the abstracts, resulting in 24 to read the full text. In total, 13 studies composed this review. The treatment regimens adopted on cost-effectiveness evaluations were varied. Eight studies compared the treatment of trastuzumab as 1st line for metastatic disease and five studies as 2nd line, which three of these used trastuzumab as comparator in the economic evaluation and not as an intervention. All studies using trastuzumab as 2nd line treatment did not consider it as a cost-effective intervention. Regarding the quality of the included studies, they showed a good quality, since most fulfilled the methodological guidelines for assessing costeffectiveness and used good evidence in the estimation of parameters. Finally, the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective as well as differences in modeling costs, outcomes and treatment regimens. The use of trastuzumab, alone or associated, was cost-effective as treatment of 1st line, unlike when used as 2nd line. Differences were found in the quality of the included studies. Conducting new cost-effectiveness analyses of trastuzumab in metastatic breast cancer, allied to political, social and administrative factors, which helps decision makers about its incorporation, is required

Novel Targeted Therapies to Overcome Trastuzumab Resistance in HER2- Overexpressing Metastatic Breast Cancer

Overexpression of the human epidermal growth factor receptor 2 (HER2) is identified in approximately 25- 30% of breast cancers and indicates a poor prognosis. Trastuzumab, the anti-HER2 monoclonal antibody (mAb), has shown significant clinical effects selectively in HER2-overexpressing metastatic breast cancer (MBC) with improved overall survival and reduced recurrent risk. However, there is an urgent need to develop new strategies to overcome innate and acquired trastuzumab resistance, which has increasingly occurred. Recently, an increased understanding of mechanisms of trastuzumab resistance significantly promotes the development of novel targeted therapies for trastuzumab refractory disease. It is believed that aberrant activations of several signaling pathways involving the human epidermal growth factor receptor (EGFR/HER) family, phosphoinositide 3 kinase/Akt (PI3K/Akt) pathway, and vascular endothelial growth factor (VEGF) family, contribute to the development of trastuzumab resistance. Novel agents that target these relevant signal pathways provide some potential solutions, such as tyrosine kinase inhibitors (TKIs) and mAbs. HER2 is also recognized as an immunotherapeutic target. The failure to induce immune-mediated antitumor response is another important reason for trastuzumab resistance. Strategies to boost T cell-mediated immune responses specific to HER2 including HER2 vaccines and bispecific antibodies (bsAbs) could be developed as a promising way to prevent relapse or combat trastuzumab resistance. In this review, the emerging data from preclinical and clinical studies related to these novel therapies will be discussed.

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.

A phase II randomized trial of lapatinib with either vinorelbine or capecitabine as first- and second-line therapy for HER2 overexpressing metastatic breast cancer (MBC).

516 Background: Lapatinib (L) is approved for the treatment of human epidermal growth factor receptor 2 (HER2) positive MBC in combination with capecitabine (C) following progression after trastuzumab, anthracyclines and taxanes. Vinorelbine (V) is an important chemotherapy option in MBC. This randomized, open-label, multicenter phase II study (NCT01013740) evaluated the efficacy and safety of L with either V or C in women with HER2+ MBC. The analysis of progression-free survival (PFS) and safety showed comparable rates of efficacy and tolerability between the 2 arms (Janni et al, SABCS 2012). Here we report the results of the overall survival (OS) and crossover analyses. Methods: Patients with MBC who had received ≤1 chemotherapy regimen in the metastatic setting were randomized 2:1 to either L 1250 mg orally once daily (QD) continuously + V 20 mg/m2 intravenously on days 1 and 8, every 3 weeks, or L 1250 mg orally QD continuously + C 2000 mg/m2/day orally in 2 doses, 12 hours apart on days 1-14 every 3 weeks. Patients were stratified by prior receipt of therapy for MBC and site of metastatic disease. The primary endpoint was PFS. Other endpoints included OS, overall response rate and safety. Patients progressing on one treatment arm were given the option of crossover to the other arm. All analyses were conducted with a descriptive intent only. The control arm of L+C was included in the study design to validate the patient population and lend support to the activity of L+V. Results: 112 patients were randomized in the study; 37 to the L+C arm and 75 to the L+V arm. The median OS in the L+C arm was 19.4 months [95% CI: 16.4-27.2] and 24.3 months [95% CI: 16.4-NE] in the L+V arm. At the time of analysis 42 patients had crossed over; 29 patients to L+C and 13 to L+V. Median PFS after crossover was 4 months [95% CI: 2.1-5.8] in the L+C arm and 3.2 months [95% CI: 1.7-5.1] in the L+V arm. Conclusions: L+V has shown consistent median OS with that reported in the pivotal study of L+C. The exploratory analysis of patients retreated with L after progression on L supports the biological rationale for maintaining HER2 suppression in HER2+ patients with progression on prior lines of anti-HER2 agents. Clinical trial information: NCT01013740.

Phase II study of lapatinib in combination with vinorelbine, as first- or second-line therapy in women with HER2-overexpressing metastatic breast cancer.

621 Background: Lapatinib (L), an inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) is approved in combination with capecitabine for second-line treatment of HER2+ metastatic breast cancer (MBC). Vinorelbine (V)is a semi-synthetic vinca alkaloid approved for use in patients (pts) with MBC. A previous phase I trial provided a maximum tolerated dose of L plus V. Methods: This was a multicenter, phase II study (LPT111110; NCT00709618) to evaluate the efficacy and safety of L plus V in women with histologically confirmed stage IV HER2+ MBC, ≤1 prior chemotherapeutic regimen (no prior L or V was allowed; prior trastuzumab was permitted) and a Zubrod performance status of 0-2. Pts received L (1500 mg daily) plus V (20 mg/m2IV on Days 1, 8, 15) in a 4-week treatment cycle until disease progression or study withdrawal. Primary endpoint: overall response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival, time to response (TTR), duration of response (DOR), time to progression, and safety assessments. Results: The study was terminated after three years due to slow enrollment; 60 pts were planned and 44 enrolled and were treated. The ORR was 41% (95% CI: 26.4%-55.4%; 4 complete responses, 14 partial responses). Investigator-assessed median (95% CI) PFS, TTR, and DOR were 24.1 (16.9-36.7), 7.5 (7.1–8.1), and 32.0 (18.0-42.3) weeks, respectively. Survival data are not available since data collection was terminated after discontinuation of study treatment. All pts experienced at least 1 adverse event (AE). Conclusions: The combination of L plus V resulted in a 41% ORR and was generally well tolerated. However, definitive conclusions could not be drawn as the study was terminated early and not powered for inference testing. Further exploration of L plus V is warranted to clearly define the role of this novel combination in the treatment of HER2+ MBC. Clinical trial information: NCT00709618. [Table: see text]

Brain and tumor penetration of carbon-11–labeled lapatinib ([11C]Lap) in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC).

635 Background: About a third of HER2-overexpressing (HER2+) breast cancer pts will develop brain metastases in the course of their disease. Drug access to normal brain and brain metastases is therefore key to prevention and treatment of cerebral metastases. To provide direct evidence of Lap drug access and evaluate whether therapeutic doses of Lap act as a substrate for efflux transporters, thereby increasing Lap concentrations, we performed positron emission tomography (PET) studies with [11C]Lap. Methods: Pts with HER2+ MBC with an ECOG of <3 were grouped into 2 cohorts: with at least one 1-cm diameter brain metastasis or without brain metastases and underwent 90-minute dynamic cranial PET-CT scans after IV administration of a microdose (<1 mg) of [11C]Lap before and after 8 days of oral Lap (1500 mg once daily). Arterial blood samples were performed to assess [11C]Lap radioactivity contribution in blood and plasma, and the fraction of plasma [11C] radioactivity corresponding to metabolites. Tissue time-radioactivity curves (TACs) were generated and [11C]Lap exposure (AUC; area under TAC) derived for normal brain and brain metastases. Signal dissection of the total image activity was performed to remove the contribution of blood volume to the image and the actual tissue contribution due to [11C]Lap obtained. Results: 6 pts (3 with brain metastasis) were recruited. Arterial plasma analysis revealed that [11C]Lap contributed to >80% of activity in plasma at 60 minutes. Tissue data revealed [11C]Lap signal in normal brain was low with no appreciable uptake observed when corrected for blood volume contribution. [11C]Lap uptake was higher in brain metastases compared with normal brain and appreciable, even after correction for tissue blood volume contribution. Uptake was also observed in extra-cranial normal tissue. There was no difference in [11C]Lap uptake in normal brain and metastases between treatment-naïve and post-treatment scans. Conclusions: [11C]Lap uptake in brain metastases was higher than in normal brain. [11C]Lap drug access to brain metastases might therefore indicate possible efficacy against HER2+ brain metastases. Clinical trial information: NCT01290354.

Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).

606 Background: Pertuzumab is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab, disrupting HER2 dimerization and signaling. Pertuzumab improves progression-free survival (PFS) and overall survival when combined with docetaxel/trastuzumab. We report results of a phase II study to evaluate the efficacy and safety of pertuzumab, trastuzumab and weekly paclitaxel. Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) were eligible. Rx is weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → 420mg). The primary endpoint is PFS at 6 months (mo). Evaluable pts are those who started study Rx and are assessed at 6 mo for PFS, including pts who progressed prior to 6mo. Secondary endpoints include response, safety (including cardiac events), and tolerability. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 1-18-13, 53 pts are enrolled; 36 are evaluable at 6 mo. At 6 mo, 29/36 pts (81%) are progression-free (4 CR, 14 PR and 11 SD); 7 pts progressed. The 6 mo PFS results for all patients will be updated. Median LVEF is 64% at baseline (range 50-72%), 63% at 3 mo (range 50-73%), and 62% at 6 mo (range 49-69%). There are no cardiac events to date. Of the 36 pts, grade 3/4 toxicities include fatigue (3 pts, 8%), peripheral neuropathy (2 pts, 6%), sepsis (1pt, 3%), cellulitis (1pt, 3%), neutropenia (1pt, 3%), and skin ulceration (1pt, 3%). There are no grade 3 diarrhea or febrile neutropenic events in the evaluable pts to date. Conclusions: The preliminary 6-month PFS is 81% (95% CI 67-91%) in evaluable patients. The study is closing to accrual. Treatment is ongoing, with few grade 3/4 toxicities and no signal of increased cardiac toxicity to date. This phase II study demonstrates efficacy and safety for pertuzumab with trastuzumab and weekly paclitaxel in HER2+ MBC. Clinical trial information: NCT01276041.

Lapatinib with trastuzumab for heavily treated HER2-positive metastatic breast cancer (mBC).

e11561 Background: Trastuzumab and lapatinib show complementary and non-cross resistant mechanisms of anti-HER2 action. Dual HER2 blockade has been preclinically and clinically assessed with encouraging results. Trastuzumab and lapatinib combination is effective in terms of survival in patients with heavily pretreated HER2-positive mBC. We aim to report our experience with lapatinib plus trastuzumab in this setting. Methods: Descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing metastatic breast cancer treated in two institutions from 01/2007 to 12/2012. The objective of this analysis is to report the response rate (RR), progression-free survival (PFS) and toxicity. Results: 23 HER2-positive mBC patients previously treated with trastuzumab received trastuzumab plus lapatinib based therapy. 15 patients (65%) received 2 or more previous lines. 17 patients (74%) had visceral disease. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%) whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. Chemotherapeutic drugs most used were: capecitabine (54%) and vinorelbine (15%). RR: partial response 22% (5/23), stable disease 39% (9/23). Median of follow-up was 11 months. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, while PFS in patients with HT was only 2. PFS in hormone receptor positive and negative was 3 and 5 months respectively. The most common toxicities were: diarrhea (48%), anemia (39%), asthenia (39%) and hand-and-foot syndrome (17%). Grade ≥ 3 toxicity was diarrhea (26%) and hand-and-foot syndrome (9%). The incidence of cardiotoxicity was 9% (grade 2). Conclusions: These findings suggest that dual HER2 blockade in combination with CT is feasible and active in heavily pretreated HER2-positive mBC patients. However, further investigation is warranted to demonstrate superiority over sequential blockade with trastuzumab and lapatinib in this setting.

Randomized Trial of Lapatinib Versus Placebo Added to Paclitaxel in the Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancer

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC). This phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety. The addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm. This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.

Abstract A22: Overcoming therapeutic MAb resistance in agressive HER2-positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells.

Abstract The HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Herceptin (Trastuzumab), a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, half of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse after one year of treatment despite Herceptin-based therapy. The goal of this project is to compare efficacy of two adoptive immunotherapies approaches by genetically engineered NK cells to overcome this resistance. For the first approach, we developed NK cells armed with an high affinity Fc domain (FcγRIIIα, CD16) linked to its transduction chain FCϵRIγ (CD16/γ) to allow recognition and interaction with Mab, inducing Antibodies Dependant Cellular Cytotoxicity (ADCC). For the second approaches, we developed NK cells expressing Herceptin sequence fused to the transduction chain FCϵRIγ (CD16/γ) to directly kill the HER2 positively cells. Results obtained in vitro demonstrated higher direct killing efficacy of NK expressing Herceptin/γ against HER2 amplified breast carcinoma cells BT474 or SKBR3. However, abnormal reactivity against cells with low or undetectable HER2 expression by FACS analysis was observed (15 to 30% of lysis). This might represent an important limitation point for clinical use. On the other hand, “two step killing by ADCC” with NK-CD16/γ demonstrated a very specific cytotoxicity against HER2 positive cells through ADCC only in the presence of Herceptin. We demonstrated that efficacy of specific lysis is linked (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression on target cells but not HER2 level of expression. We then compared in vivo efficacy of both approaches (“one step” vs “two step”ADCC) in HER2+ xenograft model using immunodeficient NOD-SCID mβ2-/- mice. Complete regression of herceptin resistant HER2+ xenograft was obtained only with NK- CD16γ in the presence of herceptin. Our last results will be presented. Because the alteration of ADCC mechanisms during Herceptin treatment is one rational explanation for the acquired resistance, restoring or improving effectors cells might represent next step in therapeutic humanized Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs (including toll-like receptor modulators, antibodies specific for the PD-1, the OX-40 ore the CD40 pathways, in order to maximize their antitumor activity. Citation Format: Sandrine Valsesia-Wittmann, Beatrice Clemenceau, Anne-Catherine Jallas, Jean-Yves Blay, Christophe Caux, Henri Vie. Overcoming therapeutic MAb resistance in agressive HER2-positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A22.

Abstract OT1-1-16: LUX-Breast 1: Randomized, Phase III trial of afatinib (BIBW 2992) and vinorelbine vs. trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment*

Abstract Background: Afatinib is a ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (non-small cell lung cancer [NSCLC]/head and neck squamous cell carcinoma) and HER2 (ErbB2)-driven (breast) malignancies, and has shown clinical efficacy in NSCLC patients with EGFR activating mutations.1,2 In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib. Afatinib monotherapy activity in this SUM190 model was increased by the addition of intravenous (i.v.) vinorelbine. Clinically, afatinib monotherapy demonstrated activity in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab, with a progression-free survival (PFS) of 15.1 weeks, an overall survival (OS) of 61.0 weeks and 10% objective response (OR).3 HER-reprogramming appears to play an important role in resistance4 and recent clinical trial results have indicated that targeting more than one ErbB Family member increases efficacy.5 Thus afatinib, as an ErbB Family Blocker, should add to the portfolio of drugs available to treat trastuzumab resistance in HER2-positive BC patients. This is currently being tested in the LUX-Breast 1 trial. Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/day oral) + vinorelbine (i.v. 25 mg/m2/week) or trastuzumab (i.v. 2 mg/kg/week after 4 mg/kg loading dose) + vinorelbine (i.v. 25 mg/m2/week). Patients receive continuous treatment in the absence of disease progression or unacceptable toxicity. Key eligibility criteria include histologically-confirmed HER2-positive MBC; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or &amp;lt;12 months after trastuzumab completion) or first-line (or &amp;lt;6 months after trastuzumab completion) setting; prior anthracycline and/or taxane chemotherapy and an ECOG score of 0 or 1. The primary endpoint is PFS and secondary endpoints include OR, OS and safety. Patients' quality of life will be evaluated alongside other endpoints. Biomarkers will be assessed on archival tissue, in serum and in voluntary fresh tissue biopsies. Analyses on fresh tissue biopsies include ErbB-receptor and ErbB-ligand reprogramming, putative resistance markers, and EGF response signature. Enrollment began in June 2010 and is ongoing, targeting &amp;gt;240 sites with a recruitment target of 780 patients. 1. Yang JCH. Lancet Oncol 2012;13:539–48. 2. Yang JCH. J Clin Oncol 2012;30(suppl; abstr LBA7500). 3. Lin NU, et al. Breast Cancer Res Treat 2012. DOI: 10.1007/s10549-012-2003-y. 4. Metro G, et al. Expert Opin Pharmacother 2008;9:2583–601. 5. Bischoff J and Ignatov A. Breast Care 2010;5:134–41. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-16.

Trastuzumab-DM1: A Clinical Update of the Novel Antibody-Drug Conjugate for HER2-Overexpressing Breast Cancer

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.

Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).

134 Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ MBC prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel (T) with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 5-1-12, 33 of the planned 69 pts were enrolled; 16 were evaluable at 6 mo. Of the 16 pts, G 3/4 toxicities included sepsis (1pt, 6%), cholecystitis (1pt, 6%), fatigue (1pt, 6%), skin ulceration (1pt, 6%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 6%). G 1/2 toxicities included alopecia (16 pts, 100%), fatigue (15 pts, 94%), ALT/AST elevation (14 pts, 88%), neuropathy (14 pts, 88%), diarrhea (12 pts, 75%), rash (9 pts, 56%), nail changes (8 pts, 50%), nausea (7 pts, 44%), mucositis (7 pts, 44%), and dry skin (6 pts, 38%). Median LVEF was 63% at baseline, 60% at 3 mo and 58% at 6 mo. There were no cardiac events. At 6 mo, 12/16 pts (75%) were progression-free (2 CR, 7 PR and 3 SD); 4 pts progressed. Conclusions: Our single-center phase II study continues to accrue, with no significant diarrhea or signal of increased cardiac toxicity to date. If the estimate of activity is similar to results with docetaxel in CLEOPATRA, this will provide support for THP as an alternative option in this setting.

Heat shock protein 90 (hsp90) expression and breast cancer.

Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles in breast neoplasia including estrogen receptors, tumor suppressor p53 protein, angiogenesis transcription factor HIF-1alpha, antiapoptotic kinase Akt, Raf-1 MAP kinase and a variety of receptor tyrosine kinases of the erbB family. Elevated Hsp90 expression has been documented in breast ductal carcinomas contributing to the proliferative activity of breast cancer cells; whilst a significantly decreased Hsp90 expression has been shown in infiltrative lobular carcinomas and lobular neoplasia. Hsp90 overexpression has been proposed as a component of a mechanism through which breast cancer cells become resistant to various stress stimuli. Therefore, pharmacological inhibition of HSPs can provide therapeutic opportunities in the field of cancer treatment. 17-allylamino,17-demethoxygeldanamycin is the first Hsp90 inhibitor that has clinically been investigated in phase II trial, yielding promising results in patients with HER2-overexpressing metastatic breast cancer, whilst other Hsp90 inhibitors (retaspimycin HCL, NVP-AUY922, NVP-BEP800, CNF2024/BIIB021, SNX-5422, STA-9090, etc.) are currently under evaluation.

A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients

It is known that one third of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) treated with trastuzumab will develop brain metastases. As the development of brain metastases is fatal, controlling its progression is clinically meaningful. However, effective therapy for MBC patients with brain metastasis after cranial radiation is limited. The international clinical study in which six Japanese patients participated indicated the antitumor activity of lapatinib against brain metastases of HER2-overexpressing breast cancer. The efficacy, safety, and pharmacokinetics of lapatinib 750 mg given twice daily to Japanese HER2-overexpressing MBC patients with brain metastases were assessed as part of the international clinical study. Of six Japanese patients treated in this study, two patients had shown volumetric reduction >20 % in their central nervous system (CNS), one of whom had >50 % reduction. Three patients, including two of these patients, had shown >20 % volumetric reduction in non-CNS lesions. Frequently reported adverse events were diarrhea and rash, all of which were controllable. The AUC0-12 of lapatinib on day 28 was 1.74 times higher than that on day 1. These results suggest that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with brain metastases after cranial radiation.

Deciphering the Role of Insulin-Like Growth Factor-I Receptor in Trastuzumab Resistance

Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-overexpressing metastatic breast cancer. Increased expression or signaling of the insulin-like growth factor-I receptor (IGF-IR) has been reported in a subset of cell lines and clinical samples derived from trastuzumab-resistant breast cancers. Genetic and pharmacologic inhibition of IGF-IR signaling has been shown to improve response to trastuzumab in trastuzumab-naïve and trastuzumab-resistant models. In this paper, we will discuss the role of IGF-IR signaling in trastuzumab resistance. Further, we will discuss cotargeting IGF-IR and HER2 as a potential therapeutic strategy for HER2-over-expressing breast cancers that have progressed on trastuzumab treatment.