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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.

PURPOSE On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States. METHODS A retrospective analysis was conducted using electronic health record–derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria. RESULTS We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3; P = .365) and rwOS (IPTW-ATT HR, 1.23; 95% CI, 0.96 to 1.58; P = .101) was observed between treatment groups. In the subgroup of CLEOPATRA-eligible patients, median rwPFS and rwOS were 16.9 months and 57.8 months, respectively. CONCLUSION There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.

Introduction: Pts with HER2-positive metastatic BC (mBC) often develop CNS mets, which is associated with poor prognosis and negative impact on quality of life. Resistance to anti-HER2 treatment can lead to disease progression; furthermore, many therapies do not cross the blood-brain barrier, leading to an unmet need for effective CNS mets treatment. In this real world study, we explored the molecular profile and clinical features of pts with CNS and non-CNS mets to better understand tumor biology in these populations. Methods: This retrospective, cross-sectional, observational study evaluated pts with CNS mets or non-CNS mets at the time of HER2-positive mBC diagnosis using the Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-FMI CGDB). The database comprised de-identified data from ~280 US cancer clinics (~800 sites of care), and included pts with FMI comprehensive genomic profiling assays covering >300 cancer-related genes. Descriptive analyses were conducted for baseline demographic, clinical, and biomarker characteristics, as well as genetic alterations including single nucleotide variants (SNVs), copy number alterations (CNAs), and rearrangements. T-tests were used to compare continuous variables, chi-squared tests for categorical variables, and non-parametric tests for non-normal distributions. Results: Of 8204 pts with BC in the CGDB, 6111 females 18+ yrs were diagnosed with mBC on or after 1-1-2011, of whom 919 had HER2-positive mBC, and 314 had an FMI assay up to 120 days after mBC diagnosis. This study population included 45 pts with CNS mets and 269 pts with non-CNS mets (Table). FMI data were derived from the primary tumor (29% from breast) or a metastatic lesion (19%, 12%, and 4% from liver, lymph nodes, and brain, respectively). Pts with CNS vs non-CNS mets were significantly younger at initial and at mBC diagnosis (p=0.04). At mBC diagnosis, a higher percentage of pts with CNS vs non-CNS mets had ≥3 sites of mets (p=0.01) and mets sites in adrenal glands (p=0.01), while there was a trend toward lower rates of lung and liver mets (not significant [NS]). Pts with CNS mets were more likely to be hormone receptor-negative vs pts with non-CNS mets (NS). Missing data for HER2 results by IHC or FISH, tumor grade, and histology limited the interpretation of any observed differences. Pts with CNS vs non-CNS mets were more likely to have SNVs in TP53 (82% vs 64%, p=0.03) and CNAs in ERBB2 (60% vs 43%, p Table. Demographic, clinical, and genetic characteristics of the study populationVariableCNS mets (n=45)Non-CNS mets (n=269)Total (N=314)p-valueMedian age at mBC diagnosis, years (interquartile range [IQR])55 (47-62)60 (51-68)59 (49-68)0.04Median age at early BC diagnosis, years (IQR)51 (43-60)55 (48-64)55 (46-64)0.04 Citation Format: Preet K. Dhillon, Peter Lambert, Thibaut Sanglier, Adam Knott, Eleonora Restuccia, Sanne L. de Haas, Chiara Lambertini. Clinical features and genetic alterations in patients (pts) with HER2-positive breast cancer (BC) and central nervous system (CNS) metastases (mets) in the real world [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-04.

There is a strong rationale for combining HER2-targeted therapies with cancer immunotherapy to increase efficacy in breast cancer, particularly in the early-stage setting, where the immune system has not been weakened by heavy pretreatment. ASTEFANIA aims to evaluate the efficacy of adjuvant atezolizumab in combination with ado-trastuzumab emtansine in patients with high-risk, HER2-positive early breast cancer and residual disease following HER2-based neoadjuvant therapy. Eligible patients will be randomized to receive ado-trastuzumab emtansine in combination with either atezolizumab or placebo for 14 cycles within 12 weeks of primary surgery. The primary outcome is invasive disease-free survival and secondary outcomes include additional efficacy end points, safety and pharmacokinetics. The study plans to enroll 1700 patients across 32 counties. Clinical Trial Registration: NCT04873362 ( ClinicalTrials.gov )

Early breast cancer; Event-free survival; Pathologic complete response Cáncer de mama temprano; Supervivencia libre de eventos; Respuesta patológica completa Càncer de mama precoç; Supervivència lliure d'esdeveniments; Resposta patològica completa The standard-of-care for patients with pathological complete response (pCR) after neoadjuvant human epidermal growth factor receptor 2 (HER2)-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. Our objective was to evaluate risk of recurrence or death in these patients and determine if outcomes differed by the HER2-targeted regimen received in each setting. We analyzed patient-level data from five randomized trials evaluating trastuzumab, pertuzumab, or both as part of systemic neoadjuvant and adjuvant therapy for HER2-positive early breast cancer, and assessed event-free survival (EFS) in 1763 patients. Patients with pCR had decreased risk of an EFS event versus those with residual disease (unadjusted hazard ratio [HR] = 0.35; 95% confidence interval [CI]: 0.27–0.46). Regardless of pCR status, after adjusting for baseline factors, reduction in EFS event risk was greater in patients administered pertuzumab/trastuzumab in both settings versus those administered only trastuzumab in both settings (HR = 0.36; 95% CI: 0.26–0.49), or pertuzumab/trastuzumab in the neoadjuvant setting and only trastuzumab in the adjuvant setting (HR = 0.67; 95% CI: 0.47–0.96). Patients with pCR had longer EFS than those with residual disease. Patients treated with pertuzumab/trastuzumab in both the neoadjuvant and adjuvant settings had the lowest risk of breast cancer recurrence. The analysis was funded by F. Hoffmann-La Roche, Ltd.

Background: Clinical practice guidelines recommend the combination of pertuzumab (PERJETA®), trastuzumab (Herceptin®) (PH) and a taxane for first-line treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer (HER2+ mBC) patients [Giordano et al., J Oncol Pract, 2018]. Most clinical trials investigating the efficacy and safety of pertuzumab and trastuzumab used docetaxel as the taxane (PHD) [Tian et al., Int J Clin Pharmacol Ther, 2017]. Paclitaxel used with pertuzumab and trastuzumab (PHP) is highly active and well tolerated and may be an effective alternative to docetaxel-based combination therapy (Bachelot et al., Ann Oncol, 2019; Dang et al., J Clin Oncol, 2017). We evaluated the use of taxanes with PH and patient outcomes after receiving PHP or PHD as first-line treatment for HER2+ mBC in a real-world setting. Methods: We conducted a retrospective cohort study, using the nationwide Flatiron Health Electronic Health Record (EHR)-derived de-identified database. Patients who received a taxane with PH as initial systemic therapy after mBC diagnosis between June 1, 2012 and April 30, 2019 were included. The taxane initiation and any switch was evaluated. An intention-to-treat analysis was adopted and we used Cox-proportional hazard model in the statistical analysis. Time To Last Administration (TTLA) was used as a proxy for treatment duration for PH and chemotherapy. Real world progression free survival (rwPFS) was used to describe the effectiveness of first-line therapies. Results: A total of 1054 patients received PH plus a taxane as first-line therapy for HER2+ mBC: 29.3% of patients received PHP (26.9% paclitaxel and 2.4% nab-paclitaxel) while 70.7% of patients received PHD. Patients in the PHP group at index date were significantly older (median age was 62.0 in PHP vs 58.0 in PHD group, Citation Format: Letizia Polito, Jinjoo Shim, Yolande Du Toit, Thy Do, Adam Knott, Thibaut Sanglier. Use of pertuzumab in combination with taxanes for HER2+ metastatic breast cancer: Analysis of U.S. electronic health records [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-14.

Background Previous trials showed that fixed-dose subcutaneous trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™; H SC) was non-inferior to weight-based intravenous trastuzumab (Herceptin®; H IV) in terms of pathologic complete response and serum trough concentration in HER2-positive early breast cancer (BC), with a comparable safety profile (NCT00950300), and demonstrated a compelling patient (pt) preference for H SC (NCT01401166). IV pertuzumab (PERJETA®; P IV) + H IV + docetaxel (D IV) was also shown to significantly improve progression-free survival (PFS) and overall survival vs. placebo + H IV + D IV in HER2-positive metastatic BC (NCT00567190). Here we report results from the final analysis of MetaPHER (NCT02402712), the largest study to evaluate safety and tolerability of first-line H SC + P IV + D IV for HER2-positive metastatic/locally advanced BC. Earlier analyses have been reported (Kümmel SABCS 2016; P4-21-42; Kümmel ESMO 2018; 323P). Methods Pts were ≥18-year-old females who had received no previous systemic non-hormonal anticancer therapy for their disease, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and a left ventricular ejection fraction (LVEF) ≥50%. Brain metastases and concomitant hormone therapy were allowed. Pts received 600 mg H SC + 840 mg loading/420 mg maintenance doses of P IV + ≥6 cycles of D IV (75 mg/m2→100 mg/m2; >6 cycles were given at the investigator’s discretion) every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. The primary objective was to evaluate safety and tolerability. Adverse events (AEs) were graded per National Cancer Institute - Common Terminology Criteria for Adverse Events version 4.0; left ventricular systolic dysfunction (LVSD) was classified according to the New York Heart Association Functional Classification system. Safety results are descriptive. Exploratory efficacy endpoints were PFS and objective response rate (ORR). Results Four hundred eighteen pts were enrolled; 412 were treated and analyzed for safety, and 160 remained on treatment at study end. Data cutoff was May 23, 2019 with median follow-up of 27 months (max. 45 months). Baseline demographics were similar to the interim analysis. Median cycles of H SC, P IV, and D IV were 22.0, 21.5, and 6.0, respectively (some discontinued P IV due to toxicity but remained on H SC per the protocol). Most pts experienced ≥1 any-grade AE (406; 98.5%); 221 (53.6%), grade ≥3 AEs; 107 (26.0%), serious AEs; 87 (21.1%), AEs leading to withdrawal from any study treatment; 87 (21.1%), investigator-reported administration-related and local injection-site reactions (21 [5.1%] H SC-related). There were 87 deaths (21.1% of pts): 73 (17.7%) from disease progression, nine (2.2%) due to AEs, and five (1.2%) due to other causes after treatment discontinuation. Three pts (0.7%) experienced grade ≥3 cardiac AEs, and one (0.2%) a serious AE suggestive of congestive heart failure. Of the 396 pts with LVEF measurements at baseline and ≥1 post-baseline visit, 40 (10.1%) had LVEF drops (to Citation Format: Sherko Kümmel, Carlo A Tondini, Jacinta Abraham, Zbigniew Nowecki, Bartosz Itrych, Erika Hitre, Bogusława Karaszewska, Alejandro Juarez, Flavia Morales-Vásquez, Jose Manuel Pérez García, Servando Cardona-Huerta, Mark Benyunes, Eleonora Restuccia, Adam Knott, Estefanía Monturus, Marco Sequi, Miguel Martín. Subcutaneous trastuzumab and hyaluronidase-oysk with intravenous pertuzumab and docetaxel in HER2-positive advanced breast cancer: Final analysis of the phase IIIb, multicenter, open-label, single-arm MetaPHER study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-05.

Background: The current standard of care for patients achieving a pCR after HER2-targeted therapy plus chemotherapy in the neoadjuvant setting is to continue HER2-targeted therapy in the adjuvant setting. The aim of this exploratory data analysis is to report the risk of recurrence and death after neoadjuvant systemic therapy in Roche-sponsored neoadjuvant trials in patients with HER2-positive early breast cancer who achieved a pCR. Methods: Data from the HannaH (NCT00950300), NeoSphere (NCT00545688), TRYPHAENA (NCT00976989), BERENICE (NCT02132949), and KRISTINE (NCT02131064) studies were pooled. Neoadjuvant → adjuvant therapeutic regimens analyzed were trastuzumab → trastuzumab (H→H), pertuzumab plus trastuzumab → trastuzumab (PH→H), and pertuzumab plus trastuzumab → pertuzumab plus trastuzumab (PH→PH). pCR was defined as the absence of residual invasive cancer in the resected breast specimen and in the axillary lymph nodes (ypT0/Tis ypN0) after neoadjuvant systemic therapy. Event-free survival (EFS) was defined as the time from the date of randomization to the date of disease recurrence or progression (local, regional, distant, or contralateral) or death due to any cause. EFS rates were estimated using the Kaplan-Meier method. A Cox regression model was used to explore factors associated with EFS. Results: 1764 patients were included in the analysis. The median duration of follow up was shorter in the PH→PH group compared to the PH→H and H→H groups (Table). Overall, patients with a pCR had an increased EFS probability compared to those with residual disease (unadjusted hazard ratio=0.33; 95% confidence interval [CI]: 0.25– 0.43]), and this was maintained in patients stratified by hormone receptor status and disease stage. The 3-year EFS rates in patients who achieved a pCR were 87% (95% CI: 82%–90%) in the H→H group, 92% (95% CI: 87%–95%) in the PH→H group, and 95% (95% CI: 90%–97%) in the PH→PH group. Conclusions: Overall, patients who attained a pCR have a better long-term outcome compared to those with residual disease, regardless of ER status or clinical stage. Some patients who achieved a pCR still had a risk of relapse. A limitation of this exploratory data analysis was the smaller number of patients with stage III disease at baseline and shorter follow-up in the PH→PH group compared to the other groups. Overall(N=1764)H→H (HannaH; NeoSPHERE)(n=703)PH→H (NeoSPHERE; TRYPHAENA)(n=439)PH→PH (BERENICE; KRISTINE)(n=622)Median Duration of Follow-up (months)42.067.961.122.3Disease StageStage II934 (52.9)285 (40.5)204 (46.5)445 (71.5)Stage III806 (45.7)397 (56.5)235 (53.5)174 (28.0)Hormone Receptor StatusPositive783 (44.4)328 (46.7)223 (50.8)232 (37.3)Negative963 (54.6)372 (52.9)215 (49.0)376 (60.5)Unknown18 (1.0)3 (0.4)1 (0.2)14 (2.3)pCR status773 (43.8)236 (33.6)185 (42.1)352 (56.6)Type of recurrence in patients who achieved a pCRDistant recurrence41 (5.3)26 (11.0)10 (5.4)5 (1.4)Local recurrence17 (2.2)12 (5.1)5 (2.7)0Regional recurrence6 (0.8)3 (1.3)2 (1.1)1 (0.3)New contralateral breast cancer2 (0.3)2 (0.8)00 Citation Format: Sandra M Swain, Harrison Macharia, Javier Cortes, Chau Dang, Luca Gianni, Sara Hurvitz, Christian Jackisch, Andreas Schneeweiss, Dennis Slamon, Pinuccia Valagussa, Yolande du Toit, Dominik Heinzmann, Adam Knott, Chunyan Song, Patricia Cortazar. Risk of recurrence and death in patients with early HER2-positive breast cancer who achieve a pathological complete response (pCR) after different types of HER2-targeted therapy: A retrospective exploratory analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-01.

e12504 Background: Representative pt populations in clinical trials are essential to address healthcare disparities between different racial/ethnic groups, including treatment access and pt outcomes. Many clinical trials mainly include White pts, which may limit the generalizability of the results to the global population. A framework that was recently developed by Genentech for improving inclusion of underrepresented pt groups, as well as the CHIMES (NCT04377555) and EMPACTA (NCT04372186) studies, have all shown the feasibility of inclusive studies. ASTEFANIA (NCT04873362) is a pt-centric study, which includes pt/investigator collaboration to keep a pt focus and tactics to recruit a diverse population and enable participation of underserved communities. We report early recruitment data. Methods: Global/local initiatives and inclusive eligibility criteria remove barriers to enrollment of underserved pts and support treatment journeys. Eligible pts (Eastern Cooperative Oncology Group performance status of 0/1; no prior immune checkpoint inhibitor treatment) are randomized 1:1 to T-DM1 (3.6 mg/kg) + atezolizumab (1200 mg)/placebo every 3 weeks for 14 cycles (stratification factors: clinical stage, hormone receptor status, preoperative anti-HER2 therapy, PD-L1 status). Primary endpoints: IDFS in intention-to-treat and PD-L1-positive populations. Secondary endpoints include overall survival, patient-reported outcomes (PROs), and safety. To remove pt access barriers and ease pt burden, consent and PRO forms are available in multiple languages, mobile nursing/telemedicine is planned for pts in rural areas, a wellness app and culturally sensitive support videos are being created, and financial support is provided for study-related expenses and loss of earnings. Results: Recruitment began in May 2021. By Feb 9, 2022, 236 pts were randomized: 147 White (62%), 72 Asian (31%; Indian [n = 4], Korean [46], Chinese [16], other [6]), 10 Hispanic (4%; 5 of whom also identify as American Indian), 2 Black (1%), and 5 pts (2%) whose race/ethnicity was unreported/unknown. Of these, 27 (11%) have received financial support. Enrollment in Africa begins later this year. Mobile nursing/telemedicine is planned for 14 countries. Conclusions: As the first study of its kind in HER2-positive EBC, ASTEFANIA actively aims to be accessible and include pts from a range of races/ethnicities and socially underserved backgrounds. There is a growing need for more compassionate and inclusive research. To do this, forward planning of pt-centric studies is essential to reduce the burden on study resources. We hope that the tactics outlined here will allow us to achieve our goals of inclusive research. Clinical trial information: NCT04873362.

Combination pertuzumab, trastuzumab, and docetaxel (D) is considered standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This post hoc, exploratory analysis of CLEOPATRA study data evaluated the clinical effects of D treatment duration within this regimen. The clinical benefits of pertuzumab and trastuzumab by different durations of D treatment were also evaluated.Patients with HER2-positive metastatic breast cancer received trastuzumab and D plus pertuzumab or placebo. Clinical outcomes were analyzed by the number of D cycles that patients received (6D, 6D, or 6D). Progression-free survival (PFS) and overall survival (OS) for each treatment arm within each D cycle group were estimated using the Kaplan-Meier approach. Time-dependent, multivariate Cox regression was applied to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for HER2-targeted therapy and D cycle groups.Overall, 804 patients received 6D (n = 119), 6D (n = 210), or 6D (n = 475) cycles. After adjusting for pertuzumab benefits versus placebo (PFS HR = 0.61, 95% CI 0.51-0.74, P 0.0001; OS HR = 0.60, 95% CI, 0.49-0.74, P 0.0001), 6D versus 6D cycles was not associated with statistically significant improvements in PFS (HR = 0.80, 95% CI 0.63-1.01, P = 0.0640) or OS (HR = 0.88, 95% CI 0.69-1.12, P = 0.3073). Consistent improvements in PFS and OS were observed with pertuzumab versus placebo, irrespective of D duration. The HRs for PFS were 0.395, 0.615, and 0.633 for 6D, 6D, and 6D cycles, respectively (P 0.05 for all D cycle groups). Corresponding HRs for OS were 0.577, 0.700, and 0.612, respectively (P 0.05 for 6D and 6D).After accounting for pertuzumab benefits, more than six cycles of D treatment was not associated with significant improvements in either PFS or OS compared with six cycles. The addition of pertuzumab to trastuzumab improved clinical outcomes versus trastuzumab plus placebo, regardless of D treatment duration.NCT00567190.

Purpose: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure–response (E–R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4–11/BO25126/TOC4939G). Methods: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug–drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma C max ,C min ,and AUC last geometric mean ratios with 90% CIs. Predictions of pertuzumab C max,ss ,C min,ss ,and AUC ss were derived from individual parameter estimates and used in an exploratory E–R analysis. Results: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E–R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E–R relationship was suggested with respect to other grade ≥ 3 AEs. Conclusion: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: In the CLEOPATRA study, pertuzumab (P) plus trastuzumab (T) and docetaxel (D) significantly improved median progression-free survival (PFS) and overall survival (OS) compared with placebo (Pla) plus T and D in pts with HER2-positive metastatic breast cancer. Study treatment was given every 3 weeks until disease progression (PD) or unacceptable toxicity. D starting dose was 75 mg/m2 and could be escalated or reduced per protocol. A minimum of 6 cycles of D was recommended. If D was discontinued, patients could continue P+T or Pla+T. To evaluate the potential association between D duration and clinical outcomes, we conducted post hoc exploratory analyses of the CLEOPATRA study. Methods: As of 11 Feb 2014 data cutoff, the safety population analyzed included 804 pts (396 Pla+T+D; 408 P+T+D) who received at least one dose of any study medication. Exposure and clinical outcomes of study treatment groups are presented by dichotomized subgroup of pts who received Results: The median number of D cycles received was 8 for both arms. Forty-one % of pts received 6 cycles. Docetaxel Duration and Clinical Outcomes D 6 cycles (n=475, 59%) Pla+T+D (n=159)aP+T+D (n=170)aPla+T+D (n=237)P+T+D (n=238)Treatment Exposure#D Cycle, median (range)6 (1,6)6 (1,6)10 (7,42)10 (7,52)# Study Treatment Cycle, median (range)7 (1,78)14 (1,90)19 (7,92)28 (7,96)Duration of Study Treatment in month, median (range)6 (1,54)10 (1,63)14 (5,67)19 (5,68)Clinical OutcomesPFS in month, median (range)8.2 (6.2,9.0)12.5 (10.5,20.7)14.5 (12.6,17.2)22.8 (17.7,N/A)95% CIHR=0.59 (0.44,0.79)HR=0.65 (0.50,0.84)OS in month, median (range)29.8 (22.2,39.2)48.9 (36.8,N/A)46.7 (39.4,53.0)N/A (56.4,N/A)95% CIHR=0.67 (0.45,0.90)HR=0.62 (0.47,0.81)N/A=not available aTwo pts in each group had missing D cycle Treatment Discontinuation Summary D 6 cycles Pla+T+D (n=159)P+T+D (n=170)Pla+T+D (n=237)P+T+D (n=238)D discontinuation before stopping anti-HER2 agents (n,%)90 (57)118 (69)180 (76)196 (82)Reason (n,%) AE/intercurrent illness34 (38)27 (23)60 (33)72 (37)Patient reasonb3 (3)5 (4)5 (3)8 (4)Standard practice36 (40)59 (50)65 (36)41 (21)Adequate therapy12 (13)22 (19)36 (20)59 (30)Other1 (1)1 (1)9 (5)11 (6)Missing4 (4)4 (3)5 (3)5 (3)Discontinuation of all study treatment (T+D+Pla or P), n159170237238Reason (n,%) AE/intercurrent illness15 (9)22 (13)25 (11)32 (13)Death10 (6)5 (3)4 (2)2 (1)Disease progression111 (70)110 (65)182 (77)154 (65)Patient reasonb17 (11)16 (9)12 (5)14 (6)Other6 (4)16 (9)12 (5)35 (15)Missing0 (0)1 (1)2 (1)1 (1)bIncluded failure to return, refused treatment, withdrawal, protocol violation Conclusions: Consistent with the overall study results, addition of P to T+D showed significant improvement in clinical outcomes regardless of whether 6 cycles of D were received. In the poster, three subgroup (6 D cycles) analyses and time-dependent Cox regression analysis to capture the dynamic variations in D exposure will be presented. Citation Format: Miles D, Fung A, Yoo B, Knott A, Heeson S, Portera C, Swain S. Effect of docetaxel duration on clinical outcomes: Results from the phase III trial CLEOPATRA. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-27.

Introduction. We report detailed safety analyses by geographic region from the phase III study CLEOPATRA with pertuzumab, trastuzumab, and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer. Patients and Methods. Patients received pertuzumab/placebo at 840 mg in cycle 1 and 420 mg in subsequent cycles, and trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles; docetaxel was initiated at 75 mg/m2. All study drugs were given intravenously, 3 times weekly. Results. Docetaxel dose reductions below 75 mg/m2 were more common in patients from Asia (47.0%) than other regions (13.4%); docetaxel dose escalations to 100 mg/m2 were less frequent in Asia (2.4%) than other regions (18.7%). Rates of edema (26.1% and 5.4% for Asia and other regions, respectively), myalgia (42.3%, 14.7%), nail disorder (39.9%, 15.1%), febrile neutropenia (18.6%, 7.1%), upper respiratory tract infection (25.7%, 10.2%), decreased appetite (47.0%, 19.1%), and rash (44.3%, 22.0%) were at least twice as high in Asia as in other regions. Adverse events did not result in a reduction in the median number of study treatment cycles administered in patients from Asia. Efficacy analyses per region showed hazard ratios similar to those of the whole intention-to-treat (ITT) population for progression-free survival (ITT: 0.63; Asia: 0.68; other regions: 0.61) and overall survival (ITT: 0.66; Asia: 0.64; other regions: 0.66). Conclusion. Despite a higher proportion of docetaxel dose reductions in patients from Asia, survival benefits were comparable between regions. The benefit-risk profile of pertuzumab, trastuzumab, and docetaxel supports this regimen as the first-line therapy for patients with HER2-positive metastatic breast cancer from all geographic regions.

1020 Background: Progression-free and overall survival (PFS and OS) were significantly improved with 1L P + H + D v Pla + H + D in 808 pts with HER2-positive MBC in CLEOPATRA (NCT00567190). OS was increased by an unprecedented 15.7 mo (median 56.5 mo with P + H + D v 40.8 mo with Pla + H + D; HR 0.68; 95% CI 0.56, 0.84; p < .001) with a median follow-up of 50 mo [Swain et al. NEJM 2015]). Here we report the end-of-study analysis with a median follow-up of 99 mo (max 120 mo). Methods: In this descriptive analysis, OS was compared between arms using the log-rank test, stratified by prior treatment status and geographic region. The Kaplan–Meier approach was used to estimate median OS, and a stratified Cox proportional hazards model was used to estimate the HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other baseline characteristics. Results: Clinical cutoff was Nov 23, 2018. Since Jul 2012, 50 pts crossed from the Pla to the P arm. These pts are counted in the Pla arm for efficacy analyses and up to the first dose of P for safety analyses. The OS HR was 0.69 (95% CI 0.58, 0.82), favoring P + H + D. Median OS was 57.1 mo in the P arm (402 pts) and 40.8 mo in the Pla arm (406 pts; Δ 16.3 mo). The 8-year landmark OS rates were 37% and 23%, respectively. The OS benefit in predefined subgroups, including in pts previously treated with H in the (neo)adjuvant setting (88 pts, HR 0.86; 95% CI 0.51, 1.43), remained consistent with the overall result and previous reports. The overall safety profile of P + H + D was consistent with the known P safety profile. There was only one new serious adverse event suggestive of congestive heart failure (onset ~77 mo on treatment in the P arm, resolution in 34 days, pt continued on study medication) and one new symptomatic left ventricular systolic dysfunction (onset ~46 mo after crossing to the P arm, resolution in 34 days) since the previous analysis. Conclusions: The OS improvement with 1L P + H + D v Pla + H + D for pts with HER2-positive MBC was maintained after an additional 4 years of long-term follow-up, as were the safety and cardiac safety profiles. Clinical trial information: NCT00567190.

Background: CLEOPATRA is a phase III study of placebo (Pla)+T+D and P+T+D in HER2-positive first-line MBC. The combination of both HER2-targeted antibodies, P+T, with D resulted in significantly improved progression-free survival (PFS) and overall survival (OS). The incidence of febrile neutropenia (FN) was higher with P+T+D versus Pla+T+D. We present analyses of adverse events (AEs) and treatment patterns for pts from Asia. Methods: Pts were from Asia, Europe, North and South America. Study drugs were given intravenously, q3w: P/Pla, 840 mg initial dose, then 420 mg; T, 8 mg/kg initial dose, then 6 mg/kg; D, 75 mg/m2 with escalation to 100 mg/m2 if tolerated. Treatment was given until disease progression or unacceptable toxicity; 6 cycles of D were recommended, >6 cycles were at investigator's discretion. Dose modifications of P or T were not permitted. Two D dose reductions by 25% to 75 mg/m2 and 55 mg/m2 were allowed in order to manage toxicities; re-escalation was not permitted. Results: The safety population comprised 253 pts from Asia (Pla+T+D: 128; P+T+D: 125) and 551 pts from other regions (Pla+T+D: 269; P+T+D: 282). The incidences of neutropenia, FN, diarrhea, mucosal inflammation, grade ≥3 AEs overall, and serious AEs were higher with P+T+D versus Pla+T+D. In the P arm, the largest increase in AEs in pts from Asia versus other regions was observed for FN and mucosal inflammation. D dose was more frequently reduced in pts from Asia; however, the incidence of AEs leading to discontinuation of all study treatment was balanced between pts from Asia and other regions. PFS and OS were improved with P+T+D in pts from all regions. In the whole study population, the hazard ratios (HR) for PFS and OS were 0.63 (95% CI 0.52-0.76) and 0.66 (0.52-0.84), respectively. In pts from Asia, the HR was 0.68 (0.48-0.95) for PFS and 0.64 (0.41-1.00) for OS. These efficacy analyses were unstratified. Pts with event, n (%)Other regionsAsia Pla+T+DP+T+DPla+T+DP+T+D n = 269n = 282n = 128n = 125Neutropenia123 (46)141 (50)74 (58)74 (59)FN15 (6)24 (9)15 (12)32 (26)Diarrhea118 (44)179 (63)66 (52)93 (74)Mucosal inflammation56 (21)67 (24)23 (18)46 (37)Grade ≥3 AEs194 (72)199 (71)95 (74)103 (82)Serious AEs69 (26)82 (29)35 (27)58 (46)AEs leading to discontinuation of all study treatment15 (6)21 (7)6 (5)4 (3)D dose escalation to 100 mg/m256 (21)47 (17)5 (4)1 (1)D dose reduction to Conclusions: AEs did not result in reduction of the median number of cycles administered in pts from Asia compared with other regions. However, given that 47% of pts from Asia had D dose reductions Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-10.

Background The phase III CLEOPATRA study demonstrated that combining pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA. Patients and methods Participants were randomly assigned to pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥2-point deterioration in Breast Cancer Subscale (BCS) score. Results Time to ≥5-point decline in TOI-PFB did not differ significantly between the pertuzumab and placebo arms [hazard ratio (HR), 0.97; P = 0.7161]. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061). Conclusions Combining pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.

Purpose The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. Methods Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (–30 and –15 min) and after (0–15 and 60–75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia’s correction was applied to QT measurements (QTcF) and change from baseline (ΔQTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure–response relationships between ΔQTcF and observed pertuzumab concentrations. Results Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔQTcF (90 % CI) values at 0–15 min, 60–75 min, and 72 h post-infusion were −6.96 (−13.69, −0.23), −6.35 (−13.57, 0.88), and −4.08 (−12.64, 4.48), all of which were

Background: In CLEOPATRA, 808 pts with HER2-positive 1L MBC were randomized to treatment with placebo (Pla)+T+D or P+T+D. The primary endpoint of independently reviewed progression-free survival was significantly improved with P+T+D vs Pla+T+D (HR = 0.62; P Methods: This interim OS analysis was performed applying the Lan-DeMets α-spending function with the O'Brien-Fleming (OBF) stopping boundary to maintain the overall Type I error at 5%. Based on the number of OS events observed, the OBF boundary for statistical significance at this analysis was P≤0.0138. The log-rank test, stratified by prior treatment status and geographic region, was used to compare OS between arms in the intention-to-treat population. The Kaplan-Meier approach was used to estimate the median OS in both arms; a stratified Cox proportional hazard model was used to estimate HR and 95% CIs. Subgroup analyses of OS were performed for the stratification factors and other key baseline characteristics. Results: At the time of this analysis, median follow-up was 30 mths and 267 deaths (69% of planned events for the final analysis) had occurred. The results showed a statistically significant improvement in OS in favor of P+T+D (HR = 0.66; 95% CI, 0.52–0.84; P = 0.0008). This HR represents a 34% reduction in the risk of death. The analysis achieved statistical significance and is therefore considered the confirmatory OS analysis. The median OS was 37.6 mths in the Pla arm and has not yet been reached in the P arm. The treatment effect was generally consistent in predefined subgroups based on baseline variables and stratification factors, including: prior (neo)adjuvant therapy (HR = 0.66; 95% CI, 0.46–0.94); no prior (neo)adjuvant therapy (HR = 0.66; 95% CI, 0.47–0.93); prior (neo)adjuvant T (HR = 0.68; 95% CI, 0.30–1.55); hormone receptor-negative disease (HR = 0.57; 95% CI, 0.41–0.79); and hormone receptor-positive disease (HR = 0.73; 95% CI, 0.50–1.06). Kaplan-Meier estimates of OS rates show survival benefit with P+T+D at 1, 2, and 3 yrs. The majority of pts received anti-cancer therapy after discontinuation of study treatment (64% Pla arm, 56% P arm). Subsequent therapy with HER2-directed agents (T, lapatinib, T emtansine) was balanced between arms. Causes of death remained unchanged from the first interim OS analysis, with the most common cause being progressive disease. Adverse events leading to death were rare and balanced between arms. Conclusions: Treatment of pts with HER2-positive 1L MBC with P+T+D compared with Pla+T+D was associated with an improvement in OS, which was both statistically significant and clinically meaningful. These results show that combined HER2 blockade and chemotherapy using the P+T+D regimen can be considered a standard of care for pts with HER2-positive MBC in the 1L setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-26.

LBA500 Background: In previous trials P significantly prolonged progression free and overall survival and increased pCR rates when added to T+C in pts with HER2-positive breast cancer (BC). The APHINITY trial was designed to test whether the addition of P to adjuvant T+C improves pt outcomes. Methods: Pts with adequately excised HER2-positive, pT1-3 EBC were randomly assigned to receive standard adjuvant C plus one year of either T + P or T + Pla. Eligible pts had either node-positive disease, or node-negative disease (pN0) and a tumor size of > 1.0 cm. Pts with pN0, T1b tumors with high risk features were initially eligible. The primary efficacy endpoint was invasive disease-free survival (IDFS); we assumed a 3-year IDFS of 91.8% with P and 89,.2% with Pla. Results: 4805 pts were randomized to C and T plus either P (n = 2400) or Pla (n = 2405). Baseline demographics and tumor characteristics between the arms were well balanced, with 63% and 36% of pts having node-positive and hormone receptor negative EBC respectively. P and Pla treatments were completed in 84.5% and 87.4% of patients, respectively. IDFS events occurred in 171 (7.1%) P pts and 210 (8.7%) Pla pts (hazard ratio (HR) 0.81 (95% CI 0.68-1.00), P = 0.045). Estimates of IDFS at 3 years were 94.1% and 93.2% in the P and Pla arms, respectively. The node-positive cohort had a 3-year IDFS rate of 92.0% for P compared with 90.2% for Pla (HR 0.77 (95% CI 0.62-0.96), P = 0.019). The pN0 cohort had a 3-year IDFS rate of 97.5% for P and 98.4% for Pla; HR = 1.13 (95% CI 0.68-1.86). The safety profile of P was consistent with previous trials. For the primary cardiac endpoint (heart failure or cardiac death) and secondary cardiac endpoint (asymptomatic or mildly symptomatic LVEF decline) rates were low, 0.7% vs 0.3% and 2.7% vs 2.8%, in the P and Pla arms, respectively. Diarrhea grade ≥3 was more frequent with P (9.9% vs 3.7%). Conclusions: The APHINITY trial met its primary endpoint: P significantly improved IDFS in patients with HER2-positive EBC when added to T+C. No new safety signals were identified. Clinical trial information: NCT01358877.

1023 Background: T-DM1 was approved for pts with HER2+ MBC previously treated with trastuzumab (H) and a taxane based on the phase III EMILIA study. P in combination with H + docetaxel (T) later became the first-line standard of care for HER2+ MBC, but there are limited data on T-DM1 efficacy in pts who previously received P. We present exploratory efficacy results from pts treated with T-DM1 any time after P from 2 phase III studies: CLEOPATRA and PHEREXA. Methods: CLEOPATRA (NCT00567190) and PHEREXA (NCT01026142) are randomized, 2-arm trials evaluating P-based regimens for HER2+ MBC. CLEOPATRA studies H + T + P vs HT + placebo in pts with no prior anti-HER2 treatment (tx) or chemotherapy for MBC, while PHEREXA studies H + capecitabine (C) +/− P in pts who progressed during/after previous H tx for MBC. We assessed overall survival (OS) in an exploratory analysis of pts who either received or did not receive T-DM1 at any time after discontinuing study-assigned tx in CLEOPATRA or PHEREXA. Results: Of 408 pts who received HTP in CLEOPATRA and 228 pts who received HCP in PHEREXA, 32 and 43 pts received subsequent T-DM1, respectively (Table). Median duration of T-DM1 tx was 7.1 mo (range 0−44) and 4.2 mo (range 0−22), respectively, and median time from discontinuation of P to start of T-DM1 was 3.5 mo (range 1−47) and 10.6 mo (range 1−28). Conclusions: Although data are limited in these exploratory analyses, our results provide additional evidence of T-DM1 clinical activity in pts with HER2+ MBC who progressed on prior P + H, a finding with real-world implications. Clinical trial information: NCT00567190, NCT01026142. [Table: see text]

Summary Background CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up. Methods The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190. Findings In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3–NE [not estimable]) in the placebo group but had not been reached (95% CI 42·4–NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52–0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4–13·5) in the placebo group and 18·7 months (16·6–21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58–0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity. Interpretation Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients. Funding F Hoffmann-La Roche, Genentech.

Introduction. We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC). Patients and Methods. Left ventricular ejection fraction (LVEF) ≥50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m2 q3w. Results. The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥10% points from baseline and to Conclusion. The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.

598 Background: CLEOPATRA established pertuzumab (P), trastuzumab (T), and docetaxel (D) as the first-line standard of care for pts with HER2-positive MBC. SSTDs were often observed in CLEOPATRA. W...

600 Background: CLEOPATRA is a global phase III trial of P + T + D vs placebo + T + D in HER2-positive 1L MBC. Results showed a significant improvement in PFS (Baselga NEJM 2012) and OS (Swain SABCS 2012) favoring P + T + D. CLEOPATRA started recruitment in 2008 soon after the approval of T in the adjuvant setting in 2006 and mandated a disease-free interval (DFI) of ≥12 mos from the end of adjuvant therapy to MBC diagnosis. Due to this, a low proportion of pts with prior T exposure was included. Here we present the efficacy and safety of 1L P + T + D in the subset of pts in CLEOPATRA with prior T exposure. Methods: Pts received P + T + D or placebo + T + D, had a DFI ≥12 mos, baseline left ventricular ejection fraction (LVEF) ≥50% and no LVEF decline to

597^ Background: In CLEOPATRA, the HER2-dimerization inhibitor pertuzumab (P) was combined with trastuzumab (T) and docetaxel (D) in HER2-positive 1st-line MBC. P+T+D significantly improved efficacy compared with placebo (Pla)+T+D while having little effect on safety. Pts were recommended to receive ≥6 cycles of D but could discontinue D prior to Cycle 6 due to poor tolerability or progressive disease (PD) or continue D beyond Cycle 6 at investigators’ discretion. Once D was discontinued, pts received Pla+T or P+T until PD. To understand the full safety profile of the regimen, adverse events (AEs) occurring before and after D discontinuation were analyzed. Methods: Treatment was given q3w (Pla/P: 840 mg loading, then 420 mg; T: 8 mg/kg loading, then 6 mg/kg; D: 75 mg/m2, escalating to 100 mg/m2 if tolerated; de-escalation by 25% allowed). AEs were graded according to NCI-CTCAE v3.0, monitored continuously during the treatment period, and their relationship to study drugs was assessed by investigators. Results: From 808 pts enrolled, 804 were analyzed in the safety population (pts who received ≥1 dose of study treatment). AEs that led to discontinuation of all study treatment were experienced by 5.3% (Pla+T+D) and 6.1% (P+T+D) of pts, whereas discontinuation of D alone due to AEs occurred in 23.2% (Pla+T+D) and 23.6% (P+T+D) of pts. Conclusions: Treatment in both arms was well tolerated. After discontinuation of D, there was a clear reduction in grade ≥3 AEs; however, the incidence of grade ≥3 diarrhea remained slightly elevated with P+T+D. The AE profile of P+T is consistent with that seen in previous Phase II studies (Gianni Lancet Oncol 2012; Baselga JCO 2010). These data suggest that the combination of P+T may also be well tolerated in other breast cancer settings, such as in adjuvant therapy, which is currently under phase III study (APHINITY; NCT01358877). [Table: see text]

e11055^ Background: In CLEOPATRA, pertuzumab (P) + trastuzumab (T) + docetaxel (D) was compared to placebo (Pla)+T+D in HER2-positive 1st-line MBC. In MBC trials, PFS rather than overall survival is often defined as the primary endpoint as PFS data are available earlier and later-line therapy does not impact results. The primary endpoint in CLEOPATRA, PFS, was assessed by an Independent Review Facility (IRF), with investigator (inv)-assessed PFS as a secondary endpoint. As a measure of consistency and robustness, concordance between IRF- and inv-assessed PFS was analyzed. Methods: PFS was defined as time from randomization to first documented radiographic evidence of progressive disease (PD) or death from any cause within 18 wk of the last IRF tumor assessment. Tumor assessments took place every 9 wk and continued until IRF-confirmed PD. Treatment decisions were solely based on the inv’s assessment of PD. Indicators of concordance between IRF- and inv-assessed PFS included: PFS event by IRF only; PFS event by inv only; PFS event by IRF and inv; no PFS event by IRF and inv. These indicators were assessed at any time on study, within 30 d or within 9 wk. Several pre-specified sensitivity analyses for PFS were also performed. Results: 808 pt were enrolled and central tumor assessments performed for 781 pt. Compliance with the schedule of tumor assessments was generally high and comparable between arms, with >78% of pt undergoing assessments within 7 d of the scheduled visit over the 1st yr. At any time on study, concordance between IRF- and inv-assessed PFS was 85%. Of the 15% discordant cases, an equal proportion was assessed by the IRF as a PFS event but not by the inv and vice versa. Estimates of the median time to PFS event based on IRF and inv assessments were identical, Pla+T+D: 12.4 mo, P+T+D: 18.5 mo (IRF: HR 0.62, P < .0001; inv: HR 0.65, P < .0001). Conclusions: Concordance between IRF- and inv-assessed PFS was high, supporting consistency and robustness of the PFS analyses. The subjective nature of PD and potential for bias were reduced by the double-blind, placebo-controlled study design; RECIST 1.0 criteria; identical schedule of assessments in both arms; IRF review and continuation of tumor assessments until IRF confirmation of PD.

598^ Background: CLEOPATRA compared the efficacy and safety of the HER2 dimerization inhibitor pertuzumab (P) plus trastuzumab (T) and docetaxel (D) with placebo (Pla)+T+D in HER2-positive 1st-line MBC. Pts in both arms received a median of 8 cycles of D; Pla/P+T was continued until progressive disease (PD). The safety profile in both arms was similar with a substantial decrease in adverse events (AEs) once chemotherapy finished. The independently assessed progression-free survival was significantly improved with P+T+D compared with Pla+T+D; objective response and duration of response were also improved with P+T+D (Baselga NEJM 2012). Here we report health-related quality of life (HRQoL) data from CLEOPATRA. Methods: Time to deterioration of HRQoL was evaluated using the FACT-B questionnaire and defined as decrease from baseline (BL) of ≥5 points in the TOI-PFB subscale score. Female pts completed questionnaires every 3rd cycle of therapy within 3 days before each tumor assessment until independently determined PD. An exploratory analysis investigated time to deterioration in breast cancer symptoms and functions. Results: 56.7% (Pla+T+D) and 59.5% (P+T+D) of pts experienced deterioration of HRQoL during the study based on TOI-PFB. The median time to deterioration was 18.3 vs 18.4 wks (~6 cycles) (HR 0.97; P = .7161). At Cycle 6, the mean reduction in TOI-PFB score from BL was –3.5 (Pla+T+D) vs –3.0 (P+T+D). At subsequent cycles, when most pts had discontinued D, mean reductions were smaller, suggesting that after an early decline patients’ scores improved slightly. Overall, mean changes were small in both arms. Compliance with completion of the FACT-B questionnaire was ≥75% beyond the 1st year in both arms. An exploratory analysis suggested that time to deterioration in BCS score, which measures symptoms and issues relevant in breast cancer, was delayed with P+T+D (18.3 vs 26.7 wks; HR 0.77; P = .0061). Conclusions: Combining P with T+D appears to have no detrimental effect on HRQoL. Results suggest that P+T+D is associated with a substantial delay in the time to deterioration in BCS score as would be expected given the improved efficacy and the low incidence of AEs once D is discontinued.

Background: Pertuzumab (P) is a fully humanized investigational monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), preventing dimerization of HER2 with other HER family members and inducing antibody-dependent cell-mediated cytotoxicity. Its mechanisms of action are complementary to those of the anti-HER2 antibody trastuzumab (H) and the two antibodies combined have superior activity compared with either antibody alone in preclinical and clinical studies. In patients with advanced disease, P in combination with H has been shown to be active in patients whose disease has progressed while on H therapy (Baselga et al. J Clin Oncol 2010). Furthermore, P has been shown to improve the activity of H and docetaxel (T) in a randomized neoadjuvant study (Gianni et al. SABCS 2010, S3-2). No increase in overall toxicity and, in particular, no increase in cardiac events was observed with the addition of P to H and HT regimens. Methods: In this double-blind Phase III study patients with centrally confirmed HER2−positive metastatic or locally recurrent, unresectable breast cancer were randomized to receive either placebo+H+T or P+H+T. Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy including prior H and T. Patients had to have a baseline left ventricular ejection fraction ≥50% and no history of declines to Study medication was as follows: P 840 mg loading dose followed by 420 mg q3w; H 8 mg/kg loading dose followed by 6 mg/kg q3w; T 75 mg/m2 q3w (with subsequent dose escalation to 100 mg/m2 if 75 mg/m2 was well tolerated). Patients were recommended to receive at least 6 cycles of T. In the case of chemotherapy discontinuation due to cumulative toxicity, antibody therapy was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were stratified according to region and prior treatment status (adjuvant therapy or de novo metastatic breast cancer). The primary endpoint for the study was progression-free survival (PFS) as determined by independent review. The primary analysis was planned to take place when approximately 381 independently confirmed PFS events had occurred. This would provide 80% power to detect a 33% improvement in PFS (HR=0.75) at the two-sided significance level of 5%. Secondary endpoints included overall survival, investigator-determined PFS, overall response rate, duration of response, safety, and quality of life. Patient safety was monitored throughout the study by an independent data monitoring committee and a cardiac review committee. This study is registered at ClinicalTrials.gov: NCT00567190. Results: 808 patients were recruited between February 2008 and July 2010. The required number of PFS events for analysis of the primary endpoint has been reached and independent assessment PFS is currently being performed. Results of the primary analysis of efficacy and safety will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-5.

Although the incidence of cancer increases with age, older patients are under-represented in cancer treatment trials, resulting in limited data availability in this patient population. Here we present results from pre-defined subgroup analyses conducted by age group (