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Background: The poor prognostic value of young age at diagnosis appears to vary according to breast cancer (BC) subtype, although this has been studied mainly in hormone receptor-positive (HR+) disease, with limited data in HER2-positive BC and short follow-up. Limited evidence exists on the benefit of anti-HER2 therapy in young women with BC. Considering that age has historically been a rationale for overtreatment, further research efforts to better investigate the prognostic and predictive value of age are needed. This exploratory analysis conducted within the APHINITY trial aimed to investigate the prognostic and predictive value of young age in patients with HER2-positive early BC treated with modern chemotherapy and concurrent anti-HER2 targeted treatment. Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in patients with HER2-positive early BC investigating the benefit of adding pertuzumab to adjuvant chemotherapy plus trastuzumab. For the purpose of the present analysis, 40 years of age at enrolment was used as the cut-off to distinguish between young (≤40 years) and older (>40 years) cohorts. Invasive disease-free survival (IDFS) was the primary endpoint. IDFS irrespective of treatment arm and the benefit of adding pertuzumab were evaluated in all patients by comparing the young and older cohorts and then according to centrally-assessed hormone receptor status. Univariate and multivariable Cox proportional hazard models were used to assess the prognostic and predictive value of age on IDFS as a continuous and dichotomous variable (≤40 years and >40 years). A STEPP analysis was also conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. Results: Out of 4,804 patients in the ITT population, 768 (16.0%) were ≤40 years at enrollment. Patients in the young cohort were less overweight/obese (29.3% vs. 50.4%), underwent mastectomy more frequently (63.2% vs. 52.6%), had higher rates of node positive (66.4% vs. 61.8%) and HR+ (71.7% vs. 64.9%) BC as compared to those in the older cohort (all p Citation Format: Matteo Lambertini, Shona Fielding, Sibylle Loibl, Wolfgang Janni, Emma Clark, Maria Alice Franzoi, Debora Fumagalli, Carmela Caballero, Luca Arecco, Sharon Salomoni, Noam F Ponde, Francesca Poggio, Hee Jeong Kim, Cynthia Villarreal-Garza, Olivia Pagani, Shani Paluch-Shimon, Alberto Ballestrero, Lucia Del Mastro, Martine Piccart, Jose Bines, Ann H. Partridge, Evandro de Azambuja. Effect of young age at diagnosis on clinical outcomes and efficacy of anti-HER2 targeted therapy in patients with HER2-positive early breast cancer: Results from the APHINITY trial [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 P2-13-42.

Background:Previous analysis of an adjuvant breast cancer trial (NCT00490139) suggested that geographical location and income affected the time required to set up a clinical trial, being significantly longer in South American and upper-middle income economies, potentially affecting access of innovative therapies in these locations. Understanding that this can be a dynamic process, we performed a similar analysis for the recent global phase III APHINITY trial (NCT01358877), which investigated the addition of pertuzumab to chemotherapy and trastuzumab as adjuvant therapy for patients with HER2-positive primary breast cancer. Methods:Time to regulatory authority (RA) submission to approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were collected prospectively. Analyses were conducted by grouping countries either by geographical region or economic income classification as per 2019 World Bank criteria. Descriptive statistics of medians and ranges were calculated for the different timelines evaluated. Differences between geographical regions and economic income classification groups were calculated using one-way analysis of variance (ANOVA) following data normalization on square roots of the time to local RA. Geographical regions represented by only one participating country were not included in the ANOVA calculations. Results:APHINITY randomized 4805 patients between November 2011 and August 2013. Of the 42 participating countries, 41 had data available regarding all relevant timelines. Of those, 21 (51.2%) were located in Europe, 9 (21.9%) in the East Asia-Pacific region, 8 (19.5%) in Latin America and Caribbean, 2 (4.8%) in North America, and 1 (2.4%) in Sub-Saharan Africa. Twenty-seven (65.8%) of the participating countries had high, 11 (26.8%) upper-middle, and 3 (7.3%) had lower-middle income economies. Except for time from first patient to last patient randomized, there was wide variation in timelines within geographical region and across economic income classification. For example, the median time from EC/IRB approval to first recruited patient across all geographical regions was 118 days, but the range was wide (13– 463 days). There was, however, no statistical difference between the time to RA according to geographical region (p=0.47) although there was a trend to longer time to RA in upper-middle income economies compared to the others (p=0.07). Conclusion Our results did not demonstrate a significantly longer time for trial activation in Latin American & Caribbean countries and upper-middle income economies compared to other groups in the APHINITY trial. When compared to a previous report, this may reflect collective work from collaborative research groups, pharmaceutical industry sponsors and regulatory authorities across the globe and is to be welcomed. Variability in timelines within geographical regions and income classifications may exist and should be further investigated. Table 1: Timelines in the activation process of APHINITY across geographical region and economic income classification.Time to RA (days)*Time to EC/IRB (days)Time from EC/IRB approval to first patient (days)Time from first patient to last patient randomized (months)Europe and Central Asia56 (4-135)67 (22-164)109 (13-257)17.6 (13.2-21.7)North America31 (30-32)73 (19-126)126 (86-165)17.6 (13.8-21.5)East Asia and Pacific53 (15-372)67 (31-421)108 (56-147)18 (8.7-19.9)Latin America and Caribbean51 (15-276)43 (19-273)232 (98-463)14.6 (6.5-17.5)Middle East and North Africa-141 (141-141)92 (92-92)13.9 (13.9-13.9)Sub-Saharan Africa103 (103-103)14 (14-14)185 (185-185)18.2 (18.2-18.2)Overall53 (4-372)56 (14-421)118 (13-463)17 (6.5-21.7)High income45 (4-276)60 (19-273)98 (13-257)18.2 (11.9-21.7)Upper middle income92 (15-372)54 (14-421)185 (73-463)14.2 (6.5-18.2)Lower middle income55 (32-111)33 (32-78)201 (147-209)15.1 (13.5-17.4)Overall53 (4-372)56 (14-421)118 (13-463)17 (6.5-21.7)Data are medians (range)*The protocol was not submitted to a country regulatory authority for Israel. The corresponding timelines for Israel cannot be calculated.EC/IRB = ethics committee/institutional review board; RA = regulatory approval Citation Format: Maria Alice Franzoi, Marion Procter, Orianne Emond, Damien Parlier, Noam Pondé, Daniel Eiger, Sebastien Guillaume, Linda Reaby, Christopher Twelves, Emma Clark, Evandro de Azambuja, Jose Bines. Timelines to initiate an adjuvant phase III trial across the globe: A sub-analysis of the APHINITY trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-21.

Background: The APHINITY trial demonstrated that pertuzumab, when added to adjuvant trastuzumab and chemotherapy, modestly but statistically significantly improved invasive disease-free survival (IDFS) among patients with HER2-positive, operable breast cancer. From November 2011 until August 2013, 2400 patients were randomly assigned to receive pertuzumab and 2405 to receive placebo. The clinical cut off-date for the primary analysis was 19 Dec 2016 after a median follow-up of 45.4 months. In the intent-to-treat (ITT) population, the estimates of the 3-year rates of IDFS were 94.1% in the pertuzumab group and 93.2% in the placebo group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The benefit appeared more pronounced in patients with node-positive disease, with a HR of 0.77 (95% CI 0.62-0.96), and in those with hormone receptor-negative disease, where the HR was 0.76 (95% CI 0.56-1.04). Based on these results, pertuzumab in combination with trastuzumab was approved for high risk early HER2-positive breast cancer patients. The first interim analysis of OS took place at that same time. A total of 169 patients had died, with no significant treatment effect with regards to mortality found at that time. Diarrhea, grade 3 or higher, was more frequent within the pertuzumab group (9.8%) compared with the placebo group (3.7%). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Results: At 74.1 months of median follow-up (clinical cut-off date June 19, 2019), we now report results of the pre-planned, calendar-driven second interim OS analysis which requires a p-value of 0.0012 to reach statistical significance. Updated descriptive analyses of IDFS and cardiac safety were also performed. Fewer deaths were observed in the pertuzumab (P) arm [125 (5.2%) vs 147 (6.1%)], however statistical significance was not reached at this interim analysis. The hazard ratio for OS is 0.85 [95% CI 0.67-1.07 (p=0.17)]; 6-year OS percents are 94.8% vs 93.9% (0.9% difference).Updated IDFS results based on 508 events in the ITT population are: hazard ratio 0.76 [95% CI 0.64-0.91]; 6-year IDFS percents are 90.6% vs 87.8% (2.8% difference). Of note, the difference was due mainly to the reduction in distant (5.9% vs 7.7%) and loco-regional (1.2% vs 2.0%) BC relapses. The node-positive cohort continues to derive clear benefit from the addition of P: hazard ratio 0.72 (95% CI 0.59-0.87). The benefit in terms of 6-year IDFS percent is 4.5% [87.9% vs 83.4%].In the node-negative cohort, the IDFS hazard ratio is 1.02 (95% CI; 0.69-1.53) with 95% of patients being event-free in both arms at 6 years.With longer follow up, a treatment benefit of P is also seen in the hormone receptor (HR) positive cohort: IDFS hazard ratio for HR positive is 0.73 (95% CI 0.59 -0.92). IDFS hazard ratio for HR negative is 0.83 (95% CI 0.63 -1.10). No new cardiac safety concerns emerged. One additional primary cardiac event (heart failure) was reported in the P arm and 1 additional patient in each arm had a secondary cardiac event resulting to 18 and 8 for primary cardiac events and 65 and 68 for secondary cardiac events in the P and placebo arms, respectively. The benefit of P in HER2+ early BC is maintained, with the greatest benefit continuing to be observed in the node positive population. With longer follow-up, the benefit of P no longer appears to depend on HR status. Continued follow up of patients is very important to determine possible benefit for OS. A calendar-driven third interim OS analysis is planned in 2.5 years, and the event-driven final OS analysis is planned when 640 deaths have occurred. Citation Format: Martine Piccart, Marion Procter, Debora Fumagalli, Evandro de Azambuja, Emma Clark, Michael S. Ewer, Eleonora Restuccia, Guy Jerusalem, Susan Dent, Linda Reaby, Hervé Bonnefoi, Ian Krop, Tsang-Wu Liu, Tadeusz Pieńkowski, Masakazu Toi, Nicolas Wilcken, Michael Andersson, Young-Hyuck Im, Ling-Ming Tseng, Hans-Joachim Lueck, Marco Colleoni, Estefania Monturus, Mihaela Sicoe, Sébastien Guillaume, José Bines, Richard Gelber, Giuseppe Viale, Christoph Thomssen. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [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 GS1-04.

Background Diarrhea is the most commonly reported adverse event (AE) on pertuzumab (Ptz) in both early and metastatic breast cancer (BC) settings. We report safety analyses of diarrhea from the large adjuvant APHINTY study in HER2 positive early breast cancer (EBC). Patients and methods In this exploratory analysis, the safety population included 2364 patients in the Ptz arm and 2405 in the placebo (Pla) arm. No specific prophylaxis was mandated by the protocol, however early intervention with loperamide as well as fluid and electrolyte replacement was recommended. Diarrhea incidence, severity (NCI-CTCAE v4.0), onset and management were analyzed. Results Diarrhea was the most common AE in the Ptz arm (71.3% vs. 45.2% in the Pla arm) and the events were mostly G1. Diarrhea ≥G3 was observed in 9.8% and 3.7% in Ptz and Pla arms, respectively. The highest incidence was reported during administration of HER2 targeted therapy and taxane (61.4% vs. 33.8% with Ptz and Pla, respectively) with a marked decrease observed upon chemotherapy cessation (18.1% vs. 9.2% with Ptz and Pla, respectively). The median time from first targeted treatment to onset of diarrhea during the chemotherapy phase was 7 and 10 days (Ptz/Pla). On average, diarrhea events lasted longer in the Ptz than in the Pla arm (median 8 vs. 6 days). Diarrhea events were more frequent with the administration of docetaxel + carboplatin and targeted agents, irrespective of the severity. Detailed results are reported in Table 1. Conclusions In the curative setting, diarrhea due to Ptz was mild, generally manageable with common antidiarrheals and did not affect patients' ability to receive treatment. The APHINITY findings are consistent with the well-characterized pattern of pertuzumab-related diarrhea across the HER2 BC spectrum. Diarrhea incidence, severity (NCI-CTCAE v4.0), onset and management Ptz, n=2364Pla, n=2405Incidence and severityTotal number of patients with at least one adverse event$1685 (71.3%)1086 (45.2%)Total number of events$34151792NCI CTC AE Grade (highest grade per patient)!n1683 (71.2%)1085 (45.1%)Grade 1829 (35.1%)690 (28.7%)Grade 2622 (26.3%)305 (12.7%)Grade 3229 (9.7%)90 (3.7%)Grade 43 (0.1%)0Onset and duration$Median time (days) from 1st HER2 targeted treatment to onset (min-max)7 (1 – 358)10 (1 - 384)Median Duration (days) of each event (min-max)8 (1 - 811)6 (1 - 1022)ManagementAntidiarrheals$898 (38.0%)386 (16.0%)Dose modification* of any study drug!210 (8.9%)74 (3.1%)Dose modification* of HER2 targeted treatment!69 (2.9%)18 (0.7%)Discontinuation of any study drug!38 (1.6%)7 (0.3%)Discontinuation of HER2 Targeted treatment!20 (0.8%)2 ( Citation Format: Bines J, de Azambuja E, Zardavas D, Procter M, Restuccia E, Viale G, Suter T, Arahmani A, van Dooren V, Clark E, Eng-Wong J, Gelber R, Piccart M, von Minckwitz G, Baselga J. Incidence and management of diarrhea with adjuvant pertuzumab and trastuzumab in HER2-Positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-07.

Background: The primary analysis of the randomized, double-blind, placebo-controlled APHINITY trial, published in 2017, including 4804 patients (pts) with HER2-positive, early breast cancer with 45.4 months' median follow-up, demonstrated that adjuvant pertuzumab (P) added to trastuzumab and chemotherapy, statistically significantly improved invasive disease-free survival (IDFS) compared with placebo (Pla) added to trastuzumab and chemotherapy overall and for pts with node-positive (N+) disease. In 2019, updated descriptive analyses of IDFS with 74.1 months' median follow-up, demonstrated sustained benefit of adding P both overall (HR, 0.76; 95% CI, 0.64-0.91), and for N+ disease (HR, 0.72; 95% CI, 0.59-0.87), while confidence intervals remained wide for the node-negative (N-) cohort (HR, 1.02; 95% CI, 0.69-1.53). There is great interest to explore how these significant overall results translate into absolute treatment benefits for different patient subpopulations. Methods: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. Four continuous covariates of interest are considered for defining subpopulations in this report: i) a clinical composite risk score (see below), ii) TILs percentage, iii) HER2 FISH copy number, and iv) a clinical-biological composite risk score combining the previous three factors. Pts with lowest values for the covariate comprise the extreme left STEPP subpopulation, and pts with highest values comprise the extreme right subpopulation. The clinical composite risk score for IDFS based on the overall cohort was calculated using a Cox regression model including the following prespecified clinical characteristics: number of positive nodes, tumor size, age, and centrally-reviewed hormone receptor status. Composite risk scores were scaled between 0 and 100 with higher scores reflecting higher risk of an IDFS event. An example of low clinical risk factors would be T1N0 and aged 40-64; while high risk would be T3N2 or higher and ages Results: Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts. For each analysis, results are shown for the two subpopulations at either extreme of the STEPP (i.e. lowest and highest risk or values) as well as the intermediate STEPP subpopulation. Conclusions: Based on the two extreme and one intermediate subpopulations of the STEPP analyses shown in the table, the intermediate clinical composite risk subpopulation and the highest TILs percentages had the largest absolute improvements in 6-year IDFS percents for P compared with Pla. Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts.6-year IDFS %Overall (N=4804)Node-Negative (N=1799)Node-Positive (N=3005)PPlaΔ±SEPPlaΔ±SEPPlaΔ±SEOverall Average Results90.687.82.8±0.995.094.90.1±1.187.983.44.5±1.2Clinical composite riskLowest risk (0 - 21)95.396.2-0.9±1.396.196.5-0.4±1.5---Intermediate (39 - 63)92.687.35.3±1.995.091.04.0±3.093.686.76.9±2.3Highest risk (81 - 100)80.575.84.7±2.8---79.475.44.0±3.2TILs percentageLowest values (0-9)90.487.82.6±2.094.795.2-0.5±2.087.282.64.6±2.7Intermediate (13-21)89.487.71.7±2.194.294.10.1±2.285.484.80.6±2.7Highest values (≥31)95.689.36.3±1.798.194.93.2±1.792.384.97.4±2.4HER2 copy numberLowest values (1-8)87.186.40.7±2.292.794.8-2.1±2.284.182.12.0±2.8Intermediate (9.5-11)91.889.02.8±1.994.996.1-1.3±1.990.783.37.4±2.5Highest values (13-32)90.588.91.6±2.096.095.10.9±2.087.785.32.4±2.6Clinical-biological composite riskLowest risk (0-21)96.796.40.3±1.298.295.72.5±1.6---Intermediate (40-60)93.489.53.9±1.991.792.7-1.0±2.594.288.85.4±2.2Highest risk (79-100)80.175.94.2±2.7---79.575.24.3±3.2 Citation Format: Richard D. Gelber, Xin Victoria Wang, Bernard F. Cole, David Cameron, Fatima Cardoso, Vivianne Tjan-Heijnen, Ian Krop, Sherene Loi, Roberto Salgado, Astrid Kiermaier, Elizabeth Frank, Debora Fumagalli, Carmela Caballero, Evandro de Azambuja, Marion Procter, Emma Clark, Eleonora Restuccia, Sarah Heeson, Jose Bines, Sibylle Loibl, Martine Piccart-Gebhardt. 6-year absolute invasive disease-free survival (IDFS) benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A STEPP analysis of the APHINITY (BIG 4-11) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-01.

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: 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.

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

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.