BACKGROUND:Responses to anti-HER2 therapy can vary based on estrogen receptor expression and HER2 gene amplification. This study assessed the magnitude of benefit by adding pertuzumab to trastuzumab and chemotherapy by estrogen receptor and HER2 levels in the APHINITY trial. METHODS:APHINITY (ClinicalTrials.gov identifier NCT01358877; BIG 4-11) was a randomized, double-blind, phase 3 trial comparing pertuzumab with placebo added to adjuvant trastuzumab and chemotherapy in 4804 patients with HER2-positive early breast cancer. The primary endpoint of this exploratory analysis was invasive disease-free survival (IDFS). Subgroup analyses used Cox models across 4 groups defined by HER2 fluorescence in situ hybridization (FISH) ratio and estrogen receptor status, adjusted for treatment arm, chemotherapy regimen, and a combined variable of nodal status and protocol version. Tumors with a FISH ratio below 2 were excluded, leaving 4782 evaluable cases. The HER2 FISH ratio was classified as low (2 to <5) or high (≥5) and estrogen receptor expression by immunohistochemistry as negative or positive using 1% and 10% cutoffs. IDFS, HER2 FISH ratio, and estrogen receptor expression were also analyzed by intrinsic molecular subtype. RESULTS:All subgroups benefited from pertuzumab, with the largest benefit in HER2 FISH-low/estrogen receptor-positive tumors (hazard ratio = 0.70, 95% CI = 0.51 to 0.95). Other subgroups showed smaller benefits, with HER2 FISH-high/estrogen receptor-negative tumors having the least numerical improvement (hazard ratio = 0.85, 95% CI = 0.59 to 1.25). No statistically significant IDFS differences were observed between HER2-enriched and non-HER2-enriched tumors. CONCLUSIONS:Pertuzumab improved IDFS in all subgroups, with the greatest improvement in HER2 FISH-low/estrogen receptor-positive tumors. These exploratory findings are hypothesis generating and support prospective validation of biomarker-guided strategies. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT01358877.

This randomized, open-label, two-arm, parallel-group, single dose, multi-center phase I study (ClinicalTrials.gov ID, NCT05275010) investigated the comparability of the pharmacokinetics of a new formulation combining pertuzumab (P) and trastuzumab (H) in one fixed-dose combination for subcutaneous injection (FDC SC) using a proprietary on-body injector (OBI) or a handheld syringe with hypodermic needle in healthy male subjects. Healthy male subjects were randomized 1:1 to either PH FDC SC using a handheld syringe (Arm 1) or an OBI device (Arm 2). Co-primary endpoints were: (i) area under the time–concentration curve (AUC) from the start of dosing to day 63 (AUC0–62) of serum P, (ii) maximum serum concentration (Cmax) from start of dosing to 63 days of serum P, (iii) AUC from the start of dosing to day 63 (AUC0–62) of serum H, and (iv) Cmax from start of dosing to 63 days of serum H. Safety was a key secondary endpoint. Liquid chromatography coupled to tandem mass spectrometry was used to measure pertuzumab and trastuzumab simultaneously in serum samples. The obtained geometric mean ratios for Cmax and AUC0–62 were within the pre-specified bioequivalence margins (0.80, 1.25) for both P and H, therefore meeting the criteria for bioequivalence. No discontinuations due to safety reasons were reported. Overall, the final safety analysis with longer follow-up was consistent with the primary analysis; there were no new or unexpected safety findings. This study demonstrated the feasibility of a hands-free device approach to deliver pertuzumab and trastuzumab in one fixed-dose combination for subcutaneous injection without compromising pharmacokinetics and safety.

Abstract Background: Some studies suggest that response to HER2-targeting agents may differ according to estrogen receptor (ER) and HER2 expression levels. This study aimed to investigate the magnitude of benefit from the addition of pertuzumab to trastuzumab and chemotherapy according to ER and HER2 expression levels in the APHINITY trial. Methods: APHINITY (NCT01358877; BIG 4-11) was a randomized, double-blind, phase III study comparing the addition of pertuzumab or placebo to adjuvant trastuzumab and chemotherapy in an ITT population of 4804 patients with HER2-positive early breast cancer. The primary objective of this exploratory, unplanned analysis was to compare whether the addition of pertuzumab to trastuzumab had an impact in invasive disease-free survival (IDFS) within different subgroups defined by HER2 FISH amplification ratio and/or ER percentage of positivity on immunohistochemistry (IHC) (centrally assessed). Patients with a FISH ratio less than 2 were excluded from this analysis, leaving 4782 patients. IDFS was defined as the time from randomization until the date of the first occurrence of an IDFS event. HER2 FISH amplification ratio was categorized as low (2≤ FISH ratio < 5) vs. high (FISH ratio ≥5). ER expression on IHC was categorized as negative ( < 1%) vs. positive (≥1%). A subgroup analysis using Cox proportional hazards regression models was used to model IDFS, assessing four categories formed by cross classifying the FISH ratio and ER groups. The model was adjusted for randomized arm, adjuvant chemotherapy regimen received, and a combined variable of nodal status and protocol version. Results: The 4782 patients had a median age of 51 years old (IQR 44-59), with a median follow up time of 73.6 months (IQR 63.0-75.2). Most patients received an anthracycline-based chemotherapy (n=3712, 77.6%). ER expression was positive in 3047 patients (63.7%). HER2 FISH amplification ratio was high in 2479 patients (51.8%). All FISH ratio/ER subgroups seem to derive IDFS benefit from the addition of pertuzumab (HR < 1) (Table 1). The HER2 FISH ratio-low/ER positive subgroup had the largest reduction in risk of an IDFS event, 30% for the pertuzumab arm (HR=0.70, 95% CI 0.51-0.95) versus placebo. Smaller differences in IDFS events were observed between the treatment arms in the other subgroups. The subgroup of tumors with HER2 FISH ratio-high/ER-negative expression showed the numerically smallest benefit in IDFS events with the addition of pertuzumab (HR 0.85, 95% CI 0.59-1.25), see Table 1. Conclusions: In this APHINITY sub-analysis, patients treated with pertuzumab/trastuzumab derive similar benefit regardless of ER and HER2 expression levels. More research is needed to find predictive biomarkers to escalate or de-escalate treatments. Table 1. Abbreviations: FISH: fluorescence in situ hybridization, ER: estrogen receptor; IDFS: invasive disease-free survival; CI: confidence interval; HR: hazard ratio Citation Format: Evandro de Azambuja, Elisa Agostinetto, Faye Samy, Serena Di Cosimo, Philippe Aftimos, Noam Pondé, Daniel Eiger, Matteo Lambertini, David Cameron, Astrid Kiermaier, Andrew Bailey, Giuseppe Viale, Sherene Loi, Martine Piccart. The benefit of adjuvant pertuzumab and trastuzumab according to estrogen receptor and HER2 expression: sub-analysis of the APHINITY trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-04.

Abstract Background HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I–II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression. Methods This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes. Discussion heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC. Trial registration ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

IMpassion050 (NCT03726879) showed no increase in pathological complete response (pCR; ypT0/is ypN0) rates for neoadjuvant A + PH + CT vs. placebo (pbo) + PH + CT in the intention-to-treat (ITT) or PD-L1+ populations in patients (pts) with high-risk HER2+ eBC. Safety was consistent with that of A in other combination studies. We report descriptive long-term efficacy and safety. Pts with a primary tumour >2 cm and histologically confirmed positive lymph node status were randomised 1:1 to A/pbo + PH + CT. After surgery, pts continued A/pbo + PH up to 1 yr. Pts with residual disease could switch to A/pbo + trastuzumab emtansine (T-DM1) for 14 cycles. Secondary endpoints: disease-free survival (DFS; time from surgery to disease recurrence or death); event-free survival (EFS; time from randomisation to disease recurrence, tumour progression or death); safety. Stratification: stage at diagnosis; hormone receptor (HR) status; PD-L1 status.Table: 127PDFS (N = 434 [217 per arm]; pts who had surgery)EFS (N = 454 [226 A, 228 pbo]; ITT population)3-yr event-free rate, % (95% confidence interval [CI])A: 92.9 (89.5, 96.4) Pbo: 88.5 (84.1, 92.8)A: 91.4 (87.7, 95.1)Pbo: 89.0 (84.8, 93.2)Hazard ratio (95% CI)0.71 (0.38, 1.32)Unstratified0.90 (0.50, 1.59)StratifiedCovariates, hazard ratio (95% CI)Stage at diagnosisT20.38 (0.13, 1.06)0.56 (0.24, 1.34)T3–T41.13 (0.50, 2.56)1.33 (0.60, 2.94)HR status+0.43 (0.17, 1.13)0.57 (0.24, 1.36)–1.07 (0.46, 2.53)1.28 (0.58, 2.82)PD-L1 status+1.38 (0.51, 3.69)1.67 (0.65, 4.32)–0.44 (0.19, 1.02)0.58 (0.27, 1.22)pCR statusNon-pCR0.71 (0.31, 1.63)0.95 (0.45, 1.98)pCR0.66 (0.26, 1.70)0.76 (0.30, 1.88) Open table in a new tab At data cut-off (24 Aug 2023), 411/454 pts (90.5%) remained on-study (A arm: 206/226; pbo arm: 205/228); median follow-up was 44.2 and 43.4 months, respectively. A median of 14 PH cycles was given in both arms. DFS/EFS, including subgroup analyses, are shown in the table. There were 24 deaths (A arm: 11; pbo arm: 13). In the adjuvant phase (A vs. pbo), more pts had adverse events of special interest (AESIs; 59.4% vs. 47.0%); there were no grade 5 AESIs; and the most common AEs (in ≥10% pts in either arm) were radiation skin injury (24.0% vs. 19.4%), arthralgia (20.7% vs. 17.1%) and diarrhoea (20.7% vs. 13.4%). Although there was no increase in pCR rates, 3-yr DFS/EFS rates were numerically improved with A in the ITT population, including in pts with PD-L1–negative, HR+ or stage T2 disease. Safety was consistent with the known profiles of PH, T-DM1 and A. These results highlight the value of long-term clinical endpoints when investigating early-stage cancer immunotherapies.

BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number: NCT05296798. Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [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 OT2-03-01.

In IMpassion050 (NCT03726879), adding atezolizumab (A) to neoadjuvant chemotherapy (CT) and pertuzumab–trastuzumab (PH) did not increase pathological complete response (pCR) vs placebo (Pl), CT and PH in patients (pts) with high-risk, HER2-positive (+) early breast cancer (EBC) in either the intention-to-treat or PD-L1+ populations. Additional BM data are warranted to better inform future immunotherapeutic strategies in HER2+ BC. We report exploratory analyses of the relationship between BMs with pCR, and their dynamics. Overall, 454 pts with centrally confirmed HER2+, node+ EBC were randomly assigned to 8 cycles of A and CT with 4 cycles of PH, followed by A plus PH until completion of 1 year of treatment after surgery, or Pl, CT and PH followed by Pl plus PH. Pre-specified HER2, hormone receptor (HR), PD-L1 and PIK3CA mutation status, and tumour-infiltrating lymphocyte (TIL) count were available at baseline; PD-L1 and TILs were available at surgery for pts with residual disease. Rate difference by BM for pCR between arms with 95% confidence intervals (CIs) was calculated using binomial distribution. Predictive factors for pCR were evaluated by calculating the odds ratio (OR) with 95% CI and selecting those with p<0.15 for multivariate analysis. BM characteristics were well balanced between arms: 89% of tumours were HER2 immunohistochemistry (IHC) 3+; 51%, HR+ (capping at 50%); 48%, PD-L1+; 28%, PIK3CA-mutated; and 37% had a high stromal TIL count (>10%: enriched in the PD-L1+ vs -negative population [56% vs 19%]). No differential treatment effect according to BM subgroup was observed between arms. Association of parameters and pCR are shown in the table. Dynamics of TILs and PD-L1 status will be presented. Table: 127POR95% CIp-valueN=411Treatment effect (reference: Pl arm)A arm1.000.65, 1.540.9972HER2 IHC 2+/3+ staining pattern (reference: focal/heterogeneous)Homogeneous (≥80% staining)2.511.46, 4.310.0009HER2 ISH gene ratio (reference: ≥2 to <4)≥41.941.18, 3.200.0091HR status (reference: oestrogen and/or progesterone receptor+)Oestrogen and progesterone receptor-negative2.411.55, 3.760.0001PD-L1 status (reference: tumour-infiltrating immune cells [IC] 0)IC 1/2/31.611.04, 2.490.0321PIK3CA status (reference: mutated)No mutation detected1.721.07, 2.770.0264 Open table in a new tab There was no differential treatment effect detected with the addition of A to CT and PH according to BMs analysed. HER2 IHC staining pattern, gene ratio, and HR, PD-L1 and PIK3CA status were predictive of pCR, in line with prior data.

To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC). ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared. Among 8381 patients recruited in ALTTO, 123 (1.5

This exploratory biomarker analysis aimed to identify prognostic gene sets in the. T-DM1 and H arms of the phase III KATHERINE study (NCT01772472). RNA sequencing was performed on post-NAT surgical samples. Genes and pathways associated with prognosis were identified using DGE, comparing pts with invasive disease-free survival (iDFS) events with censored pts at a 3-year cut-off, and gene set enrichment analysis (GSEA), using Hallmark, KEGG, xCell, and selected signatures. NMF was used to identify transcriptional subgroups; their association with iDFS was assessed by Cox regression. Association analyses were adjusted for tumour content (TC) and stratification factors. Eight hundred and fifteen samples were included in the analysis. GSEA showed that cell cycle, oxidative phosphorylation and DNA repair gene sets were associated with poor prognosis in both arms; in the H arm, metabolism-related signatures were associated with poor prognosis while immune signatures were associated with good prognosis; and in the T-DM1 arm, apoptosis and epithelial mesenchymal (EM) transition (EMT) gene sets and fibroblast, stroma and endothelial cell scores were associated with good prognosis. Trends were seen for poor prognosis with malignant-specific EM signatures in both arms. NMF clusters are described in the table. Table: 99PCluster, % prevalenceGene and signature expression, TC and association with prognosisiDFS hazard ratio,T-DM1 vs. H (95% confidence interval)CL1, 24.0%Cell cycle and DNA repair-related genes. High TC, higher HER2 and lower ESR1 levels vs. other clusters, poorest prognosis0.42 (0.24, 0.75)CL2, 8.3%Metabolism signatures and keratinisation-related genes0.58 (0.16, 2.19)CL3, 40.6%Focal adhesion, TGFβ, Wnt β catenin, EMT and extracellular matrix-related genes. Low TC, best prognosis0.25 (0.11, 0.57)CL4, 18.5%Oestrogen- and cilium assembly-related genes. High TC, highest ESR1 expression0.49 (0.22, 1.08)CL5, 8.5%Immune-related genes0.65 (0.18, 2.38) Open table in a new tab . Both DGE and NMF approaches identified cell cycle pathway-related and DNA repair genes as associated with poor prognosis in both arms. Stromal genes and high stromal content were associated with good prognosis. The advantage of T-DM1 over H was seen across all NMF clusters.

Background: Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial.Patients and methods: Left ventricular ejection fraction (LVEF) > 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as >10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board.Results: The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index > 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%).Conclusions: Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B ( p = 0.90). The safety profile was manageable in both arms.

Background: Geographic location and national income may influence access to innovation in healthcare. We aimed to study if geographical location and national income influenced the timelines to activate the global phase III APHINITY trial, evaluating adjuvant pertuzumab in patients with HER2-positive early breast cancer. Methods: Time from regulatory authority (RA) submission to approval (RAA), time to Ethics Committee/Institutional Review Board (EC/IRB) approval, time from study approval by EC/IRB to first randomised patient and from first to last randomised patient were collected. Analyses were conducted grouping countries by geographical region or economic income classification. Results: Forty-one countries (of 42) had data available regarding all relevant timelines. No statistical difference was observed between the time to RAA and geographical region (p = 0.47), although there was a trend to longer time to RAA in upper middle-income economies (p = 0.07). Except for time from first to last patient randomised, there was wide variation in timelines overall and within geographical regions and economic income groups. Conclusions: Geographical location and income classification did not appear to be the major drivers influencing time for clinical trial activation. Wide variability in activation timelines within geographical regions and income groups exists and is worthy of further investigation.

e13028 Background: Dual HER2 blockade with pertuzumab (P) + trastuzumab (H), combined with taxane induction therapy, is the standard of care for the first-line treatment of patients with HER2-positive MBC. In clinical practice, after achieving clinical benefit with approximately 4–6 cycles of PH + taxane induction, maintenance therapy is continued with PH only until disease progression or unmanageable toxicity. Approximately 50–60% of patients with HER2-positive MBC also have concurrent HR expression and may receive ET in combination with PH. This study investigated the clinical characteristics and outcomes of patients initiating ET combined with PH as maintenance therapy after completion of PH + taxane induction. Methods: We conducted a retrospective cohort study using a nationwide US electronic health record-derived de-identified database (Flatiron Health). Patients with HER2-positive and HR-positive MBC who initiated an ET between Jan 1, 2012 and Feb 28, 2021 with concomitant PH after receiving at least four cycles of first-line PH + taxane induction were included. The index date was the date of ET initiation. Progression data were abstracted from the medical charts. Mortality data were abstracted and combined with patient-level structured data (obituaries and Social Security Death Index). rwPFS was defined as the time from index date until first progression event > 14 days after the index date, or date of death; otherwise, patients were censored on the date of last clinical note abstraction. Baseline characteristics were described using summary statistics, and rwPFS in the maintenance setting was described using a Kaplan–Meier estimator from the index date. Results: Of 24,690 patients diagnosed with MBC in the database, 252 (1%) met the eligibility criteria. All patients were female. The median age was 56.6 years; 149 patients (59%) were diagnosed with de novo MBC; 248 (98%), with estrogen receptor-positive disease; and 182 (72%), with progesterone receptor-positive disease. One hundred ninety-three patients (77%) received an aromatase inhibitor as ET. The median number of taxane cycles received prior to the index date was six. Median maintenance rwPFS was 21.4 months (95% confidence interval = 16.1, 25.3). Conclusions: Given the therapeutic opportunity presented by HER2/HR co-expression and the favorable maintenance rwPFS shown here with PH + ET following taxane induction, the investigation of more potent ETs combined with PH is justified in order to further improve outcomes in first-line HER2-positive/HR-positive MBC.

PURPOSE Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)–positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)–positive populations. RESULTS At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference –0.33%; 95% CI, –9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1–positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference –8.26%; 95% CI, –20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide–paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1–positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

Background Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours. Methods The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis. Results A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7–89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0–96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3–94.4%). Conclusion With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial. Trial registration Clinicaltrials.gov identifier NCT00490139.

Background: The erythropoietin (EPO) receptor activation can stimulate tumor proliferation and may be implicated in resistance to anti-HER2 therapies. EPO administration can be used for the management of chemotherapy-induced anemia. We aim to assess if EPO intake during the adjuvant anti-HER2 treatment impacts the outcomes of HER2-positive early breast cancer (EBC) patients. Methods: For this post hoc analysis of the ALTTO trial (NCT00490139), we categorized two cohorts according to the use of EPO during adjuvant anti-HER2 treatment: i) at least one EPO dose (EPO-cohort) vs ii) no EPO (non-EPO-cohort). We compared their baseline characteristics to identify potential confounders. The primary endpoint disease-free-survival (DFS), and the secondary endpoint overall survival (OS) were compared between these two cohorts, with subgroup analysis according to menopausal status, tumor characteristics, and anti-HER2 treatment. Kaplan Meier method, log-rank test, and Cox regression model adjusted for confounders were performed for DFS and OS (removal criterion p<0.10). The frequency of cardiovascular and thromboembolic adverse events (AEs) of EPO interest was compared between both cohorts. Results: Out of the 8,381 patients recruited in the ALTTO trial, 123 (1.5%) received EPO concomitantly with adjuvant treatment, 59 in the single HER2 blockade (Lapatinib (L)-alone or Trastuzumab (T)-alone) and 64 in dual blockade (T→L or T+L) arms. The median age of EPO-cohort patients was 54 (range: 27-74) years, and 39% were premenopausal, while most had pathologic tumor size >2 cm (56.9%), positive nodal status (58.5%), positive hormone receptor (HR) status (61.8%), and poorly differentiated or undifferentiated histologic grade (64.2%). Baseline characteristics were similar in both cohorts, except for the timing of chemotherapy, for which 93.5% of patients from the EPO-cohort were enrolled in the concurrent designs (2/2B) vs 44.2% in the non-EPO-cohort (p<0.001). Median FU was 6.9 years, with 6,409 (76.5%) patients still on follow-up. For the entire ALTTO cohort, the estimated 3- and 7-year DFS were 88.3% (95% CI: 87.6% - 89.0%) and 80.1% (95% CI: 79.1% - 81.0%), respectively. No difference in DFS by EPO administration (Yes/No) was observed (log-rank p=0.70). The effect of EPO remained non-significant when controlled for the four stratification factors and all other characteristics (p=0.91). The effect of EPO administration on DFS was significant for the subgroup of premenopausal women (p=0.041), favoring the EPO-cohort, noting that this result is based on small event numbers. The interaction was found significant in Cox analysis (p=0.024), remaining significant after adjustment for important prognostic variables (p=0.032). For the entire ALTTO cohort, 758 (9.0%) deaths occurred, with 3-year OS estimate 95.7% (95% CI: 95.2% - 96.1%) and 7-year OS estimate 89.9% (89.2% - 90.6%). The OS results are consistent with those for DFS regarding the lack of a significant association with EPO and the significance (p<0.10) of menopausal status and EPO interaction. In the EPO-cohort (n=123), eight (6.5%) AEs of EPO interest were recorded, while from the non-EPO-cohort (n=8,147), 417 (5.1%) reported similar AEs. Three fatal and 25 life-threatening AEs of EPO interest were recorded in the non-EPO-cohort, and none in the EPO-cohort. Conclusion: EPO administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a harmful impact on survival outcomes, however the sample size of patients who received EPO is rather small. These findings contrast with data suggesting poorer outcomes with EPO, therefore further investigation of tumour microenvironment is needed to better understand these results, particularly in the premenopausal subgroup. Citation Format: Diogo Martins-Branco, Marie Kassapian, Véronique Debien, Rafael Caparica, Daniel Eiger, Urania Dafni, Charitini Andriakopoulou, Sarra El-Abed, Miguel Izquierdo, Malou Vicente, Saranya Chumsri, Martine Piccart-Gebhart, Alvaro Moreno-Aspitia, Ann Søegaard Knop, Janine Lombard, Evandro de Azambuja. The impact of erythropoietin administration concomitantly with adjuvant anti-HER2 treatment on the patients’ outcome: Sub-analysis of the ALTTO study [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 P1-14-05.

PH + CT is standard of care for high-risk, HER2-positive EBC. PH activates antibody-dependent cellular cytotoxicity; combining A + PH + CT may restore anti-cancer immunity and further enhance activity. IMpassion050 (NCT03726879), a double-blind, randomised, placebo (PL)-controlled study, evaluated efficacy and safety of neoadj A/PL + PH + CT. We report the primary analysis. Patients (pts) had T2–4, N1–3, M0 disease. HER2-positivity, PD-L1 and hormone receptor (HR) status were assessed centrally. Stratification factors: T stage, HR and PD-L1 status. Randomisation was 1:1 to A/PL 840 mg q2w Cycles (C) 1–4/1200 mg q3w C5–8 + dose-dense doxorubicin + cyclophosphamide (ddAC) q2w C1–4 followed by paclitaxel (Pac) qw C5–8 + standard PH q3w C5–8. Post-surgery, pts continued PH + A/PL to complete 52 weeks in total. Pts with residual disease could switch to trastuzumab emtansine + A/PL. Co-primary endpoints: Pathological complete response (pCR; ypT0/is ypN0) in the ITT and PD-L1-positive populations. Safety was a secondary endpoint. On 26/01/21 the IDMC met and recommended that A/PL treatment (Tx) be stopped due to an unfavourable benefit–risk profile. Data were analysed early (clinical cutoff: 05/02/21), with 3 pts yet to undergo surgery. 226 pts were assigned to A; 228 to PL. pCR in the ITT population of the A and PL arms: 62.4% (95% CI 55.7, 68.7) and 62.7% (56.1, 69.0), respectively (Δ –0.33%; –9.2, 8.6; P = 1.0). pCR in the PD-L1-positive population (109 per arm): 64.2% (54.5, 73.2) and 72.5% (63.1, 80.6), respectively (Δ –8.26%; –20.6, 4.0; P = 0.2). In the neoadj phase, Grade 3/4 adverse events (AEs; 51.8% v 43.6%) and serious AEs (19.5% v 13.3%) were increased with A without increased withdrawals from any study Tx. There were 4 Grade 5 AEs in the neoadj phase (alveolitis,∗ septic shock,∗ sepsis, COVID-19 [∗Tx-related, per investigator]) and 1 in the adjuvant phase (COVID-19); all with A and confounded by comorbidities and concurrent events. A + ddAC-PacPH did not result in increased pCR in the ITT or PD-L1-positive populations. Overall, the safety profile was consistent with the known profile in other combination studies with A, with no new safety signals.

Background: As women living with HIV (WLWH) become older, their risk of developing breast cancer increases. Nonetheless, literature is conflicting regarding tumor stage, distribution of subtypes and overall survival among WLWH vs. HIV-negative women with breast cancer. We assessed differences in clinicopathological characteristics and overall survival between these two groups. Methods: Systematic review and meta-analysis using MEDLINE, Scopus, ISI Web of Knowledge, LILACS, SciELO and conference abstracts up to 1 January 2020. Cross-sectional/cohort studies comparing baseline characteristics (stage and/or subtypes) and/or overall survival of WLWH vs. HIV-negative women with breast cancer were included. We performed random-effects meta-analyses to estimate summary statistics and subgroup analyses according to region of the world. Results: Eighteen studies [4 from North America, 14 from sub-Saharan Africa (SSA)] were included, with 3174 WLWH and 2 394 598 HIV-negative women. WLWH from North America and SSA were more likely to present with stage III/IV disease compared with HIV-negative women – pooled odds ratio (pOR) 1.76 [95% confidence interval (CI):1.58–1.95] and pOR 1.23 (95% CI: 1.06–1.42), respectively. WLWH from SSA were also less likely to have estrogen receptor-positive/HER2-negative tumors (pOR 0.81; 95% CI: 0.66–0.99). After adjustment, WLWH had worse overall survival compared with HIV-negative women, both in North America [pooled adjusted hazard ratio (aHR) 2.45; 95% CI: 1.11–5.41] and SSA (aHR 1.43; 95% CI: 1.06–1.92). Conclusion: Compared with HIV-negative women, WLWH are diagnosed with breast cancer at a more advanced stage and have a worse overall survival. These results should raise awareness regarding the detection and survival gap among WLWH with breast cancer and further studies are needed to decipher the reasons behind these disparities.