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PURPOSE Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339 ), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety. RESULTS Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.

Objective/Background We performed a retrospective analysis of longitudinal real-world data (RWD) from patients with breast cancer to replicate results from clinical studies and demonstrate the feasibility of generating real-world evidence. We also assessed the value of transcriptome profiling as a complementary tool for determining molecular subtypes. Methods De-identified, longitudinal data were analyzed after abstraction from records of patients with breast cancer in the United States (US) structured and stored in the Tempus database. Demographics, clinical characteristics, molecular subtype, treatment history, and survival outcomes were assessed according to strict qualitative criteria. RNA sequencing and clinical data were used to predict molecular subtypes and signaling pathway enrichment. Results The clinical abstraction cohort (n = 4000) mirrored the demographics and clinical characteristics of patients with breast cancer in the US, indicating feasibility for RWE generation. Among patients who were human epidermal growth factor receptor 2-positive (HER2+), 74.2% received anti-HER2 therapy, with ∼70% starting within 3 months of a positive test result. Most non-treated patients were early stage. In this RWD set, 31.7% of patients with HER2+ immunohistochemistry (IHC) had discordant fluorescence in situ hybridization results recorded. Among patients with multiple HER2 IHC results at diagnosis, 18.6% exhibited intra-test discordance. Through development of a whole-transcriptome model to predict IHC receptor status in the molecular sequenced cohort (n = 400), molecular subtypes were resolved for all patients (n = 36) with equivocal HER2 statuses from abstracted test results. Receptor-related signaling pathways were differentially enriched between clinical molecular subtypes. Conclusions RWD in the Tempus database mirrors the overall population of patients with breast cancer in the US. These results suggest that real-time, RWD analyses are feasible in a large, highly heterogeneous database. Furthermore, molecular data may aid deficiencies and discrepancies observed from breast cancer RWD.

MEDI4276 is a biparatopic tetravalent antibody targeting two nonoverlapping epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2-positive tumor cells in vitro. This was a first-in-human, dose-escalation clinical trial in patients with HER2-positive advanced or metastatic breast cancer or gastric cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute intravenous infusion every 3 weeks). Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (objective response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity. Forty-seven patients (median age 59 years; median of seven prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 liver function test (LFT) increases, one of whom also had grade 3 diarrhea, which resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 drug-related AE was AST increased (21.3%). Five patients had drug-related AEs leading to treatment discontinuation. In the as-treated population, there was one complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 0.75 mg/kg; breast cancer)—all had prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.

Advanced Breast Cancer; Efficacy; Margetuximab Cáncer de mama avanzado; Eficacia; Margetuximab Càncer de mama avançat; Eficàcia; Margetuximab Importance ERRB2 (formerly HER2)–positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, Setting, and Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main Outcomes and Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P

Background: Margetuximab (M) is an investigational Fc-engineered, anti-HER2 monoclonal antibody with the same epitope specificity as trastuzumab (T). Relative to T, Fc engineering of M increases binding affinity for the activating Fc receptor (FcR) CD16A and decreases affinity for the inhibitory FcR CD32B. The SOPHIA trial (NCT02492711) randomized pretreated HER2+ MBC patients to either M or T, each with chemotherapy (C). M+C improved progression-free survival (PFS) benefit over T+C. Infusion related reactions (IRR) have been observed after infusion of therapeutic proteins, typically during the first infusion, with a first-dose incidence of up to 40% for T (Herceptin Prescribing Information®). A retrospective analysis of 197 patients showed 16% IRRs on T, mostly after the first infusion; this rate was lower with (10%) compared to without (19%) premedication (Thompson, 2014). Here, we report IRR safety and tolerability data in the SOPHIA trial patients following HER2-targeted antibody therapy. Methods: The open-label Phase 3 SOPHIA trial enrolled patients with HER2+ MBC after at least 2 prior anti-HER2 therapies, including pertuzumab; 91% in both groups also received ado-trastuzumab emtansine. Randomization of 536 patients was 1:1 to M (15 mg/kg IV q3w) or T (6 [8 loading dose] mg/kg IV q3w), each with Investigator selected C (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). M was given as 120-minute infusions. T was given as a 90-minute infusion in Cycle 1, then a 30-minute infusion from Cycle 2 onward. Recommended elective premedication included acetaminophen, ibuprofen, diphenhydramine, ranitidine, dexamethasone, or equivalents. IRR safety analyses were conducted on 530 patients (264 M+C and 266 T+C) that received any study therapy. Results: A higher proportion of patients experienced IRRs on the M arm (35 [13.3%]) than on the T arm (9 [3.4%]). Most IRRs in both groups were severity Grade 1 or 2, occurred on Cycle 1 Day 1, and resolved within 24 hours. In patients receiving M, Grade 3 IRR occurred in 4 patients (1.5%), including 3 after vinorelbine and 1 after eribulin. Adverse events associated with Grade 3 IRRs included chills, fever, nausea, diarrhea, dyspnea, and/or hypertension. Two patients receiving M (0.8%) discontinued due to IRR, versus none on T. Of patients with IRRs, the most common symptoms in both treatment groups were chills (M: 17 [48.6%]; T: 5 [55.6%]) and fever (M: 13 [37.1%]; T: 2 [22.2%]). There was no observed hypotension in either group. In both groups, more than half of IRR events were addressed by dose interruption only. All IRRs all were medically manageable. IRR rates were higher in patients without premedication for both groups. Of 264 subjects receiving M, 218 (82.6%) received premedication and 46 (17.4%) did not; IRRs were observed in 28 (12.8%) of those receiving premedication and 7 (15.2%) of those not premedicated. All 4 patients on M with Grade 3 IRRs received premedication, 3 with steroids. Of 266 subjects receiving T, 173 (65%) received premedication and 93 (35%) did not; IRRs were observed in 5 (2.9%) of those receiving premedication and 4 (4.3%) of those not premedicated. IRR risk was unaffected by chemotherapy subgroup or CD16A genotype. Conclusions: In the SOPHIA trial, IRR events occurred in a greater proportion of patients on M than on T. Most were mild to moderate in severity, limited to Cycle 1, and resolved on the same day. Symptom patterns were similar between groups, and premedication did not eliminate the hazard of IRRs in either group. Severe IRRs and discontinuations due to IRRs were rare. IRRs on first infusion of M appear to resemble those observed following first infusion of T. Citation Format: Javier Cortes, Fatima Cardoso, Giuseppe Curigliano, William J Gradishar, Seock-Ah Im, Hope S Rugo, Shakeela W Bahadur, Alfredo Falcone, Serafin Morales Murillo, David A Riseberg, Antonino Musolino, Trevor M Feinstein, Miguel H Abreu, Young-Hyuck Im, Yelena Novik, Timothy Pluard, Lupe G Salazar, Rossana Berardi, Viorela Pop, Shengyan Hong, Kenneth Jacobs, Edwin Rock, Mark D Pegram. Infusion related reactions in the phase 3 SOPHIA trial of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with pretreated HER2+ metastatic breast cancer [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 PS10-24.

Expression of human epidermal growth factor receptor 2 (HER2) in breast cancer defines a subset of patients (∼15%-20%) who are candidates for anti-HER2 therapies, most notably, trastuzumab, pertuzumab, antibody drug conjugates (eg, T-DM1), and tyrosine kinase inhibitor (TKI) drugs (eg, lapatinib and neratinib), all of which have dramatically changed the prognosis for this aggressive subtype of breast cancer. A roundtable meeting of the Breast Cancer Therapy Expert Group (BCTEG) was convened in March 2018 in an effort to discuss and clarify, from the perspective of the practicing community oncologist, recent developments in the diagnosis and treatment of HER2-positive (HER2+) breast cancer. Members of the group selected 4 key topics for discussion prior to the meeting, including diagnosis of HER2+ disease, and its treatment in the neoadjuvant, adjuvant, and metastatic settings. Approved testing methods, such as immunohistochemistry and fluorescence in situ hybridization, are used to demonstrate overexpression and/or amplification of HER2 in breast tumors, and established clinical guidelines are used to appropriately define treatment plans for patients with HER2+ disease. The panel acknowledges a range of treatment options now available for treatment of HER2+ breast cancer in the neoadjuvant, adjuvant, and advanced/metastatic settings, although it is noted that many controversies remain, including the optimal sequence of therapies, the most appropriate treatment(s) for subsets of patients with HER2+ disease (eg, hormone receptor-negative or -positive/HER2+), and uncertainties surrounding the diagnosis and definition of HER2+ disease. The current report summarizes the discussion of the BCTEG panel on this topic.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% and median PFS of 5.4 months. The confirmed ORR in taxane-pretreated patients also was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA investigates tesetaxel plus a reduced dose of capecitabine as an all-oral regimen in patients with HER2-, HR+ MBC. Trial design: CONTESSA is a 600-patient, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have received a taxane in the (neo)adjuvant setting. Patients with known CNS metastases are eligible. The primary endpoint is progression-free survival (PFS) assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are overall survival, ORR and disease control rate. Enrollment began in December 2017. In June 2019, the Independent Data Monitoring Committee for CONTESSA recommended that the study continue with no modifications following a planned interim efficacy futility analysis. The interim efficacy futility analysis was based on a pre-specified analysis of the first approximate 100 PFS events that occurred in the study. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03326674). Citation Format: Joyce O'Shaughnessy, Martine Piccart, Lee Schwartzberg, Javier Cortes, Nadia Harbeck, Seock-Ah Im, Hope Rugo, Michael Untch, Denise Yardley, Igor Bondarenko, Veronique Dieras, Mark Pegram, Stew Kroll, Joseph O'Connell, Jeff Vacirca, Thomas Wei, Kevin Tang, Andrew Seidman. CONTESSA: A multinational, multicenter, randomized, phase 3 registration study of tesetaxel plus a reduced dose of capecitabine in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane [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 OT1-08-09.

Background: There is an unmet need for evidence-based systemic therapies for pts with HER2-positive MBC and progressive brain metastases. Despite assumptions that monoclonal antibodies do not cross the blood-brain barrier, molecular imaging in pts shows localization of 89Zr-trastuzumab to brain metastases. Furthermore, preclinical data support dose-dependent activity of H in intracranial tumor models. The PATRICIA study (NCT02536339) evaluated safety and efficacy of P plus high-dose H in pts with HER2-positive MBC with CNS metastases and CNS progression after RT. Herein, we present results from the primary efficacy analysis of PATRICIA. Methods: PATRICIA was a US-based, phase II, open-label, single arm study. Eligible pts had measurable (≥10 mm) CNS disease that had progressed after CNS-directed RT, in the setting of stable extracranial disease. CNS-directed RT included whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) and must have been completed ≥60 days before study entry. Pts received P (840 mg loading dose, then 420 mg every 3 weeks) and high-dose H (6 mg/kg weekly), which continued until progression (CNS or systemic) or unacceptable toxicity. Pts could continue their existing systemic anti-cancer therapy during the study, with the exception of trastuzumab emtansine (T-DM1) or lapatinib. Switch of other anti-cancer therapy was not permitted during the study. Restaging evaluations including brain MRI were completed every 2 cycles. The primary efficacy endpoint was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints included duration of response (DOR), clinical benefit rate (CBR) in the CNS, and safety. Samples were collected for exploratory pharmacokinetic analyses on Day 1 of weeks 1, 4, 10, and 16. Results: From 15 Dec 2015 to 18 May 2017, 40 pts were enrolled across 16 sites. Median age was 48 (range 34–69) years, with 33% and 67% of pts having an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, respectively. 41% of pts had received prior WBRT only, 28% had received prior SRS only, and 31% had received both. At the data cut off (1 May 2019), of 39 treated pts, 2 remained on study treatment and 37 discontinued treatment, most commonly due to CNS progression (n=27). Median treatment duration was 4.5 (range 0.3–37.3) months. Four pts in the efficacy population (N=37) experienced a confirmed partial response (Table), leading to an ORR of 11% (95% confidence interval [CI], 3–25%). Response durations were 3.2, 3.3, 4.6, and 5.6 months (median DOR 4.6 months). The CBR (complete response + partial response + stable disease [SD] of ≥4 or ≥6 months) was 68% (SD ≥4 months) and 51% (SD ≥6 months). Results from exploratory pharmacokinetic analyses confirmed greater H exposure with the high-dose schedule. The adverse event profile was similar to that previously reported for P and H, with no new safety signals. One pt discontinued treatment due to an adverse event (grade 3 left ventricular dysfunction, considered related to study treatment). No Grade 5 adverse events were reported. Conclusions: The CNS ORR of 11%, ≥6-month CBR of 51%, and lack of any new safety signals suggest that P plus high-dose H may have clinical utility in some pts with HER2-positive MBC with progressive CNS metastases. Table. Efficacy within the CNS per RANO-BM criteriaEfficacy population (N=37)n (%)95% CIORR*4 (11)3, 25CBR (CR + PR + stable disease [SD] ≥4 months)25 (68)50, 82CBR (CR + PR + SD ≥6 months)19 (51)34, 68Confirmed best response (SD ≥4 months)CR0—PR4 (11)—SD ≥4 months21 (57)—Pts without clinical benefit12 (32)—Confirmed best response (SD ≥6 months)CR0—PR4 (11)—SD ≥6 months15 (41)—Pts without clinical benefit18 (49)—*Confirmed complete response (CR) or confirmed partial response (PR). Citation Format: Nancy U Lin, Priya Kumthekar, Solmaz Sahebjam, Nuhad Ibrahim, Anita Fung, Anna Cheng, Alan Nicholas, Bei Wang, Mark Pegram. Pertuzumab (P) plus high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression after radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC): Primary efficacy analysis results from the phase II PATRICIA 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 P1-18-03.

Background: Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T) and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both the 158V (high-binding) and 158F (low-binding) allotypes of the activating Fc receptor CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, and does so more effectively than T in vitro. Based on ex vivo experiments with cells collected from patients (pts) before and after treatment, M induces adaptive immunity, including enhanced T-cell clonality and induction of HER2-specific T- and B-cell responses. The SOPHIA trial (NCT02492711) showed that in pts with pretreated HER2+ metastatic breast cancer (MBC), M+chemotherapy improved progression-free survival vs T+chemotherapy, with comparable safety. M is intended to be dosed at 15 mg/kg every 3 weeks, with infusions over 120 min at every cycle (C). A substudy of SOPHIA was conducted to evaluate the safety and tolerability of reduced infusion times from C2 onward. Methods: Eligible pts had HER2+ MBC after ≥4 lines of prior therapy for MBC, including prior T, pertuzumab, and ado-T emtansine. Enrolled pts received a 120-min M infusion, with or without chemotherapy, in C1, then either 60- or 30-min infusions in C2 and beyond. This single-arm substudy was unblinded, with no comparator. The primary objective was incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end of C2. Incidence of all IRRs was a secondary objective. Results: Of 88 pts enrolled, 69 received M+chemotherapy and 19 received M alone. Mean age was 54.5 years; 99% were female and 71% white. The median number of cycles of M received was 3 (range 1-17). Overall, 7 pts were assigned to received 60-min M infusions starting at C2 (range 1-17 cycles), and 76 pts were assigned to received 30-min M infusions starting at C2 (range 1-14 cycles). Five pts did not receive C2 treatment due to non-radiologic progressive disease, unrelated adverse event (AE), patient or physician decision, or loss to follow-up. Eighty (91%) pts had premedication for IRRs. No pt had Grade ≥3 IRR. Overall, 18 (21%) had IRRs (2 Grade 1, 16 Grade 2), all but 1 of which occurred in C1 (120 min). Of the 18 pts with IRRs, 17 (94%) were premedicated and 10 (56%) were treated for IRRs. The overall rate of IRRs in premedicated pts was 21% (17/80) and in non-premedicated pts was 13% (1/8). One pt experienced IRRs in both C1 and C2 (Grade 2 in C1 and Grade 1 in C2); the same patient then received 6 additional cycles of M (30 min) with no IRRs after C2 (C3-8) and had no premedication after C1. No pt discontinued treatment due to an IRR. Of 88 pts enrolled, 85 (97%) pts experienced an AE, and 7 (8%) had Grade ≥3 AEs. Fifty (57%) pts had M-related AEs. The most common (>5% of pts) M-related AEs were IRRs in 17 (19%), fatigue in 9 (10%), diarrhea in 5 (6%), and aspartate aminotransferase increase in 5 (6%). Serious AEs occurred in 13/88 pts (15%), none of which were considered M-related by the investigator. Conclusions: In this heavily pretreated population, shorter M infusion times did not lead to an increase in IRRs. IRRs were most likely to occur during C1 when the infusion time was 120 min. No Grade ≥3 IRRs were observed. Of 18 pts with Grade 1-2 IRRs, only 1 had an IRR after C1. These results showed that the acceptable safety and tolerability profile of M was maintained even after infusion time is reduced to 30-min from C2 onward. Shorter infusion times may reduce the burden of chronic M therapy on pts, caregivers, and clinic staff. Citation Format: William J. Gradishar, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Rosanna Berardi, Michelino De Laurentiis, Shakeela W. Bahadur, Young-Hyuck Im, Cynthia Lynch, Yelena Novik, Sutton Edlich, Edwin Rock, Shengyan Hong, Hope S. Rugo, SOPHIA Study Group. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results [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 P1-18-04.

Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) Cmax limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1–based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

It has been over three decades since anthracyclines took their place as the standard chemotherapy backbone for breast cancer in the curative setting. Though the efficacy of anthracycline chemotherapy is not debatable, potentially life-threatening and long-term risks accompany this class of agents, leading some to question their widespread use, especially when newer agents with improved therapeutic indices have become available. Critically assessing when to incorporate an anthracycline is made more relevant in an era where molecular classification is enabling not only the development of biologically targeted therapeutics but also is improving the ability to better select those who would benefit from cytotoxic agents. This comprehensive analysis will present the problem of overtreatment in early-stage breast cancer, review evidence supporting the use of anthracyclines in the pre-taxane era, analyze comparative trials evaluating taxanes with or without anthracyclines in biologically unselected and selected patient populations, and explore published work aimed at defining anthracycline-sensitive tumor types.

Background Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T). Compared with T, M has higher affinity for both the 158V (high-binding) and 158F (low-binding) allotypes of the activating Fc receptor CD16A. M enhances innate immunity more effectively than T in vitro, including CD16A-mediated antibody-dependent cellular cytotoxicity. Samples collected from patients (pts) before and after single-agent treatment also demonstrate that M induces HER2-specific adaptive immune responses, including both T- and B-cell responses. The SOPHIA trial (NCT02492711) in pts with pretreated HER2+ MBC showed that M+chemotherapy (chemo) improved progression-free survival vs T+chemo, with comparable safety. A pooled analysis of M safety across 3 clinical trials is presented. Methods Study 01 (NCT01148849), an ongoing Phase 1 dose-finding/safety study of M monotherapy, enrolled 66 pts with advanced HER2+ carcinomas, including 27 with MBC. Study 02 (NCT01828021), a completed Phase 2 study of M monotherapy in low-expressing HER2+ MBC, enrolled 25 pts. Study 04 (NCT02492711), an ongoing Phase 3 study in pts with pretreated HER2+ MBC to compare M + chemo vs T + chemo, randomized 536 pts, of whom 264 and 265 received M and T, respectively. The pooled safety population includes all pts who received any M in Study 01 (cutoff 01Oct2015), Study 02 (cutoff 02Aug2017), and Study 04 (cutoff 10OCT2018). Treatment-emergent adverse events (AEs), defined as AEs that began or worsened in severity on or after first dose of study drug through an End of Treatment Visit or 28 days after last study treatment, are reported. Results Of 355 pts that received at least 1 dose of M, 295 received 15 mg/kg Q3W, and 60 received other doses from 0.1 - 18 mg/kg. Median (mean, range) number of cycles for all dose levels was 5.0 (6.6, 1-43), higher on Study 04 (6.0) than Study 01 (1-3 across dose groups) or Study 02 (2.0). Most pts (347 [97.7%]) experienced at least 1 AE, and about half (173 [48.7%]) had at least 1 Grade >/= 3 AE. Serious AE (SAE) incidence across studies was low (58 [16.3%]), and 21 pts (5.9%) discontinued M due to AEs. Most frequently reported AEs (>/= 20%) were fatigue (124 [34.9]), nausea (103 [29.0%]), diarrhea (75 [21.1%]), and neutropenia (75 [21.1%]). Blood/lymphatic system disorders were the most frequent events by SOC, and largely restricted to Study 04. Increased neutropenia on M (26.1%), relative to T (20.4%), was observed in Study 04 yet both febrile neutropenia (M 3.0%, T 4.5%) and infections (M 36.4%, T 39.6%) were higher on T. By contrast, Study 01 and Study 02 revealed no tendency of M monotherapy to cause neutropenia. Overall, infusion related reactions (IRRs) were observed in 51 pts (14.4%), primarly at first infusion, including serious IRRs in 5 (1.4%). Also, 34 pts (9.6%) had > 15% reduction in LVEF with a median time to > 15% reduction of 49 days. In all pts with complete follow-up, these LVEF reductions were asymptomatic and reversible. No M-induced cardiac conduction abnormalities were noted. In Study 04, similar proportions in both groups experienced AEs (M 97.7%, T 96.2%), including Grade >/= 3 AEs (M 52.3%, T 48.3%), SAEs (M 14.8%, T 17.4%), discontinuations due to AEs (M 3.0%, T 2.6%), and deaths due to AEs (M 0.8%, T 0.8%). As of the 23Feb2020 safety update, 2 pts remain on M in Study 01, after 116 and 109 cycles (6.7 and 6.3 years), respectively. In Study 04, 16 pts (6%) continued on M, and 7 (2.6%) remained on T. Discussion M has demonstrated an acceptable safety profile across Phase 1, 2, and 3 studies. It has been administered for over 6 years without long-term cumulative safety issues. Combined M plus chemotherapy Q3W demonstrated acceptable safety and tolerability, similar to that for T plus chemotherapy Q3W in Study 04. Citation Format: Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Hope S. Rugo, Ursa Brown-Glaberman, Denise A. Yardley, Sung-Bae Kim, Maaike de Boer, Zbigniew Nowecki, Vesna Glavicic, Ido Wolf, Nele Claes, Joo Hyuk Sohn, Thomas Bachelot, Peter A. Kaufman, Jan Baughman, Shengyan Hong, Kenneth Jacobs, Edwin Rock, William J. Gradishar. Integrated safety summary of single agent and combination margetuximab in phase 1, 2, and 3 studies of HER2-positive advanced cancers and metastatic breast cancer (MBC) [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 PS10-12.

Background: Rintodestrant (G1T48) is a potent oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Preliminary results from Part 1 dose escalation showed robust target engagement on 18F-fluoroestradiol positron emission tomography (FES-PET), a favorable safety profile, and encouraging antitumor activity in patients with heavily pretreated ER+/HER2- advanced breast cancer (ABC), including those with ESR1 mutations (Dees et al., ESMO 2019 [abstract #3587]). Here, we present updated results from dose escalation and expansion (Parts 1 and 2). Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant monotherapy in women with ER+/HER2- ABC after progression on endocrine therapy. Part 1 was a 3+3 dose escalation (200-1000 mg once daily [QD]); Part 2 expanded 600 and 1000 mg QD; and Part 3 was added to assess rintodestrant with palbociclib in patients in earlier lines in the advanced setting. Primary objectives included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and recommended Phase 2 dose. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included pharmacodynamic inhibition of ER target engagement (FES-PET), mutation profiling (cell-free DNA [cfDNA]), and change in ER expression from baseline to on-treatment tumor biopsies. Results: As of May 13, 2020, 67 patients (Part 1: n = 26; Part 2: n = 41) were treated, with a median age of 61 years (range 34-83) and ECOG PS of 0 (49%) or 1 (51%). Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Median number of prior lines of endocrine therapy in the advanced setting was 2 (range 0-5), with 61% of patients having received ≥2 lines. Treatment-related adverse events (TRAEs) were reported in 70% of patients. The most common TRAEs in ≥10% of patients included hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%), and vomiting (10%), mostly grade 1 or 2. No DLTs were reported and MTD was not reached. Dose reduction due to TRAEs occurred in 1 patient (1%), with elevated transaminases (grade 3 ALT and grade 2 AST) at 600 mg. Serious TRAEs occurred in 2 patients at 1000 mg (grade 5 cerebral hemorrhage in the setting of low molecular weight heparin and grade 2 upper abdominal pain). Two patients (3%) discontinued treatment due to TRAEs. Overall, the frequency of patients with TRAEs at 800 mg was comparable with that at 600 mg (57% vs 63%) and less than that at 1000 mg (81%). Of 67 patients, 16 were on study treatment for ≥24 weeks and 3 (n = 1 at 600 mg; n = 2 at 1000 mg, including 1 with ESR1 mutation) had a confirmed partial response (clinical benefit rate [CBR]: 28%). FES-PET standard uptake values decreased at week 4 with a mean reduction of 87% (±8%) at doses ≥ 600 mg. Of 59 patients tested for baseline cfDNA, 41% harbored ≥1 ESR1 mutation, with a similar CBR in both groups (33% in ESR1 mutant and 29% in ESR1 wild-type). Seven of 9 patients had a decrease in ER immunohistochemistry H-score at both 600 and 1000 mg (median [range]: -27.8% [-33.8%, -3.4%]), irrespective of ESR1 mutation status. Based on safety, efficacy, and ER degradation, 800 mg was selected as the optimal dose for further study. Conclusions: Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270). Citation Format: Philippe Aftimos, Patrick Neven, Mark Pegram, Catharina Willemien Menke-van der Houven van Oordt, E. Claire Dees, Carolien Schröder, Agnes Jager, Iurie Bulat, Linnea Chap, Marina Maglakelidze, Erika Hamilton, Massimo Cristofanilli, Susanna Ulahannan, Jorianne Boers, Ramsha Iqbal, Adrian Crijanovschi, Curt D Wolfgang, Wenli Tao, Christina Sipes, Rajesh Malik, Sarika Jain. Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection [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 PS12-04.

Introduction: Although many current cancer therapies are effective, the mortality rate globally is unacceptably high. Cancer remains the second leading cause of death worldwide after heart disease and has caused nearly 10 million deaths in 2018. Additionally, current preventive therapies for cancer are underdeveloped, undermining the quality of life of high-risk individuals. Therefore, new treatment options for targeting cancer are urgently needed. In a recent study, researchers adopted an autologous iPSC-based vaccine to present a broad spectrum of tumor antigens to the immune system and succeeded in orchestrating a strong prophylactic immunity towards multiple types of cancer in mice. Areas covered: In this review, we provide an overview of how cancer develops, the role of immune surveillance in cancer progression, the current status and challenges of cancer immunotherapy as well as the genetic overlap between pluripotent stem cells and cancer cells. Finally, we discuss the rationale for an autologous iPSC-based vaccine and its applications in murine cancer models. Expert opinion: The autologous iPSC-based vaccine is a promising preventive and therapeutic strategy for fighting various types of cancers. Continuing efforts and clinical/translational follow-up studies may bring an autologous iPSC-based cancer vaccination approach from bench to bedside.

CanAssist‐Breast (CAB) is an immunohistochemistry (IHC)‐based prognostic test for early‐stage Hormone Receptor (HR+)‐positive breast cancer patients. CAB uses a Support Vector Machine (SVM) trained algorithm which utilizes expression levels of five biomarkers (CD44, ABCC4, ABCC11, N‐Cadherin, and Pan‐Cadherin) and three clinical parameters such as tumor size, grade, and node status as inputs to generate a risk score and categorizes patients as low‐ or high‐risk for distant recurrence within 5 years of diagnosis. In this study, we present clinical validation of CAB. CAB was validated using a retrospective cohort of 857 patients. All patients were treated either with endocrine therapy or chemoendocrine therapy. Risk categorization by CAB was analyzed by calculating Distant Metastasis‐Free Survival (DMFS) and recurrence rates using Kaplan‐Meier survival curves. Multivariate analysis was performed to calculate Hazard ratios (HR) for CAB high‐risk vs low‐risk patients. The results showed that Distant Metastasis‐Free Survival (DMFS) was significantly different (P‐0.002) between low‐ (DMFS: 95%) and high‐risk (DMFS: 80%) categories in the endocrine therapy treated alone subgroup (n = 195) as well as in the total cohort (n = 857, low‐risk DMFS: 95%, high‐risk DMFS: 84%, P 74% of high Ki‐67 and IHC4 score intermediate‐risk zone patients into low‐risk category. Overall the data suggest that CAB can effectively predict risk of distant recurrence with clear dichotomous high‐ or low‐risk categorization.

Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.

INTRODUCTIONWe performed a retrospective analysis of longitudinal real-world data (RWD) from breast cancer patients to replicate results from clinical studies and demonstrate the feasibility of generating real-world evidence. We also assessed the value of transcriptome profiling as a complementary tool for determining molecular subtypes.PATIENTS AND METHODSDe-identified, longitudinal data were analyzed after abstraction from U.S. breast cancer patient records structured and stored in the Tempus database. Demographics, clinical characteristics, molecular subtype, treatment history, and survival outcomes were assessed according to strict qualitative criteria. RNA sequencing and clinical data were used to predict molecular subtypes and signaling pathway enrichment.RESULTSThe clinical abstraction cohort (n=4,000) mirrored U.S. breast cancer demographics and clinical characteristics indicating feasibility for RWE generation. Among HER2+ patients, 74.2% received anti-HER2 therapy, with ~70% starting within 3 months of a positive test result. Most non-treated patients were early stage. In this RWD set, 31.7% of patients with HER2+ IHC had discordant FISH results recorded. Among patients with multiple HER2 IHC results at diagnosis, 18.6% exhibited intra-test discordance. Through development of a whole-transcriptome model to predict IHC receptor status in the molecular sequenced cohort (n=400), molecular subtypes were resolved for all patients (n=36) with equivocal HER2 statuses from abstracted test results. Receptor-related signaling pathways were differentially enriched between clinical molecular subtypes.CONCLUSIONRWD in the Tempus database mirrors the overall U.S. breast cancer population. These results suggest real-time, RWD analyses are feasible in a large, highly heterogeneous database. Furthermore, molecular data may aid deficiencies and discrepancies observed from breast cancer RWD.

Triple-negative breast cancer (TNBC), defined as breast cancer lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), accounts for up to 20% of all breast cancer, and it occurs at a higher frequency in younger, African American, and Hispanic women. Compared to breast cancers that are hormone receptor and/or HER2 positive, TNBC has an aggressive clinical course and worse prognosis. Because TNBC is by definition unresponsive to endocrine therapy (eg, tamoxifen, aromatase inhibitors) and HER2-directed therapies (eg, trastuzumab), chemotherapy continues to play an important role. TNBC constitutes a molecularly heterogeneous group of tumors that can vary in response to treatment, and clinical management can be challenging, particularly for the practicing community oncologist, for whom breast cancer may be only one of many tumor types encountered. In January 2020, the Breast Cancer Therapy Expert Group (BCTEG) convened a roundtable discussion on the topic of advances in the treatment of TNBC. Topics discussed included histopathologic classification/definition of TNBC, neoadjuvant strategies, adjuvant chemotherapy (with special emphasis on management of patients who do not experience a pathologic complete response), and treatment of metastatic disease. Also reviewed was the wide range of emerging pathways and therapies currently under investigation to expand TNBC treatment options, including immunotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. This article summarizes the BCTEG discussion and highlights the key opinions relating to the treatment of patients with TNBC.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; PCONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794. opens in new tab.)

Background This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. Methods Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. Results The risk ratio for ORR was 0.940 (95% CI: 0.842–1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80–1.25. ORR was 62.5% (95% CI: 57.2–67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3–71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. Conclusion When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT01989676

Background Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Results Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). Conclusions These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. Trial registration ClinicalTrials.gov, NCT00005970. Registered on July 5, 2000. Electronic supplementary material The online version of this article (10.1186/s13058-018-0989-8) contains supplementary material, which is available to authorized users.

Metastatic breast cancer continues to be a life-threatening diagnosis that impacts hundreds of thousands of patients around the world. Targeted therapies are usually associated with less toxicity compared with cytotoxic chemotherapies and often induce response or durable disease control in estrogen receptor (ER) and/or HER2+ breast cancers. Drugs that target CDK 4/6 either alone or in combination with endocrine therapy have demonstrated substantial improvements in progression-free survival (PFS) compared with endocrine monotherapy. Most recently, PARP inhibitors have shown longer PFS compared with physician’s choice of chemotherapy in BRCA-associated cancers, leading to the first U.S. Food and Drug Administration (FDA) approval of a targeted therapy with the potential to benefit a subgroup of patients with triple-negative breast cancer (TNBC). Finally, newer drug delivery strategies using antibody drug conjugates have also allowed a “targeted approach” to deliver moderate to extremely potent cytotoxins directly to sites of metastatic disease, with less toxicity.

Introduction: The irreversible pan-HER inhibitor NER showed modest single agent activity for HER2mut MBC in Part I of MutHER trial. In Part II, we hypothesized that (1) N+F would improve activity in estrogen receptor positive (ER+) HER2mut MBC due to ER-HER2 crosstalk and (2) dual HER2 blockade by adding trastuzumab at disease progression (PD) could overcome resistance. Methods: Pts with ER+HER2mut MBC were enrolled to 2 cohorts (FUL treated or naive) to receive N+F with diarrhea prophylaxis. ER- pts received NER in an exploratory ER- cohort. Trastuzumab was added at PD if approved by insurance. Simon's Minimax 2-stage phase II design with the primary endpoint of clinical benefit rate (CBR: rates of complete/partial response [CR/PR] plus stable disease [SD] >24 weeks [wks]), with anticipated vs null hypothesis being CBR of 55% vs 35% (FUL treated) or 65% vs 40% (FUL naïve) with 80% power, 1 sided 0.05 alpha, was used. Secondary endpoints included progression free survival (PFS) and adverse events (AEs). Serial blood samples were analyzed for circulating tumor DNA (ctDNA) by Guardant360 for concomitant mutations, HER2mut variant allele frequency (VAF) dynamics, and resistance mechanisms. Results: Between Sep. 2015 and Oct. 2020, 40 pts with HER2mut MBC were enrolled, completing the 1st stage of each ER+ cohort. 35 pts (21 FUL treated, 10 FUL naïve, 4 ER-) were evaluable for response, with median age 63 (35-82) years, 3 (0-12) prior MBC regimen, lobular BC in 13 (37%) and visceral mets in 32 (91%) pts. 21 (68%) ER+ pts had prior CDK4/6 inhibitor. All but 1 pt has come off study due to PD. Table 1 shows the efficacy by cohort. Further enrollment is closed per protocol. Adding trastuzumab at PD induced CB in 4 (3 PR, 1 SD≥24 wks) of 5 pts (1 ER-, 4 ER+), with PFS 28 (95% CI 18~NA) wks. Common AEs across cohorts were diarrhea (G3 21%) and fatigue (G3 5%). No G4 AEs. ctDNA HER2mut was detected in 72% (23/32) baseline (BL) samples tested. In pts with paired samples, HER2mut VAF decreased at C1D15/C2D1 from BL in 75% (15/20) and rose in 89% (16/18) at PD. Acquired HER2mut, including the T798I gatekeeper mutation, were detected in 2 pts at PD. Mutations in TP53 (53%), PIK3CA (43%), and CDH1 (35%) were common, but none significantly associated with PFS in all or ER+ pts. Conclusions: NER, or N+F, is active for HER2mut MBC with good tolerability. Adding trastuzumab at PD induced further response, supporting dual HER2 blockade for HER2mut MBC. Table 1.EfficacyCohortFUL treatedFUL naïveER-Best Response, n evaluablen = 21n = 10n = 4CR, n100PR, n431SD (≥ 24 wks), n300SD (< 24 wks), n1030PD, n343CBR, n with CB/total n evaluable, % (95% CI)8 of 20*, 40% (19~64%)3 of 10, 30% (7~65%)1 of 4, 25% (0.6~81%)mPFS (95% CI), wks, ITT (n)24 (16~31) wks, (n = 24)20 (8~NA) wks, (n = 11)8.5 (8~NA) wks, (n = 5)*20 of 21 pts are evaluable for CBR in the FUL treated Cohort as 1 pt had SD as best response and treatment is still ongoing. ITT (intent to treat) population is used for mPFS estimate. Citation Format: Cynthia X. Ma, Jingqin Luo, Rachel A. Freedman, Timothy Pluard, Julie Nangia, Janice Lu, Frances Valdez-Albini, Melody Cobleigh, Jason Jones, Nancy U. Lin, Eric Winer, P. Kelly Marcom, Shana Thomas, Jill Anderson, Brittney Haas, Kimberly M. Hamann, Richard Bryce, Alshad S. Lalani, Lisa Carey, Matthew Goetz, Feng Gao, Gretchen Kimmick, Mark Pegram, Matthew J. Ellis, Ron Bose. A phase II trial of neratinib (NER) or NER plus fulvestrant (FUL) (N+F) in HER2 mutant, non-amplified (HER2mut) metastatic breast cancer (MBC): Part II of MutHER [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT026.

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

Summary Background The antibody–drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. Methods EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m 2 self-administered orally twice daily on days 1–14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1–21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Findings Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3–34·1] vs 25·9 months [95% CI 22·7–28·3]; hazard ratio 0·75 [95% CI 0·64–0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5–26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar–plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]). Interpretation This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population. Funding F Hoffmann-La Roche/Genentech.

Background: Human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAb) are the standard of care in early-to-advanced HER2+ breast cancer. However, for relapsed/refractory disease, limited options exist after progression on trastuzumab (T), pertuzumab (P), and ado-trastuzumab emtansine. Margetuximab (M) is an Fc-engineered anti-HER2 mAb that targets the same epitope as T and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both 158V (high binding) and 158F (low binding) alleles of the activating Fc receptor, CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than T. M also potentiates adaptive immunity in treated patients (pts), including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses. SOPHIA (NCT02492711) is a phase 3 trial that demonstrated the benefit of M vs T, both with chemotherapy, in pts with HER2+ metastatic breast cancer (MBC). This trial is the first prospective analysis of the effect of CD16A genotype on anti-HER2 antibody efficacy. Methods: Pts with disease progression after at least 2 lines of anti-HER2 therapy, including P, and 1-3 lines of therapy for HER2+ MBC were randomized 1:1 to chemotherapy + either M (15 mg/kg intravenously every 3 wk) or T. Randomization was stratified by number of metastatic sites (≤2, >2), lines of treatment for MBC (≤2, >2), and chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Primary endpoints were central-blinded review of progression-free survival (PFS) and overall survival (OS). The first interim OS analysis at time of PFS analysis (October 10, 2018) was immature, with 158 of 385 deaths (41%) needed for final OS analysis. The stopping boundary was not crossed. A second interim OS analysis was planned after 270 deaths and will be reported here. Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; H, 270). M + chemotherapy prolonged PFS vs T + chemotherapy (median PFS, 5.8 vs 4.9 mo; hazard ratio [HR], 0.76; 95% confidence interval [CI]: 0.59-0.98; P=0.033). Results were more pronounced in pts with CD16A genotypes containing a 158F allele (median PFS, 6.9 vs 5.1 mo; HR, 0.68; 95% CI: 0.52-0.90; nominal P=0.005). OS at the first interim analysis demonstrated a HR (95% CI) of 0.95 (0.69-1.31) for the ITT population (n=536) and an HR of 0.82 (95% CI: 0.58-1.17) for the CD16A/FF or FV genotype population (n=457). Grade ≥3 adverse events (AEs) occurred in 138 pts (52%) receiving M vs 128 pts (48%) receiving T. Serious AEs were seen in 39 (15%) receiving M vs 46 (17%) receiving T. The second planned interim analysis of OS (at n=270), as well as updated safety, will be presented. Conclusions: M + chemotherapy in pts with treated HER2+ MBC improves PFS vs T. Safety was comparable. CD16A genotyping suggests a greater benefit in pts with a 158F allele. Maturing data comparing the OS of pts treated with M vs T with chemotherapy will provide important new insights in characterizing clinical activity of this regimen in pts with MBC. Citation Format: Hope S. Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Thomas Bachelot, Gail S. Wright, Michelino De Laurentiis, Peter A. Kaufman, Timothy Pluard, Francesco Ricci, Lupe G. Salazar, Denise A. Yardley, Sutton Edlich, Shengyan Hong, Edwin Rock, William J. Gradishar, SOPHIA Study Group. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival 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 GS1-02.

Background We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2–positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study. Methods Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS. Results A total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26–0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS. Conclusion Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor. Clinical trial registration numbers NCT02771795 (EudraCT 2015-005663-17).

PURPOSE To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

1043 Background: Tucatinib (TUC) is an oral tyrosine kinase inhibitor (TKI) highly specific for HER2. TUC is approved for use in combination with trastuzumab (T) and capecitabine (C) in patients (pts) with and without brain metastases (BM) who have received 1 or more prior anti-HER2–based regimens in the metastatic setting. In the primary analysis from the pivotal HER2CLIMB trial, the addition of TUC to T and C in pts with HER2+ metastatic breast cancer showed a statistically significant and clinically meaningful prolongation of progression-free (PFS) (HR = 0.54 [95% CI: 0.42, 0.71]; P < 0.001) and overall survival (OS) (HR = 0.66 [95% CI: 0.50, 0.88]; P = 0.005) (Murthy, et al. NEJM 2020). TUC in combination with T and C was well tolerated with few discontinuations other than for disease progression. Based on these data, the protocol was amended for unblinding of sites to treatment assignment to allow for crossover from the placebo arm to receive TUC in combination with T and C. Methods: HER2CLIMB (NCT02614794) is a global, randomized, double-blind, placebo-controlled trial in pts with unresectable locally advanced or metastatic HER2+ breast cancer previously treated with T, pertuzumab, and T-emtansine (T-DM1), including pts with untreated, treated stable, or treated and progressing BM. Overall 612 pts were randomized 2:1 to receive TUC 300 mg BID or placebo, each in combination with T and C. Randomization was stratified by BM, ECOG performance status, and geographic region. Protocol prespecified analysis of OS, PFS (by investigator assessment) and safety in the total study population will be performed at approximately 2 years from the last patient randomized. Results: Updated Kaplan-Meier time-to-event analysis of OS and PFS with hazard ratios and 95% confidence intervals for TUC arm vs placebo arm will be presented overall, as well as for OS in the prespecified subgroups reported previously (Murthy, et al. NEJM 2020). Safety and tolerability assessments will include frequency of adverse events by severity, dose modifications and discontinuation of study medications. Conclusions: Conclusions will be presented in the presentation. Clinical trial information: NCT02614794 .

Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, degrades the ER, and delays tumor proliferation in preclinical models. Preliminary results from Part 1 dose escalation (200-1000 mg once daily) demonstrated that rintodestrant has a favorable safety profile and encouraging antitumor activity in patients (pts) with heavily pretreated ER+/HER2- advanced breast cancer (ABC) (Dees et al., ESMO 2019 [abstract #3587]). Here, we report the pharmacodynamic (PD) analysis in peripheral blood and tumor biopsies from pts who received rintodestrant in Part 1 and 2 (600 and 1000 mg dose expansion) to characterize the pt population and mechanisms of response. Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant in women with ER+/HER- ABC after progression on endocrine therapy. PD analysis included inhibition of ER target engagement with 18F-fluoroestradiol positron emission tomography (FES-PET), mutational profiling (cell-free DNA [cfDNA]), and circulating tumor cell (CTC) enumeration. Tumor biopsies sampled at baseline and 6 weeks on treatment were evaluated for ER degradation (immunohistochemistry [IHC]) and proliferation (Ki67, IHC) to understand the on-target effects of rintodestrant. Results: As of May 13, 2020, 67 pts had been treated. FES-PET data were obtained in 14 pts and showed a decrease in all pts, with maximum standard uptake values (SUVmax) ranging from 70% to 98% after 4 weeks of rintodestrant monotherapy across all doses. Fifty-nine pts were tested for cfDNA at baseline; 95% (n = 56) harbored ≥1 somatic variant (median = 3 mutations per pt). Among pts with somatic variants, 41% had ESR1 mutations, with D538G being the most common (58%). Additionally, 46% and 42% of pts harbored mutations in TP53 and PIK3CA, respectively, and 10% had mutations in both ESR1 and PIK3CA. Similar clinical benefit rates were observed in wild-type vs ESR1 and/or PIK3CA mutant tumors. An analysis of change of variant allele fraction (VAF) in 55 pts between baseline and 2 weeks of treatment revealed that 58% had a decrease in mean VAF, with a decrease in ESR1 VAF in 16/20 pts that had ESR1 mutations at baseline. Furthermore, of 24 pts who had samples collected at baseline and progression, 16 (67%) developed additional variants (median [range]: 2 [1, 15]), including EGFR, ERBB2, TP53, and ESR1. CTC analysis (n = 45) showed the mean value of Epi+CD45- CTCs decreased from 2.8 cells/mL to 1.8 cells/mL after 8 weeks of treatment. Tumor biopsies were collected in 9 pts (5 received 600 mg and 4 received 1000 mg) at baseline and 6 weeks on treatment. Of the 7/9 pts that had a decrease in the ER H-score (median [range]: -27.8% [-33.8%, -3.4%]), 4 had ≥1 variant in ESR1 at baseline. Overall, 4 pts had a decrease in Ki67, with reductions mostly observed in pts who received 600 mg rintodestrant. Additional analyses, including correlations with clinical response, are ongoing and will be presented. Conclusions: Rintodestrant demonstrated robust ER target engagement on FES-PET, as well as substantial decreases in ER H-score, cfDNA VAF, and Epi+CD45- CTCs. These data, along with promising clinical benefit in pts with heavily pretreated ER+/HER2- ABC, regardless of ESR1 or PIK3CA mutation status, warrant additional investigation of rintodestrant (NCT03455270). Citation Format: Philippe Aftimos, Marina Maglakelidze, Andor WJM Glaudemans, Erika Hamilton, Linnea Chap, Elisabeth de Vries, Catharina Willemien Menke-van der Houven van Oordt, Agnes Jager, E. Claire Dees, Massimo Cristofanilli, Mark Pegram, Susanna Ulahannan, Patrick Neven, Iurie Bulat, Ruhi Rai, Wenli Tao, Sarika Jain, Andrew P Beelen, Jessica A Sorrentino. Pharmacodynamic analysis from a phase 1 study of rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [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 PD8-07.

Objectives: The key objectives of CONTESSA are to evaluate the efficacy and safety of tesetaxel plus a reduced dose of capecitabine as an all-oral regimen versus capecitabine alone in patients with HER2-, HR+ MBC previously treated with a taxane. Rationale: Tesetaxel is a novel, oral taxane with several properties that make it unique, including: oral administration with a low pill burden; a long (8-day) terminal plasma half-life in humans, enabling infrequent, once-every-3 weeks (Q3W) dosing; no observed hypersensitivity reactions; and significant activity against chemotherapy-resistant breast cancer cell lines. More than 1,000 patients have been treated with tesetaxel in clinical studies. Tesetaxel had encouraging monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% and median progression-free survival (PFS) of 5.4 months (Seidman et al, 2018 ASCO Annual Meeting). Methodology: CONTESSA is a multinational, multicenter, randomized (1:1), Phase 3 registration study comparing tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have received a taxane in the (neo)adjuvant setting. There was no restriction on the disease-free interval following taxane therapy. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA was designed with 90% power to detect a 2.5-month improvement in median PFS (HR=0.71). Secondary endpoints are overall survival (OS), ORR and disease control rate. Results: CONTESSA, which enrolled 685 patients, met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for capecitabine alone, an improvement of 2.9 months [HR=0.716 (95% CI: 0.573-0.895); p=0.003]. ORR was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for capecitabine alone (p=0.0002). OS data are immature. Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia (71.2% vs. 8.3%); diarrhea (13.4% vs. 8.9%); hand-foot syndrome (6.8% vs. 12.2%); febrile neutropenia (12.8% vs. 1.2%); fatigue (8.6% vs. 4.5%); hypokalemia (8.6% vs. 2.7%); leukopenia (10.1% vs. 0.9%); and anemia (8.0% vs. 2.1%). TEAEs resulting in treatment discontinuation in ≥1% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia or febrile neutropenia (4.2% vs. 1.5%); neuropathy (3.6% vs. 0.3%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone. Grade 2 alopecia occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. Conclusion: An all-oral regimen of tesetaxel plus a reduced dose of capecitabine significantly improved PFS versus capecitabine alone. Neutropenia was the most frequent Grade ≥3 TEAE. Rates of clinically significant alopecia and neuropathy were low. Citation Format: Joyce O'Shaughnessy, Lee Schwartzberg, Martine Piccart, Hope S. Rugo, Denise A Yardley, Javier Cortes, Michael Untch, Nadia Harbeck, Gail S. Wright, Igor Bondarenko, John Glaspy, Zbigniew Nowecki, Fadi Kayali, Arlene Chan, Christelle Levy, Mei-Ching Liu, Sung-Bae Kim, Julie Lemieux, Alexey Manikhas, Sara Tolaney, Elaine Lim, Andrea Gombos, Agostina Stradella, Mark Pegram, Peter Fasching, Laszlo Mangel, Vladimir Semiglazov, Veronique Dieras, Luca Gianni, Michael A Danso, Jeff Vacirca, Stew Kroll, Joseph O'Connell, Kevin Tang, Thomas Wei, Andrew Seidman. Results from CONTESSA: A phase 3 study of tesetaxel plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane [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 GS4-01.

Introduction T-DM1 is indicated for the treatment of advanced HER2-positive MBC in patients who previously received trastuzumab and a taxane (separately or in combination) based on data from the phase 3 EMILIA study (BO21977/TDM4370g; NCT00829166). In the primary PFS and second interim OS analyses, respectively, T-DM1 significantly improved PFS (median 9.6 vs 6.4 months; HR=0.65; 95% CI, 0.55–0.77; p Methods EMILIA was a randomized, open-label study of patients with centrally confirmed HER2-positive (IHC3+ and/or FISH amplification ratio ≥2.0), unresectable, locally advanced or MBC, previously treated with trastuzumab and a taxane. Patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV every 3 weeks) or X (1000 mg/m2 PO twice daily, days 1–14 every 3 weeks) plus L (1250 mg PO daily). The final OS analysis was to be conducted following 632 events, and these results are descriptive only. Since the OS efficacy boundary (HR Results From Feb 2009 to Oct 2011, 991 patients were randomized to T-DM1 (n=495) or XL (n=496). Patient disposition by the data cutoff (31 Dec 2014) is shown in Table 1. OS was longer with T-DM1 vs XL (median OS 29.9 vs 25.9 months; HR=0.75; 95% CI, 0.64–0.88; p=0.0003). In a sensitivity analysis, which censored crossover patients at the time of switching from XL to T-DM1, the HR was 0.69 (95% CI, 0.59–0.82; p Table 1. Patient disposition. T-DM1 (n=495)XL (n=496)Median treatment duration, months7.6X: 5.3 L: 5.5Median duration of follow-up, months47.841.9Discontinued study, n (%)364 (74)404 (82)Crossover, n (%) Per protocolaNot applicable136 (27)Non-protocol therapybX: 252 (54)X: 53 (11) L: 224 (48)L: 74 (15)aMedian duration of follow-up among per-protocol crossover patients was 24.1 months.bBy investigator choice after study treatment discontinuation; X or L could be given in combination with each other or other agents after progression. Table 2. Safety summary in patients who received ≥1 dose of study treatment.n (%)T-DM1 (n=490)XL (n=488)Grade ≥3 AEs233 (47.6)291 (59.6)Serious AEs91 (18.6)99 (20.3)AEs leading to dose reduction91 (18.6)X: 205 (42.0) L: 98 (20.1) Conclusions This final analysis of EMILIA shows an OS benefit of T-DM1 compared with XL. While median drug exposure was longer with T-DM1 than XL, T-DM1 was associated with fewer grade ≥3 AEs and AEs leading to dose reduction compared with XL. These final OS results confirm that T-DM1 treatment improved survival, even in the presence of treatment crossover, and reaffirm T-DM1 as the standard of care in patients with previously treated HER2-positive MBC. Citation Format: Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop I, Blackwell K, Kang B, Xu J, Green M, Gianni L. Trastuzumab emtansine improves overall survival versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer: Final results from the phase 3 EMILIA study. [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 P4-14-01.

1040 Background: Despite advances, pretreated HER2+ MBC remains incurable with ongoing need for new therapies. Investigational M has similar HER2 binding and antiproliferative effects as T. Relative to T, M Fc engineering increases binding affinity for both variants of activating Fc receptor (FcR) CD16A and decreases affinity for inhibitory FcR CD32B, coordinately activating innate and adaptive immunity. In a Phase 3 (P3) trial, M prolonged PFS over T (Table). Second interim OS results from Sept 2019 also favor M (hazard ratio [HR], 0.89; 95% CI 0.69–1.13; nominal P=0.326). Methods: SOPHIA (NCT02492711), an open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior treatment (Tx) for MBC. Randomization was 1:1 to M (15 mg/kg IV q3w + Ctx) or T (6 [8 for loading dose] mg/kg IV q3w + Ctx), stratified by met sites (≤2, >2), lines of Tx for met disease (≤2, >2), and Ctx choice, including capecitabine (Cap), eribulin (Eri), gemcitabine (Gem), or vinorelbine (Vin). Primary endpoints were central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Results: Investigator chemotherapy choices and results by chemotherapy are shown in the table. Subjects receiving Eri and Gem had the lowest PFS hazards ratios (HRs), favoring M over T, although no statistical significance of individual chemotherapy subgroups was seen. There was variable toxicity among Ctx subgroups, and fewer subjects receiving Cap had Ctx related Grade 3 or higher (>=Gr 3) AEs. In this unblinded study, more subjects on M than T in all subgroups discontinued Ctx while continuing study antibody. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improved PFS over T. Safety was manageable in all Ctx subgroups. Differences among HRs for chemotherapy subgroups may be driven by selection bias and/or sensitivity differences. Clinical trial information: NCT02492711 . [Table: see text]

578 Background: SB3 was approved in the US and EU as a biosimilar of reference trastuzumab (TRZ). Here, we report 4-year cardiac safety and survival outcomes. Methods: After completing neoadjuvant-adjuvant therapy in patients with HER2 positive early breast cancer, patients from selected countries participated in a 5-year follow-up study of a phase III trial (Pivot et al. Eur J Cancer 2019). The aim was to observe long-term cardiac safety and survival. EFS and OS were analyzed in subgroups by ADCC status within TRZ in ad-hoc analyses. Results: Of 875 patients randomized in the phase III trial, 367 patients (SB3, N=186; TRZ, N=181) were enrolled in the follow-up study. The median follow-up was 53 months. During the follow-up, the incidence of asymptomatic significant left ventricular ejection fraction (LVEF) decrease was low (SB3, n=1; TRZ, n=2), with all patients recovering with LVEF ≥ 50%. No cases of symptomatic congestive heart failure, cardiac death, or other significant cardiac condition were reported. 4-year EFS rates were 83.4% for SB3 and 80.7% for TRZ with a HR of 0.77 [95% CI 0.47, 1.27]. 4-year OS rates were 94.3% for SB3 and 89.6% for TRZ with a HR of 0.53 [95% CI 0.24, 1.16]. From ad-hoc analysis, a difference in EFS and OS was seen between Non-drifted TRZ and Drifted TRZ; Difference between SB3 and Non-drifted TRZ was not statistically significant. Conclusions: In a subset of patients from the phase III trial, comparable long-term cardiac safety and survival at 4-year supports biosimilarity between SB3 and TRZ. Ad-hoc analysis results by ADCC status suggest a possible correlation between ADCC and clinical efficacy. Further follow-up is needed. Clinical trial information: NCT02771795 . [Table: see text]

To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice. Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started. Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC. The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

Patients with HER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared with patients treated with chemotherapy alone. Polymorphisms within FCGR2A and FCGR3A are associated with binding affinity of natural killer cells to the IgG1 portion of trastuzumab, and a polymorphism in FCGR2B (I232T) is associated with impaired regulatory activity. The association of these polymorphisms with clinical response among trastuzumab-treated patients is equivocal, with both positive and negative associations. We performed genotyping analysis on the FCGR3A V158F, FCGR2A R131H, and FCGR2B I232T polymorphisms in 1,325 patients from the N9831 clinical trial. Patients in arm A (N = 419) received chemotherapy only. Patients in arms B (N = 469) and C (N = 437) were treated with chemotherapy and trastuzumab (sequentially in arm B and concurrently in arm C). Using log-rank test and Cox proportional hazard models, we compared disease-free survival (DFS) among genotypic groups within pooled arms B/C. We found no differences in DFS between trastuzumab-treated patients who had the FCGR3A 158 V/V and/or FCGR2A 131 H/H high-affinity genotypes and patients without those genotypes. Furthermore, there was no significant interaction between FCGR3A and FCGR2A and treatment. However, there was a difference in DFS for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (P < 0.001), compared with the T carriers who did not (P = 0.81). The interaction between FCGR2B genotype and treatment was statistically significant (P = 0.03). Our analysis did not reveal an association between FcγR high-affinity genotypes and outcomes. However, it seems that the FCGR2B inhibitory gene may be predictive of adjuvant trastuzumab benefit. Cancer Immunol Res; 2(10); 962–9. ©2014 AACR.

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.

580 Background: SB3 is an approved biosimilar of reference trastuzumab (TRZ). At additional 2-year follow-up after completing neoadjuvant and adjuvant treatment, there was a difference in event-free survival (EFS), but no difference in overall survival (OS) between SB3 and TRZ. Upon monitoring quality attributes of TRZ, a marked downward shift in antibody-dependent cell-mediated cytotoxicity activities (ADCC) was observed in TRZ lots with expiry dates from Aug 2018 to Dec 2019. Some of the lots were used in the Phase III study. This is a post-hoc analysis of EFS and OS by ADCC status from a 3-year follow-up to investigate the difference in EFS between SB3 and TRZ. Methods: After completion of neoadjuvant and adjuvant therapy in patients with HER2 positive early breast cancer, patients from selected countries participated in a 5-year follow-up study (NCT02771795). Within the TRZ group, patients exposed to at least one shifted ADCC lot and those never exposed to shifted ADCC lot during neoadjuvant period were considered as “Exposed” and “Unexposed,” respectively. EFS and OS after 3-year follow-up was analyzed by ADCC status in the long-term follow-up set. Results: 367 patients (SB3, N = 186; TRZ, N = 181) were enrolled in the follow-up study. Within TRZ, 55 patients were Unexposed and 126 patients were Exposed. At a median follow-up duration of 40.8 months in SB3 and 40.5 months in TRZ, 3-year EFS rates were 92.5% in SB3, 94.5% in Unexposed, and 82.5% in Exposed and OS rates were 97.0%, 100%, and 90.6%, respectively. Exposed was associated with decreased EFS compared to Unexposed (HR 0.14, 95% CI 0.04-0.51, p= 0.003). There was a trend of decreased OS in Exposed compared to Unexposed, however, there was no significant difference (HR 0.14, 95% CI 0.02-1.15, p= 0.068). Between SB3 and Unexposed, no difference was observed in EFS (HR 1.06, 95% CI 0.33-3.44, p= 0.923), or OS (HR 0.54, 95% CI 0.05-5.44, p= 0.600). Conclusions: Within the TRZ group, Exposed showed significantly lower EFS compared to Unexposed, and a similar trend was observed in OS with no statistical significance. Between SB3 and Unexposed, no significant difference in EFS or OS was observed. Clinical trial information: NCT02771795.

1000 Background: Pretreated HER2+ MBC lacks a defined standard of care, although T is commonly used. M has similar HER2 binding and antiproliferative effects as T. By contrast, M’s Fc region is engineered to increase affinity for both alleles of the activating Fc receptor (FcR), CD16A, and decrease affinity for the inhibitory FcR, CD32B. The low affinity CD16A-158F allele (~85% of population) has been associated with diminished clinical response to T. In a Phase 1 trial, M demonstrated acceptable safety, anti-tumor activity, and evidence of HER2-specific antibody and T-cell responses. Methods: SOPHIA (NCT02492711), a randomized, open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior Tx for MBC. Pts were randomized 1:1 to M (15 mg/kg IV q3w + C) or T (6 [8 for loading dose] mg/kg IV q3w + C), stratified by met sites (≤2, > 2), lines of Tx for met disease (≤2, > 2), and C choice (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). Primary endpoints are central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Objective response rate (ORR) was a secondary endpoint. 257 PFS events were required to provide 90% power to show PFS superiority at 2-sided α = 0.05. Results: Intent-to-treat analysis (536 pts: M 266; T 270) occurred after 265 PFS events. M prolonged PFS over T (median 5.8 vs 4.9 mo, hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P= 0.033). Treatment effects were more pronounced in pts with CD16A genotypes containing a 158F allele (median PFS 6.9 vs 5.1 mo, HR, 0.68; 95% CI, 0.52–0.90; P= 0.005). In 524 pts with baseline measurable disease (M 262; T 262), ORR was higher with M (22%; 95% CI, 17.3-27.7%) vs T (16%; 95% CI 11.8-21.0%). Safety profiles were comparable in 529 pts who received study therapy. Grade ≥3 AEs and serious AEs occurred in 138 (52%) and 39 (15%) vs 128 (48%) and 46 (17%) pts on M vs T, respectively. PFS data cutoff: 10/10/18. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improves PFS over T with comparable safety. CD16A genotyping suggests a differential benefit in patients with a 158F allele. OS data are maturing. Clinical trial information: NCT02492711.

TPS1107 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing regimen; no observed hypersensitivity reactions; preclinical evidence of CNS penetration; and improved activity against chemotherapy-resistant tumors. Over 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a Phase 2 study in 38 pts with HER2-, HR+ MBC who received T Q3W, with a confirmed ORR per RECIST 1.1 of 45% and median PFS of 5.4 mo. The confirmed ORR in taxane-pretreated pts was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine (C) in combination with a taxane may result in reduced toxicity without reduction in efficacy. Preclinical data also suggest that T may penetrate the brain at clinically relevant concentrations. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ LA/MBC, with revised eligibility criteria to allow inclusion of pts with CNS metastases. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ LA/MBC previously treated with a taxane in the (neo)adjuvant setting. The protocol was newly amended to allow pts with known CNS metastases. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR, and disease control rate. Enrollment began in Dec 2017. Following review in Jan 2019, the Independent Data Monitoring Committee recommended that the Study continue as planned. Clinical trial information: NCT03326674.

Introduction The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor properties of trastuzumab (H) with the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged PFS and OS vs standard therapy in a phase 3 study of patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with H and a taxane. Preclinical data suggest synergy when T-DM1 is combined with paclitaxel (T) or pertuzumab (P). In the phase 1b study TDM4652g, the maximum tolerated doses of T-DM1 + T ± P were defined. Here we present results from the phase 2a expansion, which further explored feasibility and safety. Methods TDM4652g is a phase 1b/2a open-label study of pts with HER2-positive locally advanced or MBC. Pts had no prior T-DM1 or P, no baseline peripheral neuropathy (PN; phase 2a only), and had LVEF ≥50%. Pts in phase 2a were randomized to T-DM1 3.6 mg/kg q3w + T 80 mg/m2 qw ± P 840 mg loading dose [LD], then 420 mg q3w. The primary objective, feasibility, was assessed by the percent of evaluable pts receiving ≥12 doses of T within 15 weeks of cycle 1, day 1, and those receiving 12 consecutive weeks of T. Results Forty-four pts were enrolled (T-DM1 + T, n = 22; T-DM1 + T + P, n = 22); the data snapshot date was May 23, 2013. Median age was 52.5 years (range, 35–81); median number of prior agents for MBC was 6 (range, 0–12). 43 (98%) pts had previously received H, and 36 (82%) pts had received taxane therapy. Median dose intensities were T-DM1, 94% (range 54–105); T, 50% (range 9–100) and P, 100% (range 67–100). 2 pts were not evaluable for feasibility (progressive disease [PD] before receiving 12 doses of T). 21/42 (50%) pts received ≥12 doses of T within 15 weeks; 6/42 (14%) pts received 12 consecutive doses by week 12, and 33/42 (79%) pts received ≥8 doses within 12 weeks. Grade 3/4 adverse events (AEs) were reported for 18 (82%) and 17 (77%) pts in the T-DM1 + T and T-DM1 + T + P groups, respectively (see Table for AEs and best responses). Ten pts discontinued early due to PD (n = 6), PD-related death (n = 2), AEs (n = 1), or withdrawal from the study (n = 1). 21 pts discontinued T due to AEs, most commonly PN (n = 12). Grade 3/4 AEs occurring in >1 patientAE, n (%)All patients (N = 44)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw (n = 22)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw + P 840 mg LD, 420 mg q3w (n = 22)Neutropenia10 (23)6 (27)4 (18)Peripheral neuropathy9 (20)3 (14)6 (27)Fatigue6 (14)3 (14)3 (14)Thrombocytopenia6 (14)5 (23)1 (5)Anemia3 (7)2 (9)1 (5)Abdominal pain2 (5)2 (9)0Decreased hemoglobin2 (5)1 (5)1 (5)Muscosal inflammation2 (5)1 (5)1 (5)Muscular weakness2 (5)02 (9)Nausea2 (5)1 (5)1 (5)Best response,* n (%)CR2 (5)1 (5)1 (5)CR confirmed1 (2)1 (5)0PR27 (61)13 (59)14 (64)PR confirmed8 (18)3 (14)5 (23)SD10 (23)6 (27)4 (18)PD3 (7)1 (5)2 (9)*At any time point with responses ordered CR>PR>SD>PD. Conclusions Overall, 50% of pts received ≥12 doses of T within 15 weeks. Adding P to the combination of T-DM1 + T did not appear to increase the incidence of grade 3/4 AEs. Data support further investigation of T-DM1 + T ± P in larger studies in early breast cancer. Final data from all phase 2a patients will be available for the full report. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-09.

ERBB2 gene amplification occurs in ∼20% of human breast cancers (BC) and is associated with an adverse clinical prognosis, indicating that it may be playing a critical role in disease pathogenesis. Therapeutic strategies targeting pathologic ERBB2 overexpression have revolutionized the diagnosis and treatment of BC. Indeed, humanized anti-ERBB2 antibodies, small molecule ERBB2 kinase inhibitors and ERBB2-targeting antibody-drug conjugates have proven safety and efficacy based upon evidence from randomized phase III clinical trials. Recent progress in targeting ERBB2 alteration will be reviewed, with focus on data that has informed changes in clinical practice for the treatment of BC.

Triple-negative breast cancers comprise about 20 % of breast cancers. They have poor prognosis and have no standard therapy. The aim of this study was to evaluate pathologic complete response (pCR), progression-free survival (PFS), and overall survival (OS) in patients with TNBC treated with neoadjuvant platinum-based chemotherapy. This is a retrospective study of one hundred and forty-four women with TNBC treated with neoadjuvant platinum-containing chemotherapy for locally advanced breast cancer at the University of Miami between January 1, 1999, and January 1, 2011. The medical record was reviewed to obtain data on clinical characteristics, including ethnicity, race, age, clinical stage, treatment regimen, and vital status. This study was approved by the University of Miami IRB. All patients had locally advanced breast cancer with at least one of the following features at presentation: T3, T4, N2, and N3. The mean tumor size by palpation was 9.4 cm. The clinical T-stage at presentation was 1.4 % T1, 8.3 % T2, 52.8 % T3, and 37.5 % T4 (19.4 % T4d). The nodal status by physical exam at presentation was 23 % N0, 37.5 % N1, 34 % N2, and 5.5 % N3. pCR in breast and axilla was seen in 31 %. PFS and OS were 55 and 59 %, respectively, at 7 years. Cisplatin offered a survival advantage over carboplatin in both PFS (P = 0.007) and OS (P = 0.018). Node positivity was the most important predictor of survival. Cisplatin/docetaxel neoadjuvant therapy was well tolerated and an effective therapy in locally advanced TNB.

The addition of trastuzumab to chemotherapy extends survival among patients with HER2+ breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The current study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pretreatment and posttreatment sera were obtained from 48 women with metastatic HER2+ breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies, N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA, and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically resected HER2+ patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved progression-free survival (PFS; HR = 0.5, P = 0.0042) and overall survival (OS; HR = 0.7, P = 0.038). Augmented antibody responses to HER2-ICD also correlated (P = 0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer PFS (HR = 1.6, P < 0.0001) and OS (HR = 1.4, P = 0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. Cancer Res; 76(13); 3702–10. ©2016 AACR.

Background Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)–targeted antitumor properties of tras tuz u mab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. Methods We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with tras tuz u mab and a taxane, to T-DM1 or la pa ti nib plus cap e ci ta bine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. Results Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with la pa ti nib plus cap e ci ta bine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P

Trastuzumab improves response rate, time to progression, and overall survival when combined with first-line chemotherapy in patients with human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer (MBC). However, the benefits of continuing trastuzumab beyond disease progression have not been clearly established. The literature was reviewed to obtain data on trastuzumab use beyond disease progression. In general, data from retrospective and observational studies suggest that there may be clinical benefit when trastuzumab is used beyond disease progression. These results are supported by prospective non-randomized studies. Response rates and survival outcomes have generally been superior in patients who have continued trastuzumab after disease progression compared with those who have not. Moreover, recent data from two prospective randomized phase III trials have shown that adding trastuzumab to the treatment regimen in patients with MBC who have progressed on trastuzumab-based therapy significantly prolongs progression-free survival. Emerging evidence from randomized controlled trials supports the potential clinical utility of continuing trastuzumab-based therapy beyond progression and supports the National Comprehensive Cancer Network recommendation to consider this treatment approach. Future treatment of HER2-positive MBC may involve trastuzumab being used in successive regimens in combination with other targeted therapies.