HER2-positive Advanced Breast Research Articles

Pyrotinib plus nab-paclitaxel in patients with HER2-positive advanced or metastatic breast cancer: A multicenter, single-arm, open-label phase 2 trial.

1035 Background: For human epidermal growth factor receptor 2 (HER2) positive advanced or metastatic breast cancer, the standard therapeutic strategy is HER2-targeted agents combined with a taxane. This multicenter, single-arm phase 2 trial was designed to assess the efficacy and safety of pyrotinib (a brand-new generation, irreversible anti-HER2 tyrosine kinase inhibitor) plus nab-paclitaxel in patients with HER2-positive advanced or metastatic breast cancer. Methods: This was a multicenter, single-arm, open-label phase 2 trial conducted at seven centers in China (ChiCTR1900023653). Women aged 18-75 years, with histologically or cytologically confirmed HER-2 positive (immunohistochemistry [IHC] 3+ or positive confirmed by fluorescence in situ hybridization) advanced or metastatic breast cancer and with Eastern Cooperative Oncology Group performance score (ECOG PS) of 0-1 were enrolled. Patients with primary resistance to trastuzumab and bone-only metastases were excluded. Eligible patients received pyrotinib (400 mg, po, qd) plus nab-paclitaxel (125 mg/m2, iv, day 1/8/15) for each 28-day cycle until disease progression, unacceptable toxicity, consent withdrawal or death. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, safety and quality of life. Results: Between December 2019 and December 2021, 51 patients were enrolled. The median age was 55 years (range 35–72). Twenty-three patients (45.1%) had ECOG PS of 0. Ten patients (19.6%) with metastatic disease had previously received first-line treatment and 28 (54.9%) had received prior treatment with trastuzumab. More than half (29 of 51, 56.9%) had hormone receptor-positive disease. Visceral metastases occurred in 56.9% of the patients (29 of 51) and 26 patients (51.0%) were menopausal. The data cutoff for the present analysis was January 21, 2022. Among 38 evaluable patients, four patients (10.5%) had CR, 27 (71.1%) had PR, six (15.8%) had stable disease, and one (2.6%) had progressive disease. The confirmed ORR was 81.6% (95% CI 65.1-91.7%). The PFS data were still immature. The most common grade ≥3 treatment-emergent adverse events included neutropenia (14 of 51, 27.5%), diarrhea (10 of 51, 19.6%), fatigue (5 of 51, 9.8%) and peripheral neuropathy (4 of 51, 7.8%). Conclusions: Pyrotinib combined with nab-paclitaxel showed a promising antitumor activity with good tolerance in patients with HER2-positive advanced or metastatic breast cancer. Clinical trial information: ChiCTR1900023653.

A real-world experience of TCH (docetaxel/carboplatin/trastuzumab) regimen in early, locally advanced and oligometastatic HER2 positive breast cancer from tertiary care center in North India.

e12505 Background: In HER2 positive breast cancer, TCH is a safe and efficacious anthracycline free regimen used as both adjuvant and neoadjuvant modality. Three is scarcity of data regarding its long term safety and efficacy from India. Methods: This retrospective study comprised of 210HER2 positive breast cancer female patients treated with TCH [docetaxel (75mg/m2), carboplatin (AUC=6) and trastuzumab (8mg/kg loading followed by 6mg/kg) q 21 days with GSF prophylaxis] protocol for 6 cycles at our centre between Jan 2014 and Dec 2021. All eligible patients received maintenance trastuzumab, hormonal therapy and radiotherapy as per institutional protocol. The information regarding baseline clinico-demographic characteristics, treatment details, outcomes and toxicities were collected and evaluated. Results: The median age was 49 years (23-72), 113 (53.8%) were post-menopausal and 100 (47.6%) were Estrogen receptor/Progesterone receptor positive. Sixty-eight (32.4%) patients were stage I and II, 112 (53.3%) stage III and 30 (14.3%) were oligometastatic. TCH regimen was given as neoadjuvant chemotherapy (NACT) in 130 (61.9%) patients and as adjuvant chemotherapy in 80 (38.1%) patients. Of the patients receiving NACT, 114 (87.6%) patients underwent surgery. Twenty-two (19.3%) patients underwent breast conservation surgery and 92 (80.7%) underwent modified radical mastectomy. Over the study period, 62 (29.5%) patients had progression of the disease and 22 (10.5%) patients died. With a median follow up of 31.9 months, 3-year disease free survival (DFS) was 63.5% and overall survival (OS) was 90.8%. Median DFS was 31 months in patients with node positive disease and was not reached in patients with node positive disease. Of the patients who received NACT, pathologic complete response (pCR) was recorded in 42 (36.8%) patients. Three-year DFS was 59.1% in patients who achieved pCR and 44.8% in those who did not achieve pCR. Any grade 3/4 toxicity was seen in 26.7% patients which caused dose modification in 13.9% patients. The most common grade 3/4 hematological toxicity was anemia (15.1%) and thrombocytopenia (10.4%), while non-hematological toxicity was diarrhea (11.6%). Febrile neutropenia was seen in 4 (1.9%) patients. Four patients (1.9%) had reversible decrease in cardiac left ventricular ejection fraction. Conclusions: Anthracycline free TCH regimen is an effective and safe regimen for use in curative (adjuvant and neoadjuvant) setting for HER2 positive breast cancer in Indian women with outcomes comparable to the anthracycline based regimens reported in literature.

Abstract P1-18-34: Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort

Abstract Background The combination of HP and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2+ ABC. PIK3CA mut can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mut had a shorter PFS. The AKT inhibitor IPAT blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. Patients and Methods IPATHER (NCT04253561) is an open-label, single-arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP in patients with HER2+ ABC with a PIK3CA-mut (detected in tissue or plasma ctDNA in a Central Laboratory) who are candidates to receive maintenance HP after taxane discontinuation in the first line setting for a reason different to progressive disease. The primary objective is to characterize the safety and tolerability of IPAT in combination with HP, and to identify a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The study has two phases: a dose safety phase and a dose expansion phase. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. DLT during first 28 days of therapy is defined as grade ≥3 diarrhea lasting more than 72 hours, grade ≥2 diarrhea lasting more than 5 days, and other non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy. Given the low risk for overlapping toxicities, the first cohort of the dose safety phase tested IPAT at 400 mg orally once daily D1-21 q28d and standard dose HP. Dose level -1 and -2 of IPAT were 300 mg and 200 mg in case dose de-escalation was needed. Loperamide was given as prophylaxis for diarrhea. In HR-positive tumors, endocrine therapy could be started after the DLT period. Here, we present the results of the dose safety phase of IPATHER. Results A total of 6 female patients with PI3KCA-mut/HER2+ ABC were included in the first dose safety cohort. Median age was 52 (41-78), most patients had ECOG 0 (66.6%), and 50% were postmenopausal. Five out of six patients (83.3%) had HR-negative tumors and visceral metastases. Patients received a median of 6 treatment cycles (range 4-7) with taxane plus HP. At the time of the data cut-off (28/02/2021), all the patients remained on treatment. Median follow up is 4 months (range 2-12). Treatment was well tolerated with no DLTs or grade 3/4 adverse events (AEs) observed during the DLT period or the rest of treatment period (Table 1). The most common treatment-related AEs were diarrhea (N=5, [83.3%]) and nausea (N=2,[33.3%]), mostly grade 1. There was no dose reduction and diarrhea was controlled with prophylactic loperamide. A partial response (PR) was observed in one patient, and 5 had stable disease. Of note, the addition of IPAT to HP in the patient with a PR deepened the response achieved during the induction phase with chemotherapy plus HP. Conclusion IPAT 400 mg orally once daily D1-21 q28d in combination with HP is well tolerated and has shown preliminary signs of efficacy. Given the favourable safety profile, the dose expansion phase testing IPAT 400 mg in combination with HP has started and will include 19 additional patients. Table 1.Adverse Events during treatment period related with study treatment (IPAT and/or HP).Adverse EventN AEsN patientsGrade 1Grade 2% (N=6)Diarrhea55 (83%)5083%Nausea32 (33%)2033Vomiting21 (17%)1017Anemia11 (17%)1033Lymphopenia11 (17%)1033Gastroesophageal reflux11 (17%)0117Dyspepsia11 (17%)1017Hyporexia11 (17%)1017 Citation Format: Mafalda Oliveira, Eva Ciruelos, Serafín Morales, Joaquín Gavilá, Vanesa Quiroga, Estela Vega, Javier Salvador Bofill, Alexandra Cortegoso, Fernando Henao, Pablo Tolosa, Jordi Canes, Patricia Villagrasa, Xavier Gonzalez Farré, Tomás Pascual, Cristina Saura. Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-34.

Abstract OT2-19-05: A phase I/II trial of abemaciclib and T-DM1 in women and men with HER2-positive advanced or metastatic breast cancer that has progressed on treatment with a taxane, trastuzumab and pertuzumab (THP) (ACCRU-BR-1801)

Abstract Background: Although major advances have been made in the treatment of HER2+ metastatic breast cancer (MBC), the goal of care remains largely palliative, therefore better treatments are needed. Given encouraging preclinical and clinical data, the combination of cyclin dependent 4/6 kinase inhibitors and HER2-directed therapy is further being evaluated in this trial. Trial Design: In this phase I/II multicenter trial, we will determine the maximum tolerated dose (MTD) of abemaciclib (Abem) combined with T-DM1. Three Abem dose levels will be examined, 50 mg, 100 mg and 150 mg. The phase 2 portion of this trial will examine whether PFS is increased with addition of Abem to T-DM1 in two pt cohorts - those with ER+ HER2+ MBC and those with ER-HER2+ MBC. For phase 2, a pre-registration biopsy is required to confirm ER and HER2-status and to determine levels of tumor infiltrating lymphocytes; vimentin (an epithelial-mesenchymal transition marker); and CD8 and FOXP3 expression. Blood samples will be collected pretreatment , at 6 weeks, and at progression for all pts. Eligibility Criteria: Phase I&II: All pts must have HER2+ MBC per ASCO-CAP guidelines and prior treatment with a taxane, trastuzumab and pertuzumab. For the phase Iportion, pts can have measurable or non-measurable disease with no restriction on the number of prior lines of therapy. In the phase II portion, pts must have measurable disease with ≤1-2 prior lines of chemotherapy alone, ≤1 HER2-directed therapy alone, and/or chemotherapy with HER2-directed therapies. There is no limit on prior endocrine therapy. Specific Aims: The primary objective of the phase II trial is to assess whether addition of Abem to T-DM1 increases PFS in one or both patient cohorts. Secondary objectives include an assessment of toxicity, objective response rates and overall survival. Correlative studies will assess the association between baseline TIL levels, vimentin expression, and CD8/FOXP3 expression with PFS. Changes in peripheral blood mononuclear cells, CTCs, ctDNA and serum thymidine kinase 1 during the course of treatment will be examined to determine if there is a link with PFS outcomes overall and separately for each cohort. Pharmacogenomic studies will determine if pts with the FCGR3A-158 polymorphism derive less benefit from T-DM1 and have inferior PFS outcomes compared with pts who do not have this polymorphism. Statistical Methods:Phase I: Standard 3+3 design, with dose limiting toxicities as per protocol. Phase II: For each pt cohort, a stratified randomization scheme will be used to assign pts to treatment with liver mets as a stratification factor. For each pt cohort, a stratified log rank test will be used to assess whether PFS is increased with the addition of Abem to T-DM1. A non-binding futility analysis will be applied in each cohort after 58 events in the ER+ HER2+ MBC study cohort and 48 events in the ER- HER2+ MBC study cohort. Present Accrual: 0; target accrual: minimal 120 pts., maximal 140 pts CohortOne-sidedalphaPowerAccrual Period (accrual rate)Follow-up after close of enrollmentPFS with T-DM1PFS with abema and T-DM1Number of eligible patientsER+/HER2+0.100.912 months (5-6 pts per month)12 months12 weeks24 weeks64 (32 per arm)ER-/HER2+0.100.8512 months (3-4 pts per month)12 months6 weeks12 weeks50 (25 pts per arm) Citation Format: Ciara C O Sullivan, Jun He, Vera J Suman, Krishna R Kalari, Roberto A Leon-Ferre, Jose C Villasboas-Bisneto, Pratima Chalasani, Demet Gokalp Yasar, Daniel M Anderson, Philip J Stella, Anthony J Jaslowski, Susan H Tannenbaum, Angela Saverimuthu, Donald Northfelt, Alvaro Moreno-Aspitia, Jodi M Carter, Minetta C Liu, Liewei Wang, Zhenkun Lou, Matthew P Goetz. A phase I/II trial of abemaciclib and T-DM1 in women and men with HER2-positive advanced or metastatic breast cancer that has progressed on treatment with a taxane, trastuzumab and pertuzumab (THP) (ACCRU-BR-1801) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-05.

Abstract PS18-13: Men1611 is a pi3k α/β selective and δ sparing inhibitor with long-lasting antitumor activity in different genetic backgrounds of pik3ca mutant breast cancer models

Abstract Dysregulation of the PI3K/AKT/mTOR pathway has the potential to trigger the activation of class I phosphoinositide 3-kinases (PI3Ks) and eventually lead to cancer. Class I PI3Ks are heterodimers composed of the regulatory subunit p85 and the catalytic subunit p110. There are four isoforms of p110, alpha and beta, important in solid tumors, and delta and gamma, preferentially expressed in leukocytes, and drivers in hematological malignancies. While activation of PI3K p110alpha is the most frequent oncogenic event in solid tumors, p110beta plays an important role in PTEN deficient cancers and in mediating resistance to p110alpha selective PI3K inhibitors.MEN1611 is a PI3K inhibitor active on p110alpha (both mutants and wt), beta and gamma (8.6- and 2.2- fold less potent compared to the alpha, respectively), while sparing the delta isoform (36-fold less potent compared to the alpha). Thus, MEN1611 differs from other selective PI3K inhibitors such as alpelisib (p110alpha selective) and taselisib (p110beta sparing). MEN1611 is currently in clinical development for patients with HER2 positive advanced or metastatic breast cancer in combination with trastuzumab with/without fulvestrant (B-PRECISE-01). Patient-derived xenograft (PDX) models and breast cancer cell lines with different genetic background were used to assess the antitumor activity of MEN1611 in p110 alpha- and beta- dependent tumors. Healthy-donors derived CD69+ B-cells, which are primarily dependent on p110 delta for proliferation and survival were used to test the activity of the compound against the p110delta. According to the biochemical selectivity, MEN1611 demonstrated a lower cytotoxic potential in a p110delta-driven cellular model (CD19+ B-cells), when compared to taselisib (>150-fold) and an improved cytotoxic activity in the p110beta-driven cellular model (PTEN-null breast cancer cells) when compared to alpelisib. Moreover, MEN1611 selectively decreases the p110alpha protein levels in PIK3CA mutated breast cancer cells in a concentration-dependent manner, with a corresponding reduction in pAKT. In vivo, MEN1611 monotherapy showed significant and long-lasting anti-tumor activity, reflected in tumor-stasis or tumor regression in several trastuzumab-resistant PIK3CA-mutant HER2 positive PDXs with different concomitant genomic aberrations. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment. Interestingly, MEN1611 monotherapy showed a significant tumor volume inhibition in a PTEN-null breast cancer PDX model. Overall, our data provide evidence that MEN1611 is active against HER2 positive and PTEN-null breast tumors. Moreover, its delta-sparing profile may have potential implications on MEN1611 tolerability and ability to overcome resistance to p110alpha selective inhibitors. Citation Format: Alessio Fiascarelli, Corrado Carrisi, Giuseppe Merlino, Stefania Capano, Diego Bisignano, Simone Talucci, Alessandro Bressan, Daniele Bellarosa, Mario Bigioni, Maurizio Scaltriti, Joaquin Arribas, Andrea Pellacani, Massimiliano Salerno, Monica Binaschi. Men1611 is a pi3k α/β selective and δ sparing inhibitor with long-lasting antitumor activity in different genetic backgrounds of pik3ca mutant breast cancer models [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 PS18-13.

Abstract PS13-12: Apatinib combined with taxanes and platinum neoadjuvant chemotherapy for patients with triple-negative and HER2-positive breast cancer: A multicenter, randomized, open-label, phase II trial

Abstract Background: Apatinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), has demonstrated a promising efficacy in patients with metastatic breast cancer. For triple-negative and HER2-positive subtypes, increasing the pathological complete response (pCR) of neoadjuvant therapy may benefit their clinical outcomes. Here, we assessed whether the combination of Apatinib with neoadjuvant chemotherapy elevate the pCR rate in locally advanced breast cancer. Method: In this multicenter, open-label trial, we randomized 53 patients into TP neoadjuvant chemotherapy (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2 or paclitaxel liposome 175 mg/m2 day 1, and carboplatin AUC=6 or cisplatin 75 mg/m2 or lobaplatin 30 mg/m2 day 1), or combined with apatinib (500mg day 1-21) . Trastuzumab was added to neoadjuvant therapy in HER2-positive subtype. Six cycles were repeated every 3 weeks. Results: In total patients with stage IIb-IIIc triple-negative and HER2-positive breast cancer, the addition of apatinib to TP neoadjuvant chemotherapy (Apa+TP) significantly increased the pCR rate (70.8%, 17/24), compared with TP along (41.4%, 12/29), P=0.032. When separating patients into triple-negative (Apa+TP 66.7% (8/12) vs. TP 42.9% (3/7)) and HER2-positve (Apa+TP 75% (9/12) vs. TP 40.9% (9/22)) subtypes, the effect of apatinib on pCR was also improved though no significant differences were found (P=0.377; P=0.080 separately) compared with control group. The most common Grade 3-4 adverse events (AE) included hypertension (Apa+TP 12.5% vs. TP 0%, P=0.173), hand-foot syndrome (Apa+TP 8.3% vs. TP 0%, P=0.389) and erythra (Apa+TP 4.2% vs. TP 0%, P=0.924). No significant differences of toxic effects were found between Apa+TP and control group. Conclusion: Apatinib combined with TP neoadjuvant chemotherapy significantly increased the pCR rate in patients with locally advanced triple-negative and HER2-positive breast cancer, indicating an applicable strategy in the future. EfficacyTriple-negative breast cancer efficacyHer2-positive breast cancer efficacySafety Citation Format: Yunjiang Liu, Xiangmei Zhang, Li Wang, Miao Cao, Shuo Zhang, Hui Zhang, Yarong Zhou, Jintian Wang. Apatinib combined with taxanes and platinum neoadjuvant chemotherapy for patients with triple-negative and HER2-positive breast cancer: A multicenter, randomized, open-label, phase II trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-12.

Abstract P5-11-13: Outcomes of fulvestrant therapy among Japanese women with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of the JBCRG-C06 safari study

Abstract Background: After the CONFIRM trial, fulvestrant 500 mg (F500) became a standard treatment for patients with estrogen receptor positive (ER+) advanced/metastatic breast cancer (AMBC). The JBCRG-C06 Safari study (UMIN 000015168) showed that earlier F500 use, a longer time from diagnosis to F500 use, and no prior chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with ER+ and HER2-negative AMBC (Kawaguchi H, et al. Breast Cancer Res Treat, 2017; Kawaguchi H, et al. Curr Med Res Opin, 2018). We had carried out subgroup analyses on real world data from the Safari study focusing on ER+ and HER2+ AMBC with the objective to examine further on potential interactions between TTF and the following: F500 single treatment or F500 with anti-HER2 therapy; presence or absence of visceral metastasis; progesterone receptor (PgR) status; and prior chemotherapy for AMBC. Material & methods: The Safari study was a retrospective, multicenter cohort study, conducted in 1072 patients at 16 sites in Japan for ER+ AMBC. Patients starting treatment with F500 between Nov 2011 and Dec 2014 were registered. After the data cleaning through the central review, 94 patients (9.6%) has been included in this sub-analysis among the 978 patients in which HER2 status was confirmed by the documentation. The relationship between baseline clinical/pathological factors, treatment line, and TTF (time from start to cessation of F500 treatment for any reason, including toxicity and death) were analyzed using Kaplan-Meier methods. Univariate analysis of TTF data was performed by Cox hazards model using: age, histological type, histological/nuclear grade, visceral-metastases, stage, PgR, period from AMBC diagnosis to F500 use, treatment line of F500, prior chemotherapy. Results: Median age at diagnosis of AMBC was 57.5yrs (33-85); 59(33-85) and 56.5(39-75) for F500 with/ without anti-HER2 therapy. Median age of fulvestrant start was 61yrs (35-96). 21.3% had de novo metastatic disease; 78.7% recurrent disease; 37.2% visceral metastases. All patients’ ER status was positive, and PgR status was positive in 65.9%, negative 25.5% respectively. HER2 IHC 3+ patients accounted for 44.7%, IHC 2+/1+ for 38.3%. In the case of IHC 2+/1+, HER2-positivity was confirmed by FISH. F500 alone was administered in 52 patients, while F500 with anti-HER2 therapy in 42 patients. At median follow up of 3.9 years, median TTF was 4.4m (95% CI: 3.3-5.7); 3.7m (95% CI: 2.9-5.9), 5.1m(95% CI: 3.6-6.4) for the F500 alone group, F500 with anti-HER2 therapy group respectively (p = 0.5973). F500 with/ without anti-HER2 therapy was administered in 1stor 2nd-line in 20 (21.3%), and ≥3rd-line in 74(78.7%) patients. Median TTF was 6.6m (95% CI: 4.6-8.5) and 3.7m (95% CI: 2.8-5.2) in the 1stor 2nd-line and ≥3rd-line respectively (p value:0.0145). Although no statistically significant difference was found, TTF tended to be shorter in the group receiving chemotherapy prior to F500 (median TTF: 3.7m vs 5.5m). No other clinical parameters including age, PgR status, metastatic sites were associated with the effectiveness. The median OS was 7.8-years (95% CI: 5.9-9.5), which had not been influenced by with/ without anti-HER2 therapy. The toxicity profile we observed was similar to that in the registration trial. Conclusions: Our findings suggest that F500 with/without anti-HER2 therapy appears to be effective also in the ER+ and HER2-positive ABMC setting which is consistent with the limited results previously published. Earlier line use of F500 use may be useful in HER2-positive patients as well as HER2-negative patients. Citation Format: Misato Hagi, Hidetoshi Kawaguchi, Norikazu Masuda, Shigehira Saji, Yutaka Yamamoto, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Daisuke Yotsumoto, Satoshi Morita, Masakazu Toi, Shinji Ohno. Outcomes of fulvestrant therapy among Japanese women with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of the JBCRG-C06 safari 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 P5-11-13.

Abstract P1-18-36: The safety, tolerability, and pharmacokinetics of BAT8001 in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer: An open-label, dose-up, phase 1 study

Abstract Background BAT8001 for injection is a novel antibody-drug conjugate (ADC) that targets HER2, which is composed of trastuzumab analogue (BAT0606) covalently linked to the drug-linker Batansine (a derivative of maytansine, which refers to the 3AA-MDC complex) by a stable thioether bond. Patients and methods In this open-label, phase 1 trial, we recruited 29 patients aged 18 years or older with HER2-positive advanced or recurrent breast cancer who had been previously treated with trastuzumab and/or lapatinib plus cytotoxic agents. Criteria for eligibility included HER2-positivity, having evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received BAT8001 intravenously once every 21 days, with dose escalation in five cohorts: 1.2mg/kg, 2.4mg/kg, 3.6mg/kg, 4.8mg/kg, and 6.0mg/kg. This study used a modified 3 + 3 dose escalation design to evaluate the dose-limiting toxicity (DLT) occurrence in the first cycle. Analyses included all patients who had received at least one dose of study treatment. The primary objective was to establish the safety, tolerability, pharmacokinetics (PKs), immunogenicity of BAT8001 in patients with HER2-positive metastatic breast cancer. The secondary objectives included evaluation of the metabolites and to make a preliminary assessment of the efficacy of BAT8001 for HER2 positive advanced solid tumors. Results Twenty-nine patients were enrolled in this study. The dose-limiting toxicity was grade 4 thrombocytopenia, which occurred in two patients administered of 6.0mg/kg, two patients administered of 4.8mg/kg and one patient administered of 3.6mg/kg BAT8001; thus, the maximum tolerated dose was 3.6mg/kg. The most common adverse event (AE) for any grade was increased aspartate aminotransferase, increased alanine aminotransferase, thrombocytopenia, increased alkaline phosphatase, increased uric acid, neutropenia, diarrhoea, nausea, vomiting, fatigue, and anemia. Grade 3 or greater AE occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhoea in 2 (6.9%) patients, and anemia in 1 (3.4%) patients. Objective responses (all partial responses) were observed in 11 (37.9%) and disease control rate in 24 (82.8%) of 29 patients who were evaluable for anti-tumor activity. The objective response rate and the disease control rate confirmed after 4 weeks was 27.6% and 65.5%, respectively. No pharmacokinetic interaction was observed. The total antibodies of BAT8001 were linearly correlated with the dose range of 1.2 to 6 mg/kg. Conclusions BAT8001 was safe, tolerable and the preliminary activity seems promising in patients with HER2-positive advanced or recurrent breast cancer. The results suggest that BAT8001 has the potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer. Citation Format: Shusen Wang, Ruoxi Hong, Liye Wang, Fei Xu, Wen Xia. The safety, tolerability, and pharmacokinetics of BAT8001 in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer: An open-label, dose-up, phase 1 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 P1-18-36.

Abstract P1-18-19: Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Abstract Background: Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with increased therapeutic efficacy of trastuzumab/pertuzumab-based neoadjuvant therapy (NT) in patients (pts) with HER2-positive breast cancer (BC). Subcutaneous (SC) trastuzumab has non-inferior efficacy to intravenous (IV) administration, with a similar safety profile. Interestingly, SC trastuzumab has been observed to be more immunogenic than IV trastuzumab and act at different immunologic levels. Therefore, by modifying the modality of administration of trastuzumab, it could be possible to interfere with different immune pathways and exert a favorable immunomodulation in HER2-positive BC. Methods: In this non-comparative, phase II, neoadjuvant, randomized study, pts were eligible if they had previously untreated, histologically confirmed, locally advanced, inflammatory, or early-stage HER2-positive BC. Pts were treated with FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) q21 × 3 cycles. Then, they were randomly assigned (1:1) to receive: docetaxel (75 mg/m2) plus pertuzumab (840 mg loading dose (LD), then 420 mg) plus IV trastuzumab (8 mg/kg LD, then 6 mg/kg) q21 × 4 cycles (arm A) or, docetaxel plus pertuzumab plus SC trastuzumab (fixed dose of 600 mg) q21 × 4 cycles (arm B). After surgery, pts received trastuzumab q21 × 14 cycles using the same formulation (SC or IV) of the preoperative phase. The primary endpoint was the rate of stromal TILs (sTILs) on residual disease after surgery. Tumor biopsy and posttreatment surgical samples were centrally analyzed for TILs. Blood samples were also collected during NT for tumor-specific lymphocyte cell activity analysis. Feasibility, efficacy and safety were also evaluated. ClinicalTrials.gov: NCT03144947. Results: Between November 2016 and September 2017, according to an adaptive Simon's two-stage optimal design, we enrolled 65 pts, of whom two were deemed ineligible for the study. Thus, 63 pts (31 in arm A and 32 in arm B) were assessed for the primary and secondary endpoints. The pathologic complete response (pCR; no invasive tumor in breast and axilla) rates were 64.5% (95% CI, 47-81) in arm A, and 59.4% (95% CI, 42-76) in arm B. The most common adverse events of grade 3 or higher were neutropenia (15 [48.4%] pts in arm A, and 11 [34.4%] in arm B), neurotoxicity (1 [3.2%], and 2 [6.2%], respectively), and diarrhea (1 [3.2%], and 1 [3.1%], respectively). There were no events of congestive heart failure. At surgery, 11 pts in arm A and 13 pts in arm B were evaluable for TIL analysis. The median value of sTILs (7.5%) on pre-treatment tumor biopsies was used as the cut-off value, and high sTIL levels were observed in 27.3% and in 46.1% of residual tumors after treatment arm A and B, respectively. There was a positive correlation between pretreatment sTILs and PD-L1 expression on stromal immune cells (Kendall’s τ =0.80). Interestingly, a significant inverse correlation was observed between PD-L1 expression on pretreatment sTILs and the T cell co-receptor CD3 expressed on posttreatment sTILs (Pearson’s ρ = -0.70). This finding was particularly evident in the arm B group (ρ = -0.85). Conclusions: NT with either SC or IV trastuzumab in combination with pertuzumab and chemotherapy had a significant effect on sTIL expression at surgery. In particular, the SC trastuzumab-based arm exerted the most relevant enrichment of sTILS in posttreatment residual tumors. These findings suggest a role for the SC administration of trastuzumab in determining favorable variations of host immune response parameters among pts with HER2-positive early BC who had residual disease after NT. Citation Format: Antonino Musolino, Stefania Gori, Elisabetta Cretella, Alessandra Marabese, Luigi Cavanna, Antonio Frassoldati, Giancarlo Bisagni, Chiara Casarini, Emilio Bria, Luisa Carbognin, Elena Fiorio, Alba A Brandes, Claudio Zamagni, Lorenzo Gianni, Alberto Zambelli, Filippo Montemurro, Michele Tognetto, Renata Todeschini, Giuseppe Maglietta, Gabriele Missale, Enrico M Silini. Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [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 P1-18-19.

Copanlisib in Combination With T-DM1 in Pretreated Unresectable Locally Advanced or Metastatic HER2-positive Breast Cancer

Copanlisib in Combination With T-DM1 in Pretreated Unresectable Locally Advanced or Metastatic HER2-positive Breast Cancer

The diagnostic accuracy of 12-point core biopsy of a tumor bed compared to the study of surgically obtained breast tissue in patients with locally advanced triple-negative or HER2-positive breast cancer after neoadjuvant systemic and targeted therapy.

e12097 Background: Innovative advances in neoadjuvant systemic and targeted breast cancer therapy implicate surgical treatment in specific patient groups can be avoided. The core biopsy of the tumor bed and some diagnostic approaches (breast ultrasound, mammography, SPECT/CT) allow for precise evaluation of the treatment efficacy. Methods: This research started in our department in 2018, we picked two groups of 15 patients each treated for locally advanced TNBC or grade cT1-4N1-3M0 HER2-positive breast cancer: HER2+/ER+ or HER2+/ER- breast cancer. The TNBC group received 6 cycles of NACT of paclitaxel combined with doxorubicin and carboplatin AUC5. The HER2+ group received 4 cycles of АС polychemotherapy followed by 4 cycles of monochemotherapy with the docetaxel and 3-weekly trastuzumab. The HER2+ group is receiving adjuvant trastuzumab for up to one year, where ER-positive patients are also given hormone therapy with tamoxifen or aromatase inhibitors. The response to neoadjuvant treatment was assessed in all patients using standard two-dimensional mammography, ultrasound elastography, and SPECT-CT. The 12-point core biopsy of a tumor bed was performed in the operating room setting by previously marked tumor projections. Then, all patients underwent either breast-conserving surgery or mastectomy with immediate reconstruction with expander/implant. Results: After neoadjuvant therapy, in a group of 15 patients with TNBC in surgically obtained material, the pathologic complete response (pCR) was observed in 8 patients (53.33%), whereas residual disease was found in 7 (46.67%) patients. The core biopsy results showed no tumor cells in 10 (66.67%) patients, and were detected in 5 (33.33%) patients (p = 0.0011), the accuracy of the method in this group was 80%. The overall response rate in the group of 15 patients with HER2-positive breast cancer was 8 (53.33%) patients with residual disease and 7 (46.67%) patients with pCR. According to core biopsy, tumor cells were present in 3 (20%) patients and were absent in 12 (80%) patients (p = 0.0787). Conclusions: Avoiding surgical treatment through not less than 12-point core biopsy of a tumor bed in patients with complete regression after neoadjuvant therapy is a new trend in the treatment of breast cancer. Any new approach in this sphere requires a long-term elaboration, compliance with the safety principles, rethinking standard procedures and following-up patients.

A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in elderly patients with advanced stage HER2-positive breast cancer: (JCOG1607 HERB TEA study).

TPS1100 Background: Systemic chemotherapy with anti-HER2 therapy is the standard of care for HER2-positive advanced breast cancer. Patient outcomes have improved remarkably with the use of novel anti-HER2 drugs, including trastuzumab (H), pertuzumab (P), and trastuzumab emtansine (T-DM1). The combination treatment comprising H, P, and docetaxel (D) (HPD) is highly recommended as the 1st-line treatment for patients with HER2-positive advanced breast cancer. In contrast, for elderly patients over 65 years of age, this regimen seems to be intolerable mentally and physically, and impairs their quality of life. A new standard treatment with less toxicity and non-inferior efficacy for elderly patients is needed. Methods: We have planned a randomized, multicenter, open-label, phase III trial to confirm the non-inferiority of T-DM1 compared to HPD in terms of overall survival (OS) in elderly patients with HER2-positive advanced breast cancer. The eligibility criteria are as follows: 1) histologically proven metastatic breast cancer, 2) age 65-74 years with a performance status (PS) score 0-2, or 75-79 years with a PS score 0-1, 3) HER2 overexpression or amplification confirmed in primary or metastatic tissues, and 4) no anti-HER2 therapy with chemotherapy for breast cancer, excluding (neo) adjuvant therapy. Patients are randomized to receive either HPD (H 6 mg/kg, P 420 mg/body, and D 60 mg/m2) or T-DM1 3.6 mg/kg every 3 weeks. The dose up of D (75 mg/m2) after the second cycle is defined based on the data regarding safety during the first cycle. The primary endpoint is OS. The secondary endpoints are progression-free survival, response rate, adverse events, breast cancer-related death, and deterioration of activities of daily living. The trial is designed to achieve 70% power to confirm non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.3 in terms of hazard ratio. With a median OS of 30 months in both arms, 6 years of accrual, and 5 years of follow up, the planned sample size is 330. The trial began in January 2018 and nineteen patients have been enrolled as of January 2019. Clinical trial information: UMIN000030783.

Abstract OT2-07-04: A phase 1b study of poziotinib in combination with T-DM1 in women with advanced or metastatic HER2-positive breast cancer

Abstract Background:Poziotinib represents a new class of irreversible quinazoline inhibitors of ErbB receptor tyrosine kinases that inhibit the proliferation of tumor cells in culture and in vivo by inhibiting HER-1 (EGFR), HER-2, HER-4. ErbB signaling plays important roles in the progression of HER2+ breast cancer. Poziotinib has promising clinical activity in breast cancer, and other solid tumors including lung, gastric, and colorectal cancers. Study SPI-POZ-101, is being conducted to evaluate the safety and efficacy of the combination of daily poziotinib and T-DM1, HER2 antibody-drug-conjugate every three weeks in patients with HER2+ advanced or metastatic breast cancer. Trial Objectives and Design: The primary objectives of the study are to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of daily poziotinib plus T-DM1 (every 3 weeks) in women with advanced or metastatic HER2 positive breast cancer; and to evaluate the Objective Response Rate (ORR) in these patients. The secondary objectives include disease control rate (DCR), progression-free-survival (PFS), safety and pharmacokinetics at the MTD/MAD dose level of poziotinib plus T-DM1. In Part 1, the dose of poziotinib plus standard dose of T-DM1 (3.6 mg/kg IV) on Day 1 of each cycle will be determined using a “3+3” design with up to 3 escalating dose levels, 8, 10 and 12 mg with no DLT or to de-escalate to 6 mg with DLT observed in Cycle 1. Patients in current dose cohort, if not discontinued, will continue treatment until discontinuation of therapy. In Part 2 of the study, approximately 10 patients will be treated at the MTD/MAD to confirm dose for safety of the combination and to evaluate preliminary efficacy. Eligibility Criteria: The study will enroll female patients between 18 and 90 years with confirmed HER2 overexpression or gene-amplified tumor via immunohistochemistry [IHC] with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+ or [ISH]+ and must have had at least 2 lines of anti-HER2 directed therapies either in the metastatic or early-stage disease setting. Patients must have adequate hematologic, hepatic, cardiac and renal functions and have at least one measurable lesion per RECIST 1.1 criteria. Exclusion criteria includes unstable CNS metastases or seizure disorder; anticancer chemotherapy, TKIs, biologics, immunotherapy, radiotherapy, or investigational treatment within 15 days; ≥ Grade 2 adverse events; known hypersensitivity to receptor tyrosine kinase inhibitors or any of the components of poziotinib tablets or T-DM1 IV solution. Statistical Methods: Part 1 of the study will enroll 3 to 6 patients at each dose using 3+3 design. Part 2 will enroll 10 patients at the MTD/MAD. The efficacy analysis will be conducted using the Evaluable Population based on RECIST 1.1. The Clopper-Pearson 95% confidence interval will be estimated using exact method based on binomial distribution. Target Accrual:Part 1: 6-18 patients Part 2: 10 patients ClinicalTrials.gov Identifier: NCT03429101 Contact Information: Spectrum Pharmaceuticals. SPI-POZ-101@sppirx.com Poziotinib is currently under clinical investigation and has not been approved for use in breast cancer. Citation Format: Bhat G, Potter D, Bharadwaj J, Khan N, Shabazz L, Tache J, Yang Z. A phase 1b study of poziotinib in combination with T-DM1 in women with advanced or metastatic HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-04.

Abstract OT2-07-05: A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD)

Abstract Background: Docetaxel + Trastuzumab (H) + Pertuzumab (P) provided progression-free survival (PFS) and overall survival (OS) benefits in HER2-positive advanced or metastatic breast cancer (AMBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of docetaxel at a dose of 75 mg/m2 every 3 weeks in AMBC patients (pts) is difficult due to the toxicities. Eribulin mesylate (E) is a well-tolerated microtubule inhibitor, and we have reported the efficacy and safety of EHP regimen as first- and second-line therapy for AMBC in a multicenter, phase II study (JBCRG-M03/UMIN000012232). In this M06 study, we address the clinical question as to which is the better chemotherapy partner for HP as first line regimen, in terms of efficacy, toxicity and QOL. Methods: JBCRG-M06 is a multicenter open-label randomized phase III study for HER2-positive AMBC pts who have received no prior chemotherapy except for the HER2- Antibody-Drug Conjugate (ADC). Pts will be randomized 1:1 to E (1.4mg/m2 on day 1 and 8) + H (8 mg/kg loading dose followed by 6 mg/kg) +P (840 mg loading dose followed by 420 mg) q3wks or standard taxanes (docetaxel 75mg/m2 on day1 or paclitaxel 80mg/m2 on day 1, 8 and 15) + HP q3wks. Stratification factors for randomization are; presence of visceral metastases, number of prior taxanes on perioperative adjuvant treatment, and treatment with prior anti-HER2-ADC. Primary endpoint is PFS and secondary endpoints include overall response rate, duration of response, OS, patient-reported outcomes (PRO) relating to QOL and peripheral neuropathy, new-metastases free survival, and safety. Translational research to search for biomarker for individual precision therapy will be performed. Main eligibility criteria are as follows: pts with HER2-positive AMBC, female aged 20-70 years old, ECOG PS of 0-1, LVEF ≥ 50% at baseline and adequate organ function. Pts who had progressive MBC within 6 months after the end of primary adjuvant systemic chemotherapy are excluded. The sample size was calculated by type1 error (2-sided) of 0.05 and 80% power to estimate the noninferiority margin 1.33 with an expected median PFS of 14.2 months. The target number of pts is 480 recruited over the duration of 3-years. The first patient in was achieved on August 2017. (ClinicalTrials.gov Identifier:NCT03264547). Citation Format: Masuda N, Yamashita T, Saji S, Araki K, Ito Y, Takano T, Takahashi M, Tsurutani J, Koizumi K, Kitada M, Kojima Y, Sagara Y, Tada H, Iwasa T, Kadoya T, Iwatani T, Hasegawa H, Morita S, Ohno S. A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-05.

47O - Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer

47O - Phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer

Phase II study of eribulin with trasutuzumab for pretreated locally advanced or metastatic HER2-positive breast cancer.

e12505 Background: Eribulin mesylate demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received 2 or more chemotherapy regimens. There are limited studies reported about the efficacy of eribulin with trastuzumab as first-line therapy for locally advanced or metastatic HER2-positive breast cancer. The aim of this study was to assess the efficacy and safety of eribulin with trastuzumab as late-line therapy for locally advanced or metastatic HER2-positive breast cancer. Methods: In this multicenter, phase II, single-arm study, patients with locally advanced or metastatic HER2 positive breast cancer who previously received at least one chemotherapeutic regimen, received eribulin at 1.4 mg/m2 intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary end point was ORR, and secondary end points included PFS and safety. Results: Thirty-six patients (median age: 60.5 years) were enrolled. The median number of prior treatment regimens was 4 (range, 1‐8). Twenty-two patients (61.1%) had received prior pertuzumab treatment, 10 patients (27.8%) had prior T-DM1. Patients received a median of 6 cycles of eribulin with trastuzumab (2-13 cycles). The ORR was 17% (CR 0, PR 6) with median PFS of 4.6 months (3.3-7.0 months). The clinical benefit rate was 33%. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 22 (61%) patients, peripheral neuropathy in 3 (8%; all Grade 3) patients, fatigue in 1 (3%) patients. Five (13.9%) patients had asymptomatic LVEF decline. However, no grade 3 LVEF decline or symptomatic congestive heart failure was observed. The reasons for treatment discontinuation were disease progression in 27 (75%) patients and adverse events in 8 (22%) patients. Conclusions: Eribulin with trastuzumab is an acceptable option in late-line treatment for locally advanced or metastatic HER2-positive breast cancer. Clinical trial information: 000012350.

Eribulin in combination with pertuzumab plus trastuzumab for HER2-positive advanced or recurrent breast cancer (JBCRG-M03).

1025 Background: Pertuzumab (P) provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer (MBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of intravenous docetaxel at a dose of 75 mg/m2 every 3 weeks in MBC patients is difficult. Eribulin (E) is a well-tolerated cytotoxic agent. We report the efficacy and safety of E in combination with trastuzumab (T) plus P as first- and second-line therapy for metastatic or advanced BC in a multicenter, open-label phase II study (UMIN000012232). Methods: HER2-positive advanced or recurrent BC patients with no or a single prior therapy as advanced or recurrent chemotherapy were enrolled. All patients were administered T and taxane as adjuvant or first-line chemotherapy. Treatment consisted of E 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and T (8 mg/kg loading dose > 6 mg/kg) plus P (840 mg loading dose > 420 mg) once every 3 weeks, all given intravenously. The primary end point was PFS. Results: From November 2013 to April 2016, 50 patients were enrolled. Forty-nine patients were eligible for safety analysis; full analysis set (FAS) includes 46 patients. The median patient age was 56 years (range 23–70), and 8 (16%) and 41 (84%) patients were treated in first- and second-line settings, respectively. Twenty-eight patients out of 49 patients (57%) continued the protocol therapy at the end of 8 cycles and median PFS was not yet reached. The response rate by RECIST ver.1.1 was 56.5% in FAS. The relative dose intensity of E, T, and P were 93.3% (range 77.0%–100%), 100% (range 96.0%–100%) and 100% (range 89.7%–100%), respectively in FAS. The grade 3/4 adverse effects (AE) were neutropenia in 5 patients (10.2%) including 2 patients (4.1%) with febrile neutropenia, hypertension in 3 patients (6.1%), and other AEs in only one patient. Average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusions: E in combination with T plus P was well-tolerated and could be an alternative to docetaxel-based combination therapy for HER2-positive MBC. Clinical trial information: 000012232.

Abstract P4-21-25: The importance of hormone receptor status on biomarker expression and the efficacy of lapatinib plus capecitabine therapy after progression on trastuzumab in HER2 positive recurrent and advanced breast cancer

Abstract Background: Anti-HER2 treatment using trastuzumab (Tmab) has contributed to improving the clinical outcome of HER2-positive breast cancerpatients. However, some patients do not respond to Tmab therapy and the combination of Lapatinib and capecitabine (LC) is an effective treatment option after progression on Tmab. Hormone receptor status is also an important factor for deciding if the patient should be treated with endocrine therapy as well. The aim of this study was to investigate the clinical significance of hormone receptor status in biomarker expression and to evaluate the efficacy of lapatinib therapy. Materials and Methods: Eighty patients with HER2 positive breast cancer refractory to Tmab were enrolled in this prospective trial (KBC-SG 1107) between December 2011 and March 2014. The following treatment began after enrollment; lapatinib 1250-mg tablets were administered orally once daily and capecitabine (2000 mg/m2 per day) on days 1 to 14 every 21 days until disease progression or until severe adverse events. Total HER2 (H2T), p95HER2 (p95), and total HER3 (H3T) expression levels were quantified in formalin-fixed paraffin embedded samples using VeraTag assays. ER and progesterone receptor (PgR), PTEN and p95 expressions were evaluated using immunohistochemistry (IHC) and PIK3CA mutation using direct sequencing. Statistical analyses were performed using SPSS (ver. 21). A two-sided P<0.05 was considered a statistically significant difference. Results: The ER- and PgR-positive rates were 55.0% and 33.8%, respectively. The response rate to LC was 30% (CR: 1 case; PR: 23 cases), the clinical benefit rate was 51.3% and the median progression-free survival (PFS) was 174.5 days. Both ER and PgR negativity significantly correlated with higher H2T (cutoff: 13.8), p95HER2 (cutoff: 2.8) and PTEN expression levels (cutoff: H score of 100). Lower H2T expression levels and PIK3CA mutation rates were often observed in the non-responders (both: p=0.087). The ER and PgR status did not correlate with response. A high p95 and PTEN expression significantly correlated with longer PFS in ER and/or PgR positive cases (p=0.02 and 0.03), respectively. The overall survival (OS) after LC significantly correlated with the number of recurrence organs (p=0.0002) but not with the p95 and PTEN expression levels. Conclusion: LC therapy was effective in Tmab-refractory HER2 positive breast cancer. Moreover, the biomarker expression differed depending on the ER/PgR status and a high p95 and PTEN expression correlated with longer PFS in ER and/or PgR positive cases. Further study is necessary to validate these findings. Citation Format: Arima N, Nishimura R, Toh U, Tanaka M, Saimura M, Okumura Y, Saito T, Tanaka T, Teraoka M, Shimada K, Koga T, Kurashita K, Todoroki H, Ueo H, Ohi Y, Toyoshima S, Mitsuyama S, Tamura K. The importance of hormone receptor status on biomarker expression and the efficacy of lapatinib plus capecitabine therapy after progression on trastuzumab in HER2 positive recurrent and advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-25.

Abstract P4-21-41: Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer

Abstract Background: Neoadjuvant pertuzumab (P)+trastuzumab (H)+standard chemotherapy (CT) significantly increases pathologic complete response (pCR) rates v H+CT. However, anti-HER2 therapy following anthracyclines can cause heart failure, and data are limited or lacking on combining P+H after epirubicin or doxorubicin. We report cardiac and overall safety as well as total pCR (tpCR) rates with widely used but understudied anthracycline-containing regimens. Methods: BERENICE (NCT02132949), a non-randomized, open-label, phase II study, enrolled patients (pts) with centrally confirmed HER2-positive, locally advanced, inflammatory, or early-stage, unilateral, and invasive breast cancer, Eastern Cooperative Oncology Group performance status ≤1, and baseline left ventricular ejection fraction (LVEF) ≥55%. In the neoadjuvant period, Cohort A pts received four q2w dose-dense doxorubicin+cyclophosphamide cycles (60 mg/m2/600 mg/m2 with granulocyte-colony stimulating factor support as needed) followed by 12 qw paclitaxel doses (80 mg/m2) + four q3w P+H cycles (P 840 mg, then 420 mg; H 8mg/kg, then 6 mg/kg). Cohort B received four q3w fluorouracil/epirubicin/cyclophosphamide cycles (500 mg/m2/100 mg/m2/600 mg/m2) followed by four q3w docetaxel cycles (75 mg/m2 escalated to 100 mg/m2) + four q3w P+H cycles. Surgery was performed after cycle 8 for both cohorts. The primary objective was to evaluate cardiac safety during the neoadjuvant period, assessed by incidence of 1) New York Heart Association (NYHA) Class III/IV heart failure and 2) significant LVEF declines (≥10% from baseline with a value of <50%). Secondary objectives included assessments of adverse event (AE) rates and tpCR (ypT0/Tis ypN0; NX was considered non-tpCR). Results are descriptive; no statistical hypothesis testing was planned. Results: Four hundred one pts were enrolled between Jul 2014–Aug 2015. Clinical cutoff was Mar 3, 2016. Demographics and baseline characteristics were generally balanced between cohorts; 64.3% v 61.7% of pts had centrally confirmed hormone receptor (HR)-positive disease and 95.0% v 93.0% had T1–T3 primary tumors. Three pts in Cohort A and none in Cohort B experienced NYHA Class III/IV heart failure during neoadjuvant treatment (table). Thirteen pts in Cohort A v four in Cohort B had significant LVEF declines (table). One Cohort B pt's LVEF decline was prior to anti-HER2 treatment. AE and serious AE (SAE) rates were well balanced between cohorts. The most common AEs were nausea, diarrhea, and alopecia. The most common SAE was febrile neutropenia. tpCR rates were similar between cohorts (table). Neoadjuvant periodCohort ACohort BSafety: Pts, n (%)N=199N=198NYHA Class III/IV heart failure3 (1.5%)0Significant LVEF decline13 (6.5%)4 (2.0%)tpCR (ypT0/Tis ypN0): Pts, n/N (%) Intention-to-treat123/199 (61.8%)122/201 (60.7%)HR-positive66/128 (51.6%)71/124 (57.3%)HR-negative53/65 (81.5%)51/75 (68.0%) Conclusion: Cardiac and general safety of the two anthracycline-containing regimens in BERENICE were as expected and were consistent with the known P+H+CT profiles. Both regimens were active, and tpCR rates were high. Citation Format: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Dang C. Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-41.

Abstract 868: Creating a superior, site-specific anti-HER2 antibody-drug conjugate (NG-HER2 ADC) for treatment of solid tumors

Abstract Antibody-drug conjugates (ADCs) have emerged as an important class of cancer therapeutics. The FDA approval of Kadcyla (T-DM1), a single agent for treatment of HER2-positive advanced metastatic breast cancer, was a significant milestone in the field of targeted therapy, as the first and only ADC for treatment of solid tumors. Despite the 3-month improvement over standard of care in the median survival, almost all the patients eventually became refractory to T-DM1. We have identified several possible areas for improvement: 1) The potency of T-DM1 as confirmed by the Phase III clinical data is restricted to high HER2 tumors which leaves moderate or low HER2 expressing patients without access to T-DM1 treatment; 2) The 48% overall response rate is indicative of intrinsic resistance to T-DM1 and all T-DM1 treated patients eventually relapse. 3) The randomized lysine conjugation in T-DM1 generates heterogeneity of the product. We have developed a novel, site-specific anti-HER2 ADC (NG-HER2 ADC) and evaluated it in comparative preclinical studies with T-DM1. The results show that the NG-HER2 ADC is ∼ 10 fold more potent than T-DM1 in HER2 3+ xenograft models of breast and gastric cancers. Our proprietary cleavable and permeable linker-payload can mediate bystander effect and this enables potent anti-tumor activity in non-HER2 amplified breast cancer and heterogeneous low HER2 NSCLC PDX models, where T-DM1 is ineffective. Our ADC can overcome T-DM1 resistance in in vitro and in vivo models.. Our site-specific ADC at HNSTD of 9 mg/kg in cynomolgus monkeys showed high AUC, long half-life and had normal clinical observations with no marked neutropenia. On the contrary, conventional conjugates with cleavable linker payloads typically have severe bone marrow toxicity as DLT above 5 mg/kg. The therapeutic index for NG-HER2 ADC is significantly greater than T-DM1 in all models tested. NG-HER2 ADC has a projected clinical efficacious dose of ∼1 mg/kg, compared to 3-5 mg/kg for T-DM1, based on PK/PD modeling. In addition, the activity of the NG-HER2 ADC shows increased infiltration of CD8 positive effector cells, an essential component for immuno-oncology (IO) efficacy, in a syngeneic HER2 overexpressing model. This property potentially allows the combination of the ADC with IO drugs to improve the long-term, overall survival. Our data provides preclinical proof of concept for NG-HER2 ADC with best-in-class potential and is currently being tested in preparation for clinical trials for treatment of HER2 solid tumors. Citation Format: Dangshe Ma, Bitha Narayanan, Kim Marquette, Edmund Graziani, Frank Loganzo, Manoj Charati, Nadira Prashad, Nathan Tumey, Jon Golas, Christine Hosselet, George Hu, Frank Barletta, Alison Betts, Judy Lucas, Chris O’Donnell, Lioudmila Tchistiakova, Hans-Peter Gerber, Puja Sapra. Creating a superior, site-specific anti-HER2 antibody-drug conjugate (NG-HER2 ADC) for treatment of solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 868.