Metastatic HER2 Research Articles

Trial in progress: Phase I/II study of radiation therapy followed by intrathecal trastuzumab/pertuzumab in the management of HER2+ breast leptomeningeal disease.

TPS1099 Background: HER2+ breast cancer patients with leptomeningeal disease (LMD) represent a poor prognosis population with a high unmet clinical need. Although a multitude of treatment options are available for the management of systemic disease, once metastases travel to the leptomeninges, patients have a lack of treatment options aside from traditional local approaches. Data from a phase I/II study reveals intrathecal (IT) trastuzumab to be well tolerated with improved overall survival (OS) compared to historical controls in HER2+ breast LMD. Radiotherapy can improve the flow of IT therapy through the cerebrospinal fluid (CSF) and provide symptomatic relief. The monoclonal antibody pertuzumab is used in conjunction with trastuzumab in the management of metastatic and localized HER2+ breast cancer. Given the role of radiotherapy in the management of LMD along with the role of pertuzumab in the management of HER2+ breast cancer, there is a strong clinical rationale to combine radiotherapy with IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. Methods: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. HER2+ LMD patients identified by magnetic resonance imaging (MRI) and/or CSF cytology, ≥ 18, with a life expectancy > 8 weeks are eligible. Treatment is initiated with radiotherapy, whole brain radiotherapy and/or focal brain/spine radiation followed by IT trastuzumab/pertuzumab. Safety and feasibility will be monitored by a modified toxicity probability interval-2 (mTPI-2) design. Dose reductions of IT trastuzumab will not be allowed. Once the maximum tolerated dose of IT pertuzumab is determined, the phase II portion of the study will commence to determine OS. Secondary objectives involve defining the CSF pharmacokinetics of IT trastuzumab/pertuzumab, evaluating the response rate (leptomeningeal and parenchymal), and progression free survival (leptomeningeal and parenchymal) following IT trastuzumab/pertuzumab. In the phase 2 portion, a single-arm two-stage trial is designed using the Restricted-Kwak-and-Jung’s Method. The primary endpoint is one-year OS. An interim analysis will be performed after 20 patients are enrolled. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT04588545 .

Preliminary results from a phase 1/2 study of BDC-1001, a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), in patients (pts) with advanced HER2-expressing solid tumors.

2549 Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist with a non-cleavable linker. BDC-1001 was designed to activate the innate immune system, eliciting antibody-mediated effector functions (eg, antibody-dependent cellular phagocytosis) and a durable adaptive immune response. In preclinical tumor models resistant to anti-HER2 treatments, BDC-1001 demonstrated potent and durable immune-mediated antitumor efficacy. Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 ± PD1 inhibitor pembrolizumab in pts with HER2-expressing solid tumors who had progressive disease on standard of care (NCT04278144). Preliminary results of the monotherapy dose escalation (Part 1) are reported. Pts with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors received BDC-1001 IV q3w in a 3+3 design w/ 12 pts/cohort backfill allowed. Primary objectives were to evaluate safety, tolerability, dose-limiting toxicities (DLTs) and determine a phase 2 dose; secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity. Results: As of Jan 29, 2021, 20 pts w/ a median age of 65 (46-85) have enrolled in 4 dose levels (0.15mg/kg to 5 mg/kg). Cancer types include breast, biliary, cervical, colorectal (CRC), lung, gastroesophageal, salivary, urinary tract and endometrial. Pts had received a median of 4 (1-7) prior therapies; 65% received >1 prior anti-HER2 therapy. All pts completed the 21-day DLT period; no DLTs or drug-related serious adverse events (AEs) have been observed. AEs deemed related to BDC-1001 have been mild to moderate including infusion-related reactions. The MTD has not been reached (treatment duration 5-17+wk); enrollment is ongoing. PK evaluations showed Cmax levels consistent with predicted modeling based on non-human primates (NHP). One pt with microsatellite stable (MSS) HER2+ CRC with lung metastases had a confirmed partial response after 4 cycles and remains on study; 2 additional pts with metastatic MSS HER2+ CRC had stable disease (SD) and a pt with heavily pretreated MSS endometrial cancer with lung metastases had confirmed SD and remains on treatment 17+ wk; 3 of these pts had received 2 prior anti-HER2 therapies. Conclusions: In this first-in-human study, BDC-1001 appears to be well-tolerated up to the dose tested to date (5 mg/kg), with Cmax levels achieved as predicted by NHP modeling. Evidence of clinical activity have been observed, including in pts previously treated with anti-HER2 therapy. Dose escalation is ongoing and will be followed by combination dosing with CPI and the phase 2 component in selected tumors. Clinical trial information: NCT04278144.

Genetic counseling and testing rates among community cancer programs for patients with breast cancer following site-directed quality improvement.

10529 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend testing for highly penetrant breast/ovarian cancer genes in several scenarios, including women with early-onset (≤ 45 years) or metastatic HER-2 negative breast cancer regardless of family history. A 2018 Association of Community Cancer Centers (ACCC) survey (N = 95) showed that > 80% of respondents reported ≤ 50% testing rate of patients with breast cancer who met guidelines. To improve rates of genetic counseling(GC)/testing, ACCC partnered with 15 community cancer programs to support site-directed quality improvement (QI) interventions. Methods: Pre- and post-intervention data from 9/15 partner programs for genetically at-risk women with early-onset or HER-2 negative metastatic breast cancer (MBC) were analyzed. Pre-intervention data were collected between 01/01/2017 and 06/30/2019 while post-intervention data were collected as early as 07/01/2019 and as late as 10/01/2020. QI project scope ranged from creation of testing eligibility education to implementation of a virtual GC clinic. De-identified data collected included: family history documentation; GC appointment; test results; and timing of results relative to surgical date. Results: The pre-intervention cohort included 2691 women and the post- cohort included 3104 women who were eligible for GC. Early-onset patients in the post-intervention group attended a GC appointment 83% (331/401) of the time and 74% (296/401) had genetic test results, with 92% (271/296) receiving results before surgery. Sixty-one percent (1387/2267) of women with HER-2 negative MBC in the post-intervention group received GC, compared to 36% (658/1845) in the pre-intervention group. There was an overall increase in the number of MBC patients with documented test results following GC in the post-intervention cohort (55% (1243/2267) versus 15% (273/1845); p < 0.0001). Rates of GC appointments improved overall, regardless of family history documentation. Rates among those with a documented high-risk family history improved from 57% (729/1284) to 85% (1485/1741) following QI interventions (p < 0.0001). There was also a significantly higher rate of GC provided in the post-intervention group among women with negative family histories (40% (462/1155) versus 23% (181/778); p < 0.0001). GC also increased from 6% (35/629) to 45% (94/208) of women in the post-intervention cohort with no documentation of family history (p < 0.0001). Conclusions: Genetic testing is underutilized in women with breast cancer. Significant improvement was achieved with QI initiatives specifically designed to target easily identified populations meeting guidelines for GC/testing. This project demonstrates the importance of attention to practice-directed strategies aimed at improving identification of risk as well as follow through to GC/testing.

Incorporating HER2/HER3 targeted therapies across solid tumors: Assessing the impact of digital education on clinician practice patterns.

11036 Background: Improved understanding of the interactions between HER2 and HER3, the heterogeneity of HER-expressing disease, and mechanisms of resistance to anti-HER2 therapy has led to increasing number of treatment options to address clinical needs. Tumor types of interest, impacted by HER2/HER3 expression and pathophysiology were breast cancer, non-small cell lung cancer (NSCLC), gastric cancer, and colorectal cancer (CRC). Increasing competency in these areas is deemed critical to clinician’s ability to individualize treatment plans and improve patient outcomes. Methods: A 2-hour CME activity was broadcast live-online in September 2020 and remains on-demand through September 2021 at OMedLive.com. The educational initiative was divided into one hour addressing HER2 and HER3, testing guidelines, resistance mechanisms and emerging data elucidating recent and ongoing clinical trials across NSCLC, gastric cancer, and CRC. The second hour focused on individualizing metastatic HER2+ breast cancer, HER2-low breast cancer as an emerging subtype, and management of side effects. Knowledge and competence questions were administered pre-, immediate post-, and 2 mos. post-activity. Behavioral impact questions were also asked at follow-up. Data from these questions were analyzed to determine engagement and clinical impact. Results: To date, 448 clinicians participated in the activity. Across the seven CME test questions, improvements in knowledge and competence were observed in the clinical applications of HER2-directed agents and HER3 antibody drug conjugates (ADCs), first-line standard of care for HER2+ breast cancer, and adverse event management for HER2 ADCs. At 2-mos. follow-up, 67% reported improved behavioral impact on both clinical practice and patient experience and outcomes. Clinicians provided specific write-in examples of these changes, noting improved patient-reported outcomes, improved treatment adherence, improved competence developing treatment plans, and increased understanding of HER2/HER3 pathophysiology. Updated and expanded results will be shared. Conclusions: The activity was successful in improving clinician understanding of the relationship between HER2/HER3, pathophysiology across tumor types, and applications of emerging targeted therapies. Open-ended responses to behavioral impact questions illustrated clear improvements in clinician-reported patient experience and outcomes, clinical practice management, and knowledge of emerging HER2/HER3 therapies and their uses across multiple solid tumors.

126TiP HER2CLIMB-02: Tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US, Canada, Switzerland, Australia, and Singapore for combined treatment with trastuzumab (Tras) and capecitabine for patients with HER2+ metastatic breast cancer (MBC), including patients with brain metastases (BM) who received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-Tras emtansine (T-DM1), approved for treatment of HER2+ MBC after Tras and a taxane, has improved progression-free survival (PFS) and overall survival (OS). Further improvements are needed, including in patients with active BM. A phase Ib trial evaluated TUC+T-DM1 in 50 patients with HER2+ MBC who received prior treatment with Tras and a taxane; 60% of patients had BM at baseline (Borges 2018). Common adverse events, mostly Grade 1/2, were nausea (72%), diarrhea (60%), and fatigue (56%). Median PFS was 8.2 months and objective response rate (ORR) in patients with measurable disease (n=34) was 47%. Brain specific response rate (RECIST v1.1) in patients with measurable BM (n=14) was 36%. This encouraging clinical activity, including in patients with BM, provides rationale to evaluate TUC+T-DM1. HER2CLIMB-02 is a randomized, double-blind, placebo-controlled, phase III study enrolling patients with centrally confirmed HER2+ unresectable locally-advanced or MBC previously treated with Tras and taxane. Patients must have ECOG ≤1. Approximately 460 patients will be randomized 1:1 for 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Prior treatment with investigational anti-HER2 agent, anti-EGFR agent, or HER2 TKI is not permitted. Prior pertuzumab treatment is permitted. Baseline brain MRIs are required; patients with stable, progressing, or untreated BM may be eligible. Treatment response assessments per RECISTv1.1 occur every 6 weeks for the first 24 weeks, and then every 9 weeks. Primary endpoint is PFS per investigator assessment, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US, Canada, EU, Japan, South Korea, Australia, and Israel, and is planned for Singapore. NCT03975647. Editorial assistance was provided by Craig Bolte of MMS Holdings. Seagen Inc.

Update Breast Cancer 2021 Part 2 - Advanced Stages, Long-Term Consequences and Biomarkers.

This review summarises and discusses significant aspects of recently published studies on patient treatment in advanced breast cancer and on biomarkers in breast cancer. In recent years, a large number of drugs for all molecular subtypes have been developed up to phase III trials. With regard to immune checkpoint inhibitors in metastasised breast cancer, the recent discussion has centred on the best candidate for combined chemotherapy. The oral taxanes could become a new type of oral chemotherapies. There is a growing body of data on biomarkers for the use of CDK4/6 inhibitors, which could also signify further development for other molecular subtypes. New substances have been developed for metastatic HER2+ breast cancer that still result in good remission even after massive prior treatment and/or cerebral metastasis. Similarly, knowledge is growing about targeted therapies with antibody-drug conjugates (ADC) against Trop-2, which could bolster our therapeutic armoury in triple-negative breast cancer (TNBC). In addition, the clinical focus is on understanding how to maintain fertility after breast cancer treatment. Here, pooled analyses provide new insights.

O80: GREMLIN-1 PROMOTES TUMOURIGENESIS AND METASTASIS IN HER2 POSITIVE BREAST CANCER

Abstract Introduction HER2 over-expression denotes poor prognosis in breast cancers.Bone morphogenetic protein(BMP) signalling is known to interact with EGF signalling, co-regulating breast cancer progression.BMP antagonist Gremlin-1 may influence breast cancer disease progression, but this remains unexplored in HER2 positive breast cancers. Method GREM1 and HER2 expression, and clinical outcomes were examined in clinical cohorts.GREM1 overexpression or pEF control plasmid were transduced into BT474 HER2+breast cancer cells. In vitro function tests using BT474 pEF and BT474GREM1cells include 2D/3D growth, migration, and expression of epithelial to mesenchymal transition(EMT)markers. Signalling cascades were examined in BT474 treated with RhGremlin-1. In vivo, BALB/c nude mice underwent either mammary injection or intra-cardiac injection of BT474pEF or BT474GREM1 cells and disease burden assessed. Result GREM1 expression correlates with HER2 in breast tumours(p=0.03) and is higher in metastatic HER2 positive cancers (p = 0.04). HER2 positive patients with high GREM1 have poor survival(p = 0.0002). BT474GREM1cells have up-regulated markers of EMT compared to control. BT474 RhGremlin-1 treated cells have active AKT pathway signalling, independent of BMP signalling. In vitro, BT474GREM1cells significantly proliferate and migrate compared to control(p<0.05 and p < 0.001).This is confirmed in vivo, BT474GREM1 mice grew significantly larger mammary tumours(p<0.05) and had more PETCT metastatic hotspots. Conclusion Gremlin-1 is correlated with poor outcomes in HER2 patients and promotes breast cancer cellular growth, migration and metastasis.Gremlin-1 is a novel area of research with potential as a prognostic biomarker and therapeutic target for personalised, effective, breast cancer outcomes. Take-home message BMP antagonists are gaining interest for their potential in breast cancer prognosis and therapeutics.This novel area of research shows BMP antagonist Gremlin-1 is of importance in HER2 positive breast cancers. DRAGONS DEN

Pharmacoeconomic analysis of pertuzumab in treatment of HER2-positive breast cancer in Ukraine

Background. The incidence of breast cancer tends to be increasing worldwide in recent years. It is characterized by various clinical manifestations and potential treatment approaches. The choice of treatment strategy, its sequence as well as the efficiency of administered chemotherapy is quite relevant these days.
 Purpose – assessing economic feasibility of targeted therapy with pertuzumab (Perjeta®) in patients with metastatic HER2+ BC from the perspective of the health care system of Ukraine.
 Materials and methods. The treatment outcomes as well as related costs were determined by means of Markov analytical modelling based on a randomized multicenter open clinical study of CLEOPATRA phase III [2]. The model time horizon was 20 years. The alternative schemes of frontline therapy of metastatic HER2+ breast cancer were compared: PTD regimen pertuzumab + trastuzumab + docetaxel and TD regimen trastuzumab + docetaxel. Based on Markov modelling, pharmacoeconomic analysis by means of cost-effectiveness and cost-utility methods was carried out. As an efficiency criterion, LYG amount was used, as a utility criterion − QALY indicator. Direct medical costs were counted, the structure of which had been determined according to the current Protocol. The cost of drugs was calculated in accordance with the Register of wholesale prices for pharmaceuticals of the Ministry of Health of Ukraine; the cost of treatment procedures was determined in accordance with the available price lists of paid medical services provided by licensed medical institutions. Discounting at the level of 3 % per year was applied. Sensitivity analysis of the outcomes was carried out before pertuzumab price changed.
 Results. According to the modelling, the average life expectancy of patients with HER2+ BC, receiving PTD scheme is 15.69 years compared to 13.95 years in the TD group. Along with prolonging life, associated with PTD scheme, its quality increases. Patients in the TD group gain 7.8 QALY on average, while in the PTD group it is 9.24. The total expenses for the simulated (involved into modeling) study period in the PTD group averaged UAH 1 970 369.6 per patient, in the TD group − UAH 732 517.7. ICER (cost of 1 additional life year) and ICUR (cost of 1 additional qualityadjusted life year) incremental coefficients amounted to UAH 710924.6 and UAH 861175.4 respectively.
 Conclusions. 1. Pertuzumab target drug is an effective pharmaceutical when administered to patients with metastatic HER2 + breast cancer. 2. The frontline therapy regimen for patients with metastatic HER2 + breast cancer with pertuzumab being included is more expensive in comparison with trastuzumab + docetaxel regimen; at the same time it makes it possible to achieve better results, i. e. to provide on average extra 1.74 life years and 1.44 QALY in 20-year perspective. 3. Pharmacoeconomic analysis based on Markov model and cost-effectiveness and cost-benefit calculations make it possible to consider pertuzumab (Perjeta®), included into frontline targeted therapy regimen of trastuzumab + docetaxel in patients with metastatic HER2+ breast cancer, as an economically feasible medical technology under current health care conditions in Ukraine.

185TiP A phase Ib dose-escalation study evaluating trastuzumab deruxtecan (T-DXd) and durvalumab in combination with chemotherapy as first-line treatment in patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (DESTINY-Lung03)

Background: In patients (pts) with metastatic NSCLC without EGFR/ALK/ROS1 genomic aberrations, platinum doublet chemotherapy (ctx) + anti–PD-1/L1 immunotherapy is the current first-line standard of care. HER2 overexpression, an established target for treatments in breast and gastric cancers, is observed in up to 30% of pts with NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer “PantHER”

Simple SummaryPatients with HER-2 positive breast cancer who progress through available HER2-targeted therapy, at present, have few effective treatment options. PIK3CA is mutated in approximately 20% of HER2 positive breast cancers, contributes to HER-2 therapy resistance and may be predictive of response to PI3K inhibitors, including copanlisib. PIK3CA gene mutations were assessed in archival tumour tissue and serially in plasma circulating tumour DNA over the course of treatment with copanlisib. Disease stabilisation (stable disease ≥16 weeks) was seen with copanlisib and trastuzumab in a proportion of participants (n = 6, 50%). PIK3CA mutation detected in archival tumour tissue did not appear to predict tumour response to copanlisib and trastuzumab in this small, heavily pre-treated cohort. Notably, PIK3CA circulating tumour DNA mutations were detected in the plasma of all trial participants, including those who tested negative for the mutation in tissue. This study established a dosing strategy for the novel combination of the PI3K inhibitor copanlisib with trastuzumab and suggested clinical activity for the combination in heavily pre-treated HER-2 positive advanced breast cancer. Further evaluation in a phase 2 study in patients with HER2 therapy resistant tumours is ongoing (NCT02705859).Background: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab. Methods: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly. Results: Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%). PIK3CA mutations were detected in archival tumour of six participants (50%). PIK3CA hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the TRRAP gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling. Conclusion: Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT: 02705859.

Phase II study of neratinib in older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer

ObjectiveThe tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60. MethodsPatients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log2 Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated. Results25 patients were enrolled with median age of 66 (range 60–79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0–11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56–5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA]). ConclusionsNeratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding.

Abstract OT-28-01: HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ breast cancer

Abstract Background - Tucatinib (TUC), an oral tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR, is approved in the US for use in combination with trastuzumab (Tras) and capecitabine for treatment (tx) of adult patients (pts) with metastatic HER2+ breast cancer (MBC), including pts with brain metastases (BM), who have received 1 or more prior anti-HER2-based regimens in the metastatic setting. Ado-trastuzumab emtansine (T-DM1), approved for tx of pts with HER2+ MBC after Tras and a taxane, has led to significant improvements in progression-free survival (PFS) and overall survival (OS). Still, further improvements are needed, including pts with active BM. A phase 1b trial evaluated TUC (300 mg PO BID) with T-DM1 in 50 pts with HER2+ MBC who received prior tx with Tras and a taxane (Borges 2018). Common AEs included nausea (72%), diarrhea (60%), and fatigue (56%); mostly grade 1/2. Median PFS was 8.2 months and the objective response rate (ORR) in pts with measurable disease (n=34) was 47%. Sixty percent of pts treated with TUC + T-DM1 had BM at baseline and showed a brain specific response rate (RECISTv1.1) of 36% in pts with measurable BM. This encouraging clinical activity, including in pts with BM, provides rationale for a randomized trial to further evaluate this combination. Trial design - HER2CLIMB-02 is a randomized, double-blind, placebo-controlled phase 3 study to evaluate efficacy and safety of TUC + T-DM1 in pts with unresectable locally advanced or metastatic HER2+ breast cancer; ~460 pts will be randomized 1:1 to receive 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV). Pts must have had prior tx with Tras and a taxane in any setting, be ≥18 yrs, with an ECOG ≤1 and histologically confirmed HER2+ MBC. Prior tx with any investigational antiHER2 or anti-EGFR agent or HER2 TKI is not permitted. Prior pertuzumab tx is allowed, but not required. Baseline brain MRIs are required for all pts; pts with stable, progressing, or untreated BM not requiring immediate local therapy are eligible. While on tx, radiographic disease evaluations (RECISTv1.1) will occur every 6 weeks for the first 24 weeks, and then every 9 weeks. The primary endpoint is PFS per investigator, with OS and ORR as key secondary endpoints. Enrollment is ongoing in the US (NCT03975647) and planned for Canada, the EU, and the Asia/Pacific region. Citation Format: Sara Hurvitz, Linda Vahdat, Nadia Harbeck, Antonio C. Wolff, Sara M. Tolaney, Sherene Loi, Norikazu Masuda, Joyce O’Shaughnessy, Cassie Dong, Luke Walker, Evelyn Rustia, Virginia F. Borges. HER2CLIMB-02: A randomized, double-blind, phase 3 study of tucatinib or placebo with T-DM1 for unresectable locally-advanced or metastatic HER2+ 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 OT-28-01.

Abstract PS9-64: Impact of online education regarding novel HER2 therapies on translating evidence to practice

Abstract Background:The treatment armamentarium for patients with refractory metastatic HER2+ breast cancer was limited due to a lack of effective agents after the use of ado-trastuzumab emtansine, trastuzumab, and pertuzumab. Novel therapies such as trastuzumab deruxtecan and tucatinib provided high response rates to a patient subgroup with unmet clinical needs for having effective therapy. As data from clinical trials become available, landmark trials are published, and FDA approvals and guidelines incorporate novel therapies, continuing medical education (CME) for oncologists is necessary to facilitate the translation of evidence to their clinical practice. Methods: A series of 4 CME-certified activities were launched to educate physicians on new therapies in metastatic HER2+ breast cancer following data releases from the 2019 San Antonio Breast Cancer Symposium. Education followed adult learning principles starting with a goal of increasing awareness on novel agents and outcomes presented at national conferences and then integrating these agents into clinical practice, including adverse event management. Panel discussions were utilized to provide multiple faculty perspectives and clinical examples. Effectiveness was analyzed using 3 multiple-choice and 1 self-efficacy question measuring knowledge, competence, and confidence, presented as pre-/post-CME repeated pairs for each of the activities. Oncologists who completed both the pre- and post-CME questions were included in analysis and McNemar’s tests were conducted to assess statistical significance of the results with p < .05 being considered significant. The CME activities launched from December 2019 through March 2020 and data collected June 2020. Results:As of 6/9/2020, 6,473 global physicians had participated in the activities including 3,036 oncologists. 62% of the Oncologists identified themselves as practicing in a community setting, with 87% reporting a plan to make changes to their practice. Analyses from the activities found significant improvements in knowledge, competence, and confidence, measured as relative changes in % of correct responses or % of confident physicians from pre- to post-CME, across the various themes of learning objectives in metastatic HER2+ breast cancer:• 62% increase in knowledge of clinical trial outcomes (n = 339; pre: 53% vs. post: 86%, p < .001)•35% increase in understanding the mechanism or rationale for novel agents (n = 368; pre: 52% vs. post: 70%, p < .001) •15% increase in the ability to identify patients eligible for novel therapies (n = 210; pre: 61% vs. post: 70%, p < .05) •38% increase in managing adverse events of novel therapies (n = 158; pre: 37% vs. post: 51%, p < .001) •83% increase in the percent of oncologists who were mostly or very confident in treating metastatic HER2+ breast cancer patients (n = 368; pre: 18% vs. post: 33%, p < .001) Conclusions: This series of online, expert-led, CME-certified educational activities resulted in significant improvement in knowledge, competence, and confidence among learners regarding the use of novel anti-HER2 therapies in the management of metastatic breast cancer. These results demonstrate the effectiveness of on-demand education to translate information from data to clinical practice and directly benefit patients. Grantors:This educational initiative was supported through educational grants from Astra Zeneca Pharmaceuticals LP and Daiichi Sankyo. Citation Format: Kinjal Parikh, Nabil Dorkhom, Pan Chen, Davecia Ragoonath Cameron, Richard Caraico, Kelly Hanley, Shanu Modi. Impact of online education regarding novel HER2 therapies on translating evidence to practice [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 PS9-64.

Abstract PS12-15: Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC)

Abstract RATIONALE: Addition of CDK 4/6 inhibitors to endocrine therapy has become standard for patients (pts) with ER+ and HER2- BC with improvements in overall survival. However, acquired resistance to front-line therapy is inevitable, and response to later-line therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα). H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). METHODS: PK samples in phase I were obtained at day 1 and day 15 of cycle 1 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose) and sparse PK samples were collected in the phase II part of the trial. For pts enrolled in the food effect sub-study of phase II, plasma samples were collected during cycle 1 on day 15 and day 22 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose). Nonlinear mixed effect model (NONMEM) was applied for development of population PK models to fit H3B-6545 plasma concentration data with NONMEM® version 7.4 software. R was used for data management, visualization and statistical summaries. RESULTS: This phase I-II trial enrolled 47 pts in phase I part and 83 pts in the phase II part at the recommended phase II dose of 450 mg QD as of May 15, 2020. The 1180 plasma concentrations of H3B-6545 from a total of 103 pts at doses of 100-600 mg available as of January 15, 2020 were included in this analysis, with the following characteristics [n or (median, min-max) unit]: race (n=91/5/1/6 for White/Black/Asian/others), age (62.5, 31-81) yrs, body weight (79.5, 49-140) Kg, BMI (26.9, 17.6-45.6) Kg/m2, albumin (40, 29-52) g/dL, ALP (88.5, 39-917) IU/L, ALT (28, 10-193) IU/L, AST (36.5, 13-259) IU/L, bilirubin (8.6, 1.7-25.7) µM and creatinine clearance (112, 49.5-389) mL/min. The median number of prior therapy in the metastatic setting was 3 (range: 1 - 10). Out of 103 patients, 32 pts received treatment with a single high-fat meal to test food effect on PK over a randomized crossover design. H3B-6545 plasma concentrations were best described with a one compartment disposition PK model, plus a combined first- and zero-order parallel absorption and lag time. The estimated apparent clearance (CL/F) and volume of distribution (V/F) were 31 L/h and 422 L, respectively, with a typical terminal half-life of about 10 hours. H3B-6545 was absorbed fast, with a typical tmax of about 4 hours. A moderate to high variability (40-60%) was identified in major PK parameters (CL/F, V/F, bioavailability [F1]). A high-fat meal increased bioavailability by approximately 45% and prolonged tmax, roughly from 4 hours to 6 hours post dose. No significant effect was identified from other covariates: age, body weight, race, albumin, AST, ALP, ALT, bilirubin and creatinine clearance. CONCLUSIONS: H3B-6545 PK profiles in breast cancer patients were well described by a one-compartment disposition model with no significant effect of demographics, liver and renal function. When administered with a high fat meal, H3B-6545 exposure was modestly increased. Citation Format: Oneeb Majid, Jianjun Alan Xiao, Tarek Sahmoud, Sanae Yasuda, Lisa Cantagallo, Erika P Hamilton, Timothy Pluard, Dejan Juric, Antonio Gualberto, Ziad Husseiin. Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC) [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 PS12-15.

Abstract PS10-34: Clinical outcomes in de novo metastatic HER2-positive inflammatory breast cancer

Abstract Background: Advances in HER2-directed therapy have significantly improved survival in HER2+ metastatic breast cancer. Approximately 30% of de novo metastatic inflammatory breast cancer (mIBC) is HER2+, though there has been limited IBC representation in clinical trials evaluating the role of HER2-directed agents as first-line metastatic therapy. Elevated rates of locoregional progression or recurrence (LRPR) with systemic therapy alone also raise the question of whether trimodality therapy (TMT) may improve outcomes in IBC patients (pts) with limited metastatic disease, particularly in the setting of increasingly effective anti-HER2 therapy. Methods: Pts diagnosed with de novo HER2+ mIBC were identified from an IRB-approved IBC registry at Dana-Farber Cancer Institute. Clinical, pathology and treatment data were manually abstracted by chart review. Progression-free survival (PFS) was defined as time from IBC diagnosis to LRPR, distant progression/relapse or death (in the absence of event, censored at date of last follow-up). Overall survival (OS) was defined as time from IBC diagnosis to death from any cause or censored at date last known alive. For pts who underwent surgery of the primary tumor, pathologic complete response (pCR) was defined as no residual invasive carcinoma in the breast and axilla and survival was estimated from date of surgery. Median PFS and OS were estimated by Kaplan-Meier method; cumulative incidence of CNS metastasis and LRPR were estimated with death as competing risk. Results: 78 pts diagnosed between 1998-2019 with de novo HER2+ mIBC (41 hormone receptor (HR)-positive; 37 HR-negative) were identified. Median age at diagnosis was 53 years (yr; range: 24-91). Sites of metastatic disease at presentation included bone only (n=12), lymph node/contralateral chest wall only (n=17), bone and lymph node (n=5), visceral (n=40) and CNS with extracranial disease (n=4). As initial HER2-directed therapy, 37 pts received trastuzumab (H), 40 H plus pertuzumab and 1 T-DM1. At a median follow-up of 2.7 yr in the overall cohort, median PFS was 1.0 yr (IQR: 0.5-2.8 yr; 60 events) and median OS was 4.6 yr (IQR: 2.9-8.7 yr; 39 deaths). 34 pts had CNS metastasis with a cumulative incidence of 20% and 28% at 1 and 2 yr, respectively. LRPR developed in 26 pts, of which 16 occurred within 12 months (mo) of diagnosis. Cumulative incidence of LRPR at 1 and 2 yr was 21% and 29%, respectively. In 41 pts (53%), mastectomy was performed after receipt of systemic therapy. Median time from IBC diagnosis to surgery was 7.5 mo (IQR: 6.0-9.9 mo). Radiation was administered in 33 pts, 3 pre- and 30 post-mastectomy. Median OS from surgery was 5.2 yr (IQR: 3.1-8.4 yr). 9/41 pts (22%) achieved pCR; all pCR pts were alive at 1.3-8.9 yr since surgery. To investigate the value of therapy for locoregional control, a landmark analysis was performed in the subset of pts alive and LRPR free at 12 mo from diagnosis (n=56). 27 had surgery within 12 mo from diagnosis and 29 did not. LRPR occurred in 10/56; 9 were among pts who did not undergo surgery. Cumulative LRPR incidence at 1 and 2 yr since the 12 mo landmark was 21% and 29%, respectively, in pts who did not undergo surgery, and 0% at both time points in pts who had surgery (1 LRPR at 8 yr). Conclusion: Long-term outcomes in de novo HER2+ mIBC are overall similar to those reported in metastatic HER2+ non-IBC. More than half of pts underwent systemic and local therapy with good locoregional control and prolonged survival, suggesting a potential role for aggressive local therapy in this mIBC subset with favorable prognosis and effective systemic therapy. The high incidence of early CNS involvement in de novo HER2+ mIBC prompted us to explore this group in detail (Warren SABCS 2020 abstract). Larger studies are needed to better understand the effectiveness of TMT in HER2+ mIBC, highlighting the importance of collaborative research efforts in this rare subset. Citation Format: Ana C. Garrido-Castro, Samuel M. Niman, Marie Claire Remolano, Jennifer M. Rosenbluth, Caroline Block, Laura E. Warren, Jennifer Bellon, Beth T. Harrison, Faina Nakhlis, Meredith Regan, Beth Overmoyer. Clinical outcomes in de novo metastatic HER2-positive inflammatory 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 PS10-34.

Abstract PS14-20: Retrospective analysis of time to progression intracranially in HER2+ breast cancerpatients with brain metastases who receive treatment with radiation

Abstract Human epidermal growth factor receptor 2 (HER2) positive (+) breast cancer is a disease with distinct clinicopathological features. Survival for women with HER2+ disease has increased with the development of novel systemic therapeutic agents, however the brain is increasingly reported as the first site of relapse. As patients with HER2-positive breast cancer live longer, CNS progression after radiation therapy and / or surgery is an emerging clinical challenge. The average progression free interval intracranially is unknown for women who receive radiation for brain metastases while on modern HER2 targeted therapy. Multiple novel systemic agents are under investigation for the treatment of HER2 positive breast cancer metastatic to the brain. In order to establish a historical control for early phase clinical trials, understanding this time to progression is critical. In our retrospective chart review, we sought to determine the time to progression intracranially for women with HER2+ breast cancer who receive CNS radiation and/or surgery while on modern HER2 targeted systemic therapy. We present preliminary results from our review of 48 patients with HER2+ breast cancer with brain metastases treated at two academic referral centers between 2010-2017. 36 of these patients received some form of local therapy for brain metastases. Mean age at the time of diagnosis with primary breast cancer was 52, with a mean age of 55 at the time of diagnosis of brain metastases. The minority of patients (n=16) were stage IV at the time of their initial diagnosis. Standard of care systemic treatment was given in 43/48 cases. Mean length of time from the diagnosis of the primary breast cancer to the diagnosis of brain metastases was 34.6 months, including 3 patients diagnosed at initial presentation and at the other extreme, 2 patients diagnosed 9 years after their primary diagnosis of cancer. Of the patients who received treatment for brain metastases and for whom data was available (n=33), mean time from first treatment for brain metastases to first brain recurrence was 8.24 months (range: 1 to 24 months). 7 patients (21%) recurred within 3 months. In 9 patients mortality data was available. Mean time from treatment to death was 20 months (range 1 - 58 months). For patients who underwent surgery alone as primary treatment, mean time until first recurrence was 7.1 months (n=14), compared with a mean of 7.8 months for patients who received WBRT (n=26). Patients who received both surgery and radiation as a primary treatment had a mean time from first treatment to recurrence of 11.5 months (n=4). Only 34% of patients changed systemic treatment after the diagnosis of brain metastases. 5 patients had brain metastases as their only site of measurable disease. Only 1 of these patients had a change in systemic treatment after the diagnosis of brain metastases. These results suggest that the time from initial local treatment for brain metastases to recurrence is devastatingly short. Future clinical trials in metastatic HER2+ breast cancer should consider the impact novel therapeutics have on brain metastases in addition to overall and progression free survival. These data provide a historical reference for evaluating the impact of novel therapies on HER2-postive brain metastases. Citation Format: Jacklyn Marie Nemunaitis, Krisha Mehta, Selina Liu, Ursa Brown-Glaberman, Alison Stopeck. Retrospective analysis of time to progression intracranially in HER2+ breast cancerpatients with brain metastases who receive treatment with radiation [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 PS14-20.

Abstract OT-03-08: A Phase 2, open-label study to evaluate the safety and efficacy of the probody therapeutic (Pb-Tx) CX-2009 in metastatic HR-Positive/HER2-negative breast cancer (mHR+/HER2− BC) and of CX-2009 as monotherapy and in combination therapy with CX-072 in metastatic triple-negative breast cancer (TNBC)

Abstract Background: Probody® therapeutics (Pb-Tx) are masked antibodies designed to be selectively activated in the tumor microenvironment by tumor-associated proteases, while remaining largely inactive in normal tissue and in circulation. This allows Pb-Tx to address previously undruggable targets that are highly expressed in both tumor and normal tissue, such as the activated leukocyte cell adhesion molecule (ALCAM) CD166. CX-2009 is an investigational Probody drug conjugate consisting of an anti-CD166 monoclonal antibody conjugated to the microtubule inhibitor DM4. A Phase 1 study demonstrated safety and durable clinical activity in patients with mHR+/HER2− BC and in mTNBC patients who had received a median of 7 prior regimens. In the efficacy evaluable subgroup receiving doses of at least 4 mg/kg Q3W, the overall response rate (ORR; includes confirmed and unconfirmed responses) was 11% (HR+/HER2−; n=18) and 38% (TNBC; n=8), with a clinical benefit rate at 24 weeks (CBR24) of 35% in all breast cancer patients. Gr ≥3 DM4-associated ocular toxicities related to CX-2009 ≤7mg/kg were reported in 2%. In this Phase 2 study, CX-2009 monotherapy will be evaluated in patients with mHR+/HER2− BC and mTNBC. In addition, CX-2009 will be combined with CX-072, a Probody therapeutic directed against PD-L1, to evaluate the safety of the combination and whether the cytotoxic activity of the DM4 payload is additive with PD-L1 blockade via CX-072 in patients with mTNBC. CD166 expression in patients with HR+/HER2− BC was high (>90%) in the Phase 1 study; this cohort will enroll without screening for CD166. CD166 expression in patients with TNBC was variable and, as such, patients will undergo screening for CD166 positivity. Methods: This Phase 2, open-label noncomparative study with 3 parallel arms (n≈40/arm) is investigating the safety and activity of CX-2009 monotherapy (7 mg/kg Q3W) and the combination of CX-2009 (7 mg/kg Q3W) + CX-072 (1200 mg Q3W) in patients with previously treated locally advanced or metastatic HER2− BC. All patients will be adults with an ECOG status of 0-1, acceptable end-organ function, measurable disease, and willingness to receive ocular prophylaxis for DM4 related toxicities. Tumor tissue is required for CD166 expression analysis. Key eligibility criteria for the mHR+/HER2− BC cohort include 2-4 prior regimens (not including single-agent hormonal therapy). Patients with mTNBC must be CD166 positive by IHC and have received 1-3 regimens. For mTNBC patients who receive the doublet, key exclusion criteria include known PD-L1-negative tumor status, history of or active autoimmune disease, and progression within 120 days of first dose of an IO agent. Patients with active or chronic corneal disorders will be excluded from the study. All treatments will be given until disease progression or unacceptable toxicity. Radiology assessments will be done Q6W. The primary endpoint will be ORR assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints will include ORR, DoR, CBR16 and CBR24, and PFS by investigator, OS will also be assessed. This study will also evaluate tolerability, pharmacokinetics, and antidrug antibodies with CX-2009 as monotherapy and in combination with CX-072. Exploratory endpoints will include potential predictive markers of response or toxicity. This trial is actively enrolling. Email address for questions or comments: gpaton@cytomx.com Citation Format: Kathy D. Miller, Leisha A. Emens, Sara Tolaney, Sara A. Hurvitz, Erika Hamilton, Virginia Paton, Alison Hannah, Valentina Boni. A Phase 2, open-label study to evaluate the safety and efficacy of the probody therapeutic (Pb-Tx) CX-2009 in metastatic HR-Positive/HER2-negative breast cancer (mHR+/HER2− BC) and of CX-2009 as monotherapy and in combination therapy with CX-072 in metastatic triple-negative breast cancer (TNBC) [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 OT-03-08.

Abstract OT-35-01: Solti-1507 A phase ib study of ipatasertib and anti-her2 therapy in her2-positive advanced breast cancer with pik3ca mutation (ipather)

Abstract Background The combination of trastuzumab, pertuzumab (HP) and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive (HER2+) advanced breast cancer (BC). PIK3CA mutations 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 mutation (mut) had a shorter PFS. The AKT inhibitor ipatasertib (IPAT) blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. We hypothesize that ipatasertib + HP is safe and can be beneficial in patients with PIK3CAmut HER2+ BC. Trial design This is an open-label, single arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP (+/- endocrine therapy [ET]) in patients with PIK3CA mut HER2+ BC. Key inclusion criteria include the presence of locally advanced/unresectable or metastatic HER2+ BC with a PIK3CA mut (detected in tissue or plasma ctDNA); candidates to receive maintenance HP (+/- ET) after taxane discontinuation in first line setting for a reason different to progressive disease; male and female (pre and postmenopausal status); adequate performance status (ECOG 0-1); and adequate bone marrow, cardiac and hepatic function. Key exclusion criteria include: active or progressive brain metastases; diabetes mellitus requiring insulin, and prior exposure to an AKT inhibitor. The primary endpoint is to define the maximum tolerated dose (MTD) and the recommended phase 2 dose of the combination. 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. Grade ≥3 diarrhea for more than 72 hours or Grade ≥2 diarrhea for more than 5 days are considered DLTs amongst others. Secondary endpoints include objective response rate, duration of response, clinical benefit rate and PFS. Exploratory objectives include identification of molecular biomarkers of response to treatment both in ctDNA (Amplicon-seq) and tumor tissue (Breast Cancer 360 panel), as well as to characterize the pharmacokinetics of study drugs. Given the low risk for overlapping toxicities, full doses of IPAT (400mg orally once daily D1-21 q28d) and standard dose HP will be used in the first cohort. Dose reductions of IPAT (300mg and 200mg) are allowed if the full dose exceeds MTD. Loperamide is given as prophylaxis for diarrhea. In HR-positive tumors, ET may be started after the DLT period. Approximately 25 evaluable patients in a given dose level will be required to assess the safety of the combination of IPAT plus HP. Patients are currently being screened for PIK3CA mutations at 7 sites in Spain. The first patient was enrolled in March 2020 and the recruitment is ongoing. This study is sponsored by SOLTI and financially supported by Roche. For further information on this trial, visit ClinicalTrials.gov (NCT04253561) Citation Format: Mafalda Oliveira, Patricia Villagrasa, Eva Ciruelos, Joaquín Gavilá, Alexandra Cortegoso, Fernando Henao, Estela Vega, Javier S. Bofill, Vanesa Quiroga, Laura García-Estevez, Serafín Morales, Pablo Tolosa, Pamela Céliz, Xavier Gonzalez Farré, Cristina Saura. Solti-1507 A phase ib study of ipatasertib and anti-her2 therapy in her2-positive advanced breast cancer with pik3ca mutation (ipather) [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 OT-35-01.

Abstract PD3-09: HER2 L755S mutation is acquired upon resistance to lapatinib and neratinib and confers cross-resistance to tucatinib and trastuzumab in HER2-positive breast cancer cell models

Abstract Background: The role of HER2 mutations in anti-HER2 resistance is gaining more importance in HER2-positive (+) breast cancer (BC). The common HER2 L755S mutation is further enriched in metastatic lesions compared to primary tumors. Despite their mounting significance, effective therapies for HER2-amplified/mutant tumors are lacking. We recently reported that acquired resistance to lapatinib (Lap)-containing regimens is mediated by HER2 L755S, which could be overcome by the irreversible pan-HER tyrosine kinase inhibitor (TKI) neratinib (Nrb). However, less is known about the role of L755S in resistance to new generation TKIs, and the clinically implementable therapeutic strategies to overcome it. Materials and Methods: Our recently developed HER2+ BT474 cell models with acquired resistance to Lap (LapR) or Nrb (NrbR), developed through long-term exposure to increasing doses of the respective drug, and their naïve parental (P) counterparts were used. The resistant derivatives and their cognate P cells were subjected to proteomic (Reverse phase protein array (RPPA) and western blot) and transcriptomic (RNA-seq) characterization. For drug efficacy studies, change in cell growth was assessed using the in situ imaging-based high-throughput IncuCyte system. Results: Proteomic profiling of the resistant models and their P equivalents revealed partial restoration of HER2 phosphorylation and downstream signaling in the LapR and NrbR derivatives. Consistent with activated mTOR signaling observed in the resistant cells, we detected reduced levels of phospho (p)-RAPTOR S792, which is otherwise essential to inhibit the mTOR complex 1 (mTORC1). In addition, p-P38MAPK T180/Y182 levels were reduced. RNA-seq analysis revealed the presence of HER2 L755S mutation in the LapR and NrbR derivatives, but not in P cells, suggesting that the HER signaling reactivation could be attributed to acquisition of HER2 L755S. Interestingly, the NrbR cells co-harbor other pathogenic mutations in key BC related genes, the therapeutic and functional significance of which is being investigated. Importantly, the NrbR derivatives were cross-resistant to Lap and the monoclonal antibody trastuzumab (T). Next, we determined the efficacy of Nrb and the HER2-selective TKI tucatinib (Tuca), both recently approved for metastatic HER2+ BC, either alone or in combination with T. Nrb effectively inhibited the growth of LapR cells, although a higher dose (IC50: ~50nM) was required to inhibit the growth compared to that needed for naïve P cells (~IC50: ~2nM). When combined with T, Nrb was effective in inhibiting the LapR cell growth, though the inhibitory effect may very well be driven entirely by Nrb. On the other hand, the resistant derivatives were cross-resistant to Tuca, both as a single-agent and in combination with T. We then evaluated the efficacy of the antibody drug conjugate TDM1 and the irreversible pan-HER TKI poziotinib. In contrast to the high sensitivity of P cells to both these agents, a spectrum of effect was observed in the NrbR derivatives, with responses ranging from partial growth inhibition by poziotinib to complete response with TDM1, suggesting their therapeutic potential against tumors harboring HER2 mutations. Conclusions: Our findings suggest that HER2 mutations, particularly HER2 L755S, that emerge under the pressure of potent HER2-targeted therapy may confer cross-resistance to other single agent or combination HER2-targeted therapy. This holds important therapeutic implications in light of current treatment landscape. An in-depth molecular characterization of our resistant models to determine the differential gene expression and mutational profile is ongoing to gain additional mechanistic insights and to guide discovery of other actionable targets. Citation Format: Jamunarani Veeraraghavan, Ragini Mistry, Sarmistha Nanda, Vidyalakshmi Sethunath, Martin Shea, Tamika Mitchell, Meenakshi Anurag, Michael A. Mancini, Fabio Stossi, C. Kent Osborne, Mothaffar F. Rimawi, Rachel Schiff. HER2 L755S mutation is acquired upon resistance to lapatinib and neratinib and confers cross-resistance to tucatinib and trastuzumab in HER2-positive breast cancer cell 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 PD3-09.

Abstract PS13-16: Pharmacokinetic evaluation of an oral paclitaxel DHP107 (Liporaxel®) in patients with recurrent or metastatic breast cancer (MBC): Phase II study (OPERA, NCT03326102)

Abstract Background: Paclitaxel is a microtubule stabilizing anticancer therapy used to treat multiple cancers including breast cancer. DHP107 is an oral paclitaxel solubilized in lipid components using DaeHwa-Lipid bAsed Self-Emulsifying Drug delivery system (DH-LASED) technology. It demonstrated comparable efficacy and safety to IV paclitaxel in a phase 3 study for patients with advanced gastric cancer (Ann Oncol 2018) leading to regulatory approval in Korea, and also met the primary endpoint (ORR 54.5%) as first-line therapy (ESMO 2019) in the OPTIMAL Phase II study in patients with HER2 negative metastatic breast cancer (MBC). The confirmatory OPTIMAL Phase III study is ongoing in Asia and Europe. The OPERA Phase II study was designed as multinational, multicenter, randomized, open-label study to establish pharmacokinetic (PK) profile and efficacy of DHP107 in patients with MBC in the U.S. Method: A total of 72 patients with metastatic HER2 negative (HR+/HER2- or triple-negative breast cancer (TNBC)) will be randomized in a 2:1 fashion to receive DHP107 (200mg/m2 orally twice a day on Days 1, 8, and 15 in a 28-day cycle) or IV paclitaxel (80 mg/m2 on Days 1, 8, and 15 in a 28-day cycle) until disease progression or unacceptable toxicity. Tumor assessments are performed every 8 weeks. PK analyses were performed in a subset of patients receiving DHP107. A total of 103 blood samples were collected on Day 1 of Cycle 1 at predose and 1, 2, 3, 4, 6, and 10 hours post dose (before the 2nd dose administration on Day 1), and at predose on Day 8 of Cycle 1. All PK parameters were calculated by non-compartmental analysis using Phoenix WinNonlin version® 8.1. Results: A total of 13 subjects were enrolled in the PK substudy, All 13 patients were female and of Caucasian, non-Hispanic, ethnicity. Median Tmax was 2.17 h (range 1.92-4.08). Mean Cmax and AUC0-10h and their coefficient of variations (CV) were 330 ng/mL (31.1%) and 1233 ng·h/mL (30.3%), respectively (Table 1). The PK parameters of DHP107 were similar to those in a previous Phase I study in Korean cancer patients where Cmax and AUC0-48h were 235 ng/mL (43.9%) and 1348 ng·h/mL (19.7%) (Invest New Drugs 2012). Conclusion: PK profiles were well characterized from plasma concentrations in 13 Caucasian patients with MBC up to 10 hours after oral 200mg/m2 BID administration. DHP107 was rapidly absorbed and eliminated and inter-individual variability in exposure such as Cmax and AUClast was considered low. Compared to previous phase I PK results in Korean patients, Cmax and AUC parameters were similar after dosing with DHP107, demonstrating no clinically significant differences between Asian and Caucasian patients. Safety and efficacy will be evaluated in the ongoing OPERA and OPTIMAL studies. Table 1StatisticTmax(h)Cmax(ng/mL)AUClast, 0-10h(ngh/mL)AUCinf(ngh/mL)N13131311Mean(SD)330(103)1233(374)1462(411)CV%31.130.328.1Median[Min-Max]2.17[1.92-4.08] Citation Format: Hope S Rugo, Timothy J Pluard, Priyanka Sharma, Michelle Melisko, Ghassan Al-Jazayrly, Neelima Vidula, Yan Ji, David Weng, Hyeong-Seok Lim, Koung Eun Yoon, Hyun Ju Cho. Pharmacokinetic evaluation of an oral paclitaxel DHP107 (Liporaxel®) in patients with recurrent or metastatic breast cancer (MBC): Phase II study (OPERA, NCT03326102) [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 PS13-16.