Trastuzumab-containing Regimens Research Articles

1425P Efficacy and safety of KN026 in combination with chemotherapy in patients (pts) with unresectable or metastatic HER2 positive gastric or gastroesophageal cancers (GC/GEJC) after first-line treatment with a trastuzumab-containing regimen

1425P Efficacy and safety of KN026 in combination with chemotherapy in patients (pts) with unresectable or metastatic HER2 positive gastric or gastroesophageal cancers (GC/GEJC) after first-line treatment with a trastuzumab-containing regimen

Systemic Treatment Strategies and Outcomes of Patients With Synchronous Peritoneal Metastases of Gastric Origin: A Nationwide Population-Based Study.

Palliative systemic treatment is currently standard of care for metastatic gastric cancer. However, patients with peritoneal metastases of gastric origin are often underrepresented in clinical studies due to unmeasurable radiologic disease. This study describes the systemic treatment strategies and outcomes in patients with peritoneal metastases in a nationwide real-world setting. Patients with gastric adenocarcinoma and synchronous peritoneal metastases (with or without other metastases) diagnosed in the Netherlands between 2015 and 2020 were identified from the nationwide Netherlands Cancer Registry. Median overall survival (OS) and time-to-treatment failure were determined and multivariable Cox regression analyses were used to compare treatment groups, corrected for relevant tumor and patient characteristics. In total, 1,972 patients were included, of whom 842 (43%) were treated with palliative systemic therapy. The majority received capecitabine + oxaliplatin (CAPOX; 44%), followed by fluorouracil/leucovorin/oxaliplatin (FOLFOX; 19%), and epirubicin + capecitabine + oxaliplatin (EOX; 8%). Of the 99 (45%) patients who received second-line systemic treatment, ramucirumab + paclitaxel were administered most frequently (63%). After adjustment for sex, age, comorbidities, performance status, tumor location, Lauren classification, and the presence of metastases outside of the peritoneum, patients treated with a triplet containing docetaxel and those treated with a regimen containing trastuzumab had a significantly longer OS compared with patients treated with a doublet containing a fluoropyrimidine derivate + oxaliplatin (hazard ratio [HR], 0.69; 95% CI, 0.52-0.91, and HR, 0.68; 95% CI, 0.51-0.91, respectively). Monotherapy was associated with a shorter OS (HR, 2.08, 95% CI, 1.53-2.83). There is substantial heterogeneity in systemic treatment choices in patients with gastric cancer and peritoneal metastases in the Netherlands. In this study, patients treated with triplets containing docetaxel and with trastuzumab-containing regimens survived longer than patients who received doublet therapy. Despite this, median OS for all treatment groups remained below one year.

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P< 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P< 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-02.

Abstract PO2-10-07: Patterns of presentation, treatment and survival for older patients with metastatic breast cancer (MBC): results from a large prospective registry

Abstract Background: The median age of breast cancer diagnosis in the U.S. is 62 years; however, older pts with breast cancer are consistently underrepresented in clinical research. In population-based studies, older pts, particularly those aged 70+, do worse than their younger counterparts at every stage of disease, including stage IV. However, our understanding of patterns of recurrence, treatment patterns, and outcomes for older pts with MBC is limited by a lack of available data. Methods: We identified pts age >60 years seen at least once at a single, NCI-designated cancer center for a diagnosis of MBC between 1999-2022 with 1+ years of follow-up from the time of their metastatic diagnosis. We categorized pts into 5-year age groups (60-65; 66-70; 71-75; 76-80; >80) and two groups of 60-70 and >70. Clinicopathologic characteristics, treatment patterns, reason for treatment discontinuation, and the proportion enrolling on clinical trials were compared by tumor subtype and age group using Chi-Square testing. Median overall survival using Kaplan-Meier method was calculated from the date of initial MBC diagnosis to date of death or last follow-up, examined by tumor subtype and age. Results: The final analytic cohort included 1,115 patients diagnosed with MBC with median follow-up of 2.9 years (1.0-18.5). Median age at MBC diagnosis was 66.3 years (60.0-95.4) and 10% were non-White; disease subtype distribution was the following: 70.7% HR+HER2-, 11.9% HER2+, 17.4% TN. Overall, 22.2 presented with de novo MBC. Presentation of MBC did not vary by ages 60-70 vs. 70+, with no differences in disease characteristics such as grade and disease sites at MBC diagnosis (except for bone). However, the proportion of pts with HR+HER2- disease increased with age, from 69% of MBC in ages 60-70 and 76% in ages >70 (p=.02). In pts with this subtype receiving first-line (1L) therapy (n=783), use of endocrine therapy as 1L (with or without a CDK4/6 inhibitor) increased by age (77.8% in ages 60-65 v. 94.7% in ages >80); use of 1L chemotherapy also varied by age (22.2% in ages 60-65 v. 5.3% in >80). Among pts with HER2+ BC, 89% received a trastuzumab-containing regimen in the 1L setting; in pts with TN MBC, 94% received at least 1L line of chemotherapy. Overall, most pts discontinued 1L therapy for progression, not toxicity, and there was no variation in rates of discontinuation due to toxicity by age with 10.4% noted in both age groups, 60-70 and >70. The proportion of patients receiving 3+ lines of chemotherapy across disease subtype decreased with increasing age (e.g., 54% in ages 60-65 v. 25% in ages >80 among HR+HER2-; 69% in ages 60-65 and 33% in ages >80 among TN MBC). Overall, enrollment on a clinical trial in the MBC setting steadily decreased with older age from 40% in ages 60-65 to 13% in ages >80 (p=.0004). Overall median overall survival differed with increasing age from 4.4 yrs in ages 60-65 to 2.7 yrs in ages >80 (p< 0.005). In descriptive analyses, the proportion of pts alive at 2 yrs was variable. For those ages 60-65, 37.8%, 17.1%, and 42.9% of pts with HR+HER2, TN, and HR-HER2+, respectively were alive at 2 yrs. For those ages >80, 23.7%, 0%, and 0% of pts with HR+HER2-, TN, and, HR-HER2+ disease were alive at 2 yrs. Median survival times were < 2 years for pts with TN regardless of age. Conclusions. In a unique, large prospective cohort of older pts with MBC, we examined detailed information on disease presentation, treatments, and outcomes, lending new information on patterns of care and experiences for older pts with MBC in a modern real-world experience. Limitations include a single center experience and small numbers of older pts with HER2+ and TN disease. Although the oldest pts with MBC had similar disease characteristics as younger pts in our dataset, survival outcomes were poor, particularly for those ages 80+. Therapeutic approaches, likely including improved supportive care, are urgently needed to optimize outcomes in the oldest pts with MBC. Table 1. Outcomes for older pts with MBC Citation Format: Melissa Hughes, Alyssa Patterson, Alexandra Newman, Amanda Higgins, Gregory Kirkner, Janet Files, Molly Skeffington, McKenna Moore, Sarah Strauss, Nicole Kuhnly, Lindsey Crowley, Sara Tolaney, Nancy Lin, Rachel Freedman. Patterns of presentation, treatment and survival for older patients with metastatic breast cancer (MBC): results from a large prospective registry [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-10-07.

HER2-Positive Metastatic Colorectal Cancer.

Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

A Systematic Review of Health-Related Quality of Life in Women with HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab.

Many trials of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer treatment with trastuzumab have provided evidence of improved clinical outcomes. This systematic review examined how a regimen that includes trastuzumab affects patients' health-related quality of life (HRQoL) during and after treatment. A systematic search for articles published up to February 2023 without restrictions of language or publication year was performed using the Pubmed, Embase, and Scopus databases. We included studies of women aged >18 years with metastatic HER2-positive breast cancer treated with a trastuzumab-containing regimen. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) tool (2.0) for randomized controlled trials (RCTs) and the Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) tool for cross-sectional studies. We used Microsoft Excel to extract and synthesize data, and documented the review procedure following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In total, eight studies compared 1104 trastuzumab-treated patients and 1003 non-trastuzumab-treated patients. Most studies were RCTs (n=7) and one was a prospective observational study. All the included studies used the EORTC-QLQ-C30, EORTC-QLQ-BR23, FACT-B, or FACT-G questionnaires. During treatment, patients taking regimens that included trastuzumab showed clinical improvement in HRQoL, social functioning, and role functioning. After the treatment, patients' HRQoL profiles in the trastuzumab and chemotherapy arms were similar. However, trastuzumab (versus chemotherapy) treatment led to clinically improved functional status, role and physical functioning, and fatigue. The quality assessment revealed some concerns in most RCTs, with the risk of bias being high in two studies, low in one study, and moderate in the cross-sectional study. Trastuzumab-containing regimens administered to HER2-positive breast cancer patients at the metastatic stage evidenced beneficial effects on total HRQoL during and after treatment. Upon therapy cessation, patients' HRQoL scores for both interventions improved. Nevertheless, HRQoL profiles of patients treated with trastuzumab were more favorable, particularly for functional status, role functioning, physical well-being, and fatigue. This review was registered in PROSPERO (registration number: CRD42021259826).

Phase 1b/2, open-label dose-escalation and -expansion study evaluating trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with HER2+ and HER2-low gastric cancer (GC): DESTINY-Gastric03 (DG-03).

TPS424 Background: T-DXd is approved for treatment of advanced/metastatic HER2+ GC after a trastuzumab-based regimen. The efficacy of T-DXd in advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC has been shown (confirmed objective response rate [ORR], 43% vs 12% with standard chemotherapy) in previously treated Japanese or South Korean pts (DG-01) and in Western pts with progression on a trastuzumab-containing regimen (confirmed ORR, 42%; DG-02). Also, antitumor activity was shown in pts with HER2-low GC (confirmed ORR, 26.3% [IHC 2+/ISH−], 9.5% [IHC 1+]) in DG-01. Other studies have shown benefits of immunotherapies combined with trastuzumab and other chemotherapies for treatment of HER2+ GC. The DG-03 trial is evaluating the safety and efficacy of T-DXd in combination with chemotherapy and/or immunotherapy in HER2-expressing GC. Previously, confirmed ORRs of 50% and 43% were reported with T-DXd + 5-fluorouracil (5-FU) and T-DXd + capecitabine (Cap), respectively, in the second-line or later setting in part 1 of DG-03. The protocol was amended to add an additional arm in part 2 and a new part 3, which will investigate T-DXd in combination with a fluoropyrimidine and volrustomig (MEDI5752), a PD-1/CTLA-4 bispecific antibody, in pts with HER2+ and HER2-low (IHC 2+/ISH− or IHC 1+) GC. Methods: DG-03 (NCT04379596)is a multicenter, dose-escalation (part 1) and -expansion (parts 2 and 3) study in HER2-expressing, locally advanced or metastatic, unresectable gastric, gastroesophageal junction, or esophageal adenocarcinoma. In arm F of part 2, pts with previously untreated HER2+ GC will be treated with T-DXd + investigator’s choice of 5-FU or Cap + pembrolizumab. In part 3, pts with previously untreated HER2+ (arm 3A) or HER2-low (arm 3B) GC will receive T-DXd + investigator’s choice of 5-FU or Cap + volrustomig. The primary endpoint in parts 2 and 3 is investigator-assessed confirmed ORR per RECIST v 1.1. Secondary endpoints include safety, duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596 .

Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study

Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe. DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing. Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis. These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Daiichi Sankyo and AstraZeneca.

The role of education in adjusting to changes in clinical practice for gastric or gastroesophageal junction adenocarcinomas.

470 Background: Gastric or gastroesophageal junction (GEJ) adenocarcinomas are difficult to treat and associated with poor prognosis, specifically in advanced disease. Recently approved and investigational immune checkpoint inhibitors (ICIs) and HER2-directed antibody-drug conjugates (ADCs) are changing the treatment landscapes for gastric cancer and GEJ cancer, allowing clinicians to manage difficult-to-treat patients. However, these advances also create knowledge and practice gaps that pose many challenges warranting education to close these gaps and to assess current practices. Methods: PlatformQ Health’s proprietary workflow digital technology was utilized to launch a 4-part CME series online in December 2021 which remains on-demand through December 2022 at OMedLive.com. Each module focused on the following topics: 1) HER2 testing, 2) Current care for HER2+ gastric or GEJ cancer, 3) Treatment for unresectable disease and trastuzumab-resistant disease, and 4) adverse event management. This series was conducted in partnership with the American Gastroenterological Association and accredited by the Postgraduate Institute for Medicine. Clinicians engaging in this educational series were assessed at pre- and immediate post-activity. Practice pattern insights and education impact were assessed post-activity. Results: To date, 2,568 US-based clinicians have participated in the educational series. All 6 questions across the 4 modules in the series showed significant improvements in knowledge and competence related to HER2 testing, defining the standard of care, treatment beyond trastuzumab resistance, treatment for unresectable disease, and managing adverse events. Provider insights evaluated post-series revealed 41% of clinicians will consult with a pulmonologist upon development of interstitial lung disease; 51% identified trastuzumab deruxtecan as a novel HER2-targeted therapy having the greatest potential to improve patient outcomes; and 26% reported not repeating HER2 expression testing following progression on a trastuzumab-containing regimen. Evaluating the impact of the educational series, 88% of clinicians reported a positive impact on patient experience and 94% on clinical practice change following participation. The qualitative data depicting the reported impact will be shared. Conclusions: This serialized education was effective in improving knowledge and competence across four major themes of practice within gastric and GEJ cancer management. Provider insights revealed practice shifts following participation and practice impact assessments demonstrated the rapid application of real-time digital education.

Computational pathology–based HER2 quantification to identify novel biomarkers in gastric cancer (GC).

449 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for treatment of HER2-positive GC/gastroesophageal junction adenocarcinoma (GEJA) after chemotherapy (Japan) and for advanced/metastatic GC/GEJA after a trastuzumab-containing regimen (US/Israel/Singapore). Conventional HER2 immunohistochemistry (IHC) scoring identifies potential responders to trastuzumab but may not be suitable for next-generation ADCs capable of bystander killing, such as T-DXd [Modi NEJM 2022]. Use of computational pathology–based tools enables precise and accurate quantification of HER2 expression and spatial analysis, which enables design of better scores to reflect the T-DXd mechanism of action. Methods: Quantitative continuous scoring (QCS) was performed to quantify HER2 expression and distribution per cell in digitized images of HER2-stained (IHC, Ventana 4B5) GC. A QCS-derived signature was identified, called the continuous spatial proximity score (cSPS), which considers spatial location of tumor cells in addition to HER2 expression level and can be used as a surrogate for potential bystander activity. We retrospectively stratified patients in DESTINY-Gastric01 (DG-01; NCT03329690; T-DXd arm: n=123a; standard of care [SOC] arm: n=59a) using cSPS to give a binary QCS biomarker positive (BM+) or negative (BM−) status. QCS cSPS signature was independently validated on the DESTINY-Gastric02 cohort (DG-02; NCT04014075; n=71a). Results: In the DG-01 cohort, enrolled per HER2-positive status by IHC using ASCO/CAP GC scoring guidelines, median progression-free survival (mPFS) was 5.5a mo with T-DXd and 2.8a mo with SOC. QCS-derived cSPS scores showed significant survival benefit for BM+ vs BM− in the DG-01 T-DXd arm ( P<0.0001; HR=0.37 [0.24-0.58]) and longer mPFS for BM+ (8.3 mo) vs BM− (3.9 mo). Within the SOC arm, this signature showed the inverse prognosis ( P=0.034; HR=2.17 [1.06-4.44]; mPFS, 2.8 mo for BM+ vs 4.9 mo for BM−), strongly suggesting the signature is predictive of T-DXd response. This signature was validated in the DG-02 cohort (mPFS, 5.5 mo on enrollment by IHC status, 10.1 mo for BM+ vs 3.7 mo for BM−; HR=0.24 [0.13-0.45]; P<0.0001). Conclusions: We established QCS, a novel scoring method for tissue biomarkers. Our validated data and results support possible future use of this quantitative approach against manual scoring for identification of patients with GC who may benefit from T-DXd therapy. Clinical trial information: NCT03329690 , NCT04014075 . [Table: see text]

Translational Results of Zo-NAnTax: A Phase II Trial of Neoadjuvant Zoledronic Acid in HER2-Positive Breast Cancer.

Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR.

Effect of the HER-2/CEP17 ratio in IHC 2+/FISH-amplified breast cancer on pathological complete response to neoadjuvant pertuzumab and trastuzumab treatment-a retrospective cohort study.

Human epidermal growth factor receptor-2 (HER-2) protein expression level could serve as a predictor of pathological complete response (pCR) to neoadjuvant trastuzumab-containing regimens. The aim of the present study was to evaluate whether pCR to neoadjuvant trastuzumab and pertuzumab treatment is dependent on the level of the HER-2/CEP17 (chromosome enumeration probe 17) ratio in immunohistochemistry (IHC) 2+/fluorescence in situ hybridization (FISH)-amplified breast cancer. Patients with primary IHC 2+/FISH-amplified breast cancer who underwent neoadjuvant anti-HER-2 dual-targeted therapies were retrospectively included between January 1, 2020 and May 30, 2021. The primary predictive variable was HER-2/CEP17 ratio, and the primary outcome variable was pCR. Other variables consisted of age, menopausal status, tumor-node-metastasis (TNM) stage, estrogen receptor (ER), progesterone receptor (PgR), and Ki-67. Association between clinicopathologic variables and pCR was evaluated using the chi-square test and logistic regression analysis. The median age of the patients was 51.78 years (25-67 years), and 50.7% of the patients were in the premenopausal stage. The clinical stage at diagnosis was Stage III in 38 patients (55.1%). Of all patients, 40.6% patients were estrogen receptor positive, and 75.4% patients had a Ki-67 index of ≥30%. The overall pCR (ypN0/isypN0) rate was 31.9%. Patients with HER-2/CEP17 ratio ≥6.0 had a pCR rate of 55.0%, it was statistically higher than 22.4% in patients with HER-2/CEP17 ratio <6.0. Logistic regression analysis confirmed the independent association between HER-2/CEP17 ratio and pCR (P=0.020, OR: 5.203, 95% CI: 1.302-20.783). A HER-2/CEP17 ratio ≥6.0 might be related to more achievement of pCR in the neoadjuvant anti-HER-2 dual-targeted therapies. Further studies are needed to validate the finding.

1205MO Updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen

Primary results of DESTINY-Gastric02 (NCT04014075; data cutoff [DCO] April 9, 2021), a single-arm, phase II trial of T-DXd in Western pts with HER2+ gastric/GEJ cancer, demonstrated a confirmed objective response rate (cORR) of 38.0% (95% CI, 27.3-49.6), and safety consistent with the established T-DXd safety profile. We report OS and updated efficacy and safety. Pts with centrally confirmed HER2+ (IHC3+ or IHC2+/ISH+ biopsy after progression on trastuzumab-based therapy) unresectable/metastatic gastric/GEJ cancer who progressed on or after 1L therapy received T-DXd 6.4 mg/kg Q3W. The primary endpoint was cORR per RECIST v1.1 by independent central review (ICR). Progression-free survival (PFS) by ICR, duration of response (DOR) by ICR, OS, and patient-reported outcomes based on the European Organization for Research and Treatment of Cancer 5-dimension 5-levels (EQ-5D-5L) quality-of-life (QoL) and Functional Assessment of Cancer Therapy-Gastric (FACT-GA) questionnaires were secondary endpoints. At DCO (November 8, 2021), 79 pts from the US/EU had received T-DXd. 76 pts (96.2%) had received 1 prior line of therapy and 3 (3.8%) had received 2 lines. With a median duration of follow up of 10.2 mo, 10 pts (12.7%) remained on treatment. Median OS was 12.1 mo (95% CI, 9.4-15.4); landmark 12-mo OS rate was 50.6%. cORR was 41.8% (33/79; 4 complete and 29 partial responses). Median DOR was 8.1 mo (95% CI, 5.9-NE). Median PFS was 5.6 mo (95% CI, 4.2-8.3). All pts experienced ≥1 treatment-emergent adverse event (TEAE); 55.7% experienced grade ≥3 TEAEs. The most common TEAEs were nausea (67.1%), vomiting (44.3%) and fatigue (57.0%). Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 pts (10.1%); 6 (7.6%) had grade 1-2 and 2 (2.5%) had grade 5. At DCO (April 9, 2021), QoL assessed by EQ-5D-5L and FACT-GA had been maintained over the treatment course. T-DXd continues to demonstrate substantial clinical benefit and a tolerable safety profile in 2L+ Western pts with HER2+ unresectable/metastatic gastric/GEJ cancer.

P-159 Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma who have progressed on or after a trastuzumab-containing regimen (DESTINY-Gastric04): A randomized phase 3 study

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. T-DXd is approved globally to treat HER2-positive (HER2+) metastatic breast cancer, and to treat HER2+ GC after trastuzumab-based therapy (United States and Israel) or GC that has progressed after chemotherapy (Japan). In the primary analysis of DESTINY-Gastric01 (DS8201-A-J202; NCT03329690), an open-label, multicenter, randomized, phase 2 trial in patients with HER2+ advanced GC or GEJ adenocarcinoma, T-DXd demonstrated clinically relevant improvement compared with standard of care in objective response rate (ORR; 51% versus 14%; P P = 0.01) in the third-line or later (Shitara, N Engl J Med 2020). The DESTINY-Gastric04 study aims to evaluate the efficacy and safety of T-DXd compared with the combination of ramucirumab and paclitaxel in patients with HER2+ GC or GEJ adenocarcinoma in the second-line setting. DESTINY-Gastric04 (NCT04704934) is a global, multicenter, open-label, 2-arm, randomized, phase 3 study in patients with HER2+ metastatic and/or unresectable GC or GEJ adenocarcinoma. Eligible patients must be adults (according to local regulations), with an ECOG performance status of 0 or 1 at screening, with documented GC or GEJ adenocarcinoma that has been previously treated in the metastatic first-line setting (including neoadjuvant or adjuvant therapy if progression on or within 6 months of completing therapy) with a trastuzumab-containing regimen. HER2-positivity (IHC 3+ or IHC 2+/ISH+) must be centrally confirmed on tumor biopsies obtained after progression on or after trastuzumab. Patients must not have received anticancer therapy after a first-line trastuzumab-containing regimen. Patients will be randomized 1:1 to receive T-DXd (6.4 mg/kg every 3 weeks) or ramucirumab (8 mg/kg on days 1 and 15 of a 28-day cycle) in combination with paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 28-day cycle). This study is actively enrolling from 24 different countries across Europe and Asia with approximately 490 participants planned. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of T-DXd. NCT04704934. Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc. This study was funded by Daiichi Sankyo, Inc., and AstraZeneca.

A prognostic scoring system for conversion surgery after trastuzumab-based chemotherapy for human epidermal growth factor receptor 2-positive advanced gastric cancer

PurposeTo investigate the clinical indications and prognostic significance of surgical interventions after chemotherapy using trastuzumab-containing regimens for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC).MethodsA total of 146 patients with AGC who underwent chemotherapy were enrolled in this retrospective study. Tumors with an immunohistochemistry (IHC) score of 3 + or an IHC score of 2 + plus fluorescence in situ hybridization positivity were defined as HER2-positive AGC. We devised a scoring system for predicting prognosis associated with conversion surgery.ResultsThirty-three patients received trastuzumab-based chemotherapy for HER2-positive tumors. Multivariate analyses identified advanced age, peritoneal dissemination, histologically undifferentiated tumors, and tumor response of progressive disease as independent prognostic factors for a worse prognosis. Twelve patients with HER2-positive AGC underwent conversion surgery. The conversion surgery group of patients with HER2-positive AGC had a better prognosis than the chemotherapy-alone group. A prognostic scoring system based on age, peritoneal dissemination, and histological type was significantly correlated with the presence or absence of conversion surgery and the prognosis of patients with HER2-positive AGC.ConclusionsOur scoring system has the clinical potential to predict prognosis associated with conversion surgery after trastuzumab-containing chemotherapy for patients with HER2-positive AGC.

Abstract PD8-04: Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results

Abstract Introduction: HER2 is overexpressed on 15-20% of breast cancers and is a clinically important cancer driver. In spite of the HER2 targeted therapy’s success, most patients in the metastatic setting will eventually experience disease progression. ARX788 is an antibody drug conjugate (ADC) that consists of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269, that is site-specifically conjugated to the antibody via a non-natural amino acid incorporated into antibody by using a proprietary EuCODE technology platform. The phase 1 study ACE-Breast-01 (ZMC-ARX788-111 [CTR20171162]) evaluates the safety, pharmacokinetics, and efficacy of ARX788 in patients in China with metastatic HER2-positive breast cancer. Methods: ACE-Breast-01 is an open label, single site, dose escalation study using a 3+3 study design in 69 heavily pretreated patients (median of 6 prior lines of therapy, range: 2-17) with metastatic HER2-positive breast cancer who received intravenous ARX788. While the ARX788 MTD has not been determined, the 1.5 mg/kg of ARX788 dose is reported herein. Eligible patients had histologically documented, incurable, locally advanced or metastatic HER2+ (IHC 3+ and/or FISH positive) breast cancer whose disease had failed prior anti-HER2 treatments in the advanced disease setting; ECOG performance ≤1; adequate organ function; no history of interstitial lung disease or other significant lung disease; no radiotherapy for pulmonary diseases including lung parenchyma; no history of keratitis, corneal disease, or active ocular infection; no unstable brain or spinal cord metastasis; and no history of hypersensitivity to trastuzumab or any component of ARX788. The DLT assessment period was 84 days for pulmonary toxicity and one cycle of duration for all other toxicities. Investigators assessed efficacy using RECIST 1.1 and evaluated safety using NCI-CTCAE V.4.1. Results: Nineteen patients showed clinical response in the 1.5 mg/kg Q3W cohort, with the confirmed objective response rate of 66% (19/29, exact 95% CI, 45.7% to 82.1%), with median duration of response of 14.4 months [95% CI (9.0, NA)]. The disease control rate (CR + PR + SD) among the 29 patients treated was 100%. All patients (29/29, 100%) received prior trastuzumab in addition to other anti-HER2 treatments. Patients were heavily treated with prior HER2-targeted therapies and demonstrated robust ORR ranging from 65-80% (Table 1). ARX788 was generally well tolerated with most adverse events being grade 1 or 2 and were manageable. Low systemic toxicity (low incidence and low grade of neutropenia, thrombocytopenia, anemia, decrease WBC counts, nausea, vomiting, constipation, fatigue, etc.) was observed. No DLT or drug-related deaths occurred, as of data cut-off of 30-Jun-2021. Conclusion: At the 1.5 mg/kg dose level, ARX788 had robust anti-tumor activity in patients whose disease was resistant/refractory to other HER2 targeted therapies and was generally well tolerated with low systemic toxicity. Table 1.Summary of ACE-Breast-01 Confirmed ORR in patients whose disease is resistant or refractory to prior HER2 treatment (trastuzumab, ADCs, TKIs, and bispecific antibodies) at ARX788 1.5 mg/kg Q3WPrior anti-HER2 therapy*Confirmed ORRTrastuzumab containing regimens*19/29 (66%)HER2 ADCs (T-DM1, DX126-262, A166, BAT8001, and HS630) regimens**4/5 (80%)​HER2 TKIs (lapatinib, pyrotinib, neratinib, AST-1306, and Hemay-022) regimens15/23 (65%)​Both HER2 ADC and HER2 TKI regimens3/4 (75%)Bispecific antibodies (KN026 and M802) containing regimens3/4 (75%)*All patients (29/29) received prior trastuzumab-containing regimens.**One patient who received prior pertuzumab also achieved confirmed PR. Citation Format: Jiang Zhang, Dongmei Ji, Weina Shen, Qin Xiao, Yajia Gu, Joyce O’Shaughnessy, Gang Xia, Yanping Ji, Gaozhun Xiong, Matt Li, Dong Xu, Robert Cartmell, Cynthia Song, Jinchun Yan, Xichun Hu. Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results [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 PD8-04.

Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03.

295 Background: T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. T-DXd is approved for HER2+ advanced/metastatic GC/GEJA after a prior trastuzumab-based regimen (US/Israel) and GC after chemotherapy (Japan). In DESTINY-Gastric01, T-DXd showed improved efficacy vs standard chemotherapy in Japanese and Korean pts (≥2 prior therapies) with advanced HER2+ GC/GEJA. Preclinical data of T-DXd combinations suggest encouraging antitumor activity. DESTINY-Gastric03 is the first study of T-DXd combinations in GC/GEJA. Methods: DESTINY-Gastric03 (NCT04379596) is a 2-part, phase 1b/2, multicenter, open-label, 3+3 dose-escalation (part 1) and -expansion (part 2) study in advanced/metastatic HER2+ GC/GEJA. In part 1, pts with locally confirmed HER2+ GC/GEJA (IHC 3+ or IHC 2+/ISH+) who progressed on/after ≥1 prior therapy including a trastuzumab-containing regimen received T-DXd intravenously (IV) every 3 weeks + assigned combination. Primary objectives were safety and recommended phase 2 dose (RP2D). Preliminary antitumor activity was a secondary objective; confirmed objective response rate (ORR) was a secondary endpoint. We report the T-DXd + fluoropyrimidine cohorts. Results: In part 1, 15 pts were assigned to T-DXd + IV 5-fluorouracil (5-FU) and 10 pts to T-DXd + oral capecitabine (Cap). In addition to trastuzumab, all pts had received prior treatment with 5-FU and/or Cap and a median of 2 (range, 1-5) prior lines of therapy. The most common grade ≥3 AEs (%) were anemia (33), decreased neutrophil count (33), nausea (13), and stomatitis (13) with T-DXd + 5-FU and decreased neutrophil count (40), anemia (30), and nausea (20) with T-DXd + Cap. Starting doses were T-DXd 5.4 mg/kg + 5-FU 800 mg/m2 and T-DXd 5.4 mg/kg + Cap 1000 mg/m2 twice daily (BID). There were 2 dose-limiting toxicities of grade 3 stomatitis with T-DXd 6.4 mg/kg + 5-FU 800 mg/m2; this exceeded the maximum tolerated dose and was discontinued. RP2Ds were T-DXd 6.4 mg/kg + 5-FU 600 mg/m2 and T-DXd 6.4 mg/kg + Cap 1000 mg/m2 BID. Preliminary confirmed and confirmed + unconfirmed ORR at the RP2D for T-DXd + Cap were 3/7 and 5/7, respectively; 3/3 pts at the starting dose of T-DXd + Cap had confirmed ORR. ORR data for T-DXd + 5-FU are not yet mature. Conclusions: In the first T-DXd + fluoropyrimidine combination study in HER2+ GC/GEJA, preliminary part 1 results suggest tolerability and feasibility of the RP2Ds for T-DXd + 5-FU and T-DXd + Cap. Preliminary ORR with the T-DXd + Cap RP2D (n = 7) showed efficacy with this combination in heavily pretreated, trastuzumab- and fluoropyrimidine-refractory, HER2+ GC/GEJA. This study is ongoing, with further combinations and follow-up planned. Clinical trial information: NCT04379596.

LBA55 Primary analysis of a phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen

Overexpression and/or amplification of HER2 occurs in ∼20% of gastric or GEJ cancers. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate T-DXd improved response and overall survival vs physician’s choice irinotecan/paclitaxel in pts from Japan/Korea with locally advanced or metastatic HER2+ gastric/GEJ cancer who progressed on ≥2L therapy including trastuzumab. Here, we report data from the single-arm, phase 2 DESTINY-Gastric02 trial, the first 2L study of T-DXd in Western pts with HER2+ gastric/GEJ cancer.

1436TiP Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-positive gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma who have progressed on or after a trastuzumab-containing regimen (DESTINY-gastric04, DG-04): A randomized phase III study

T-DXd is an antibody–drug conjugate of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. T-DXd is approved globally to treat HER2-positive (HER2+) metastatic breast cancer, and in the US and Japan to treat advanced HER2+ GC. In the primary analysis of DESTINY-Gastric01 (DS8201-A-J202; NCT03329690), an open-label, multicenter, randomized, phase II trial in pts with HER2+ advanced GC or GEJ adenocarcinoma, T-DXd demonstrated clinically relevant improvement compared with standard of care in objective response rate (ORR; 51% vs 14%; P < 0.001) and overall survival (OS) benefit (12.5 vs 8.4 mo; hazard ratio [HR] 0.59 [95% CI 0.39-0.88]; P = 0.01) in the third-line or later (Shitara, N Engl J Med 2020). The DG-04 study aims to evaluate the efficacy and safety of T-DXd vs the combination of ramucirumab (ram) and paclitaxel (ptx) in pts with HER2+ GC or GEJ adenocarcinoma in the second-line setting. DG-04 (NCT04704934) is a phase III, global, multicenter, randomized, open-label study in pts with HER2+ metastatic and/or unresectable GC or GEJ adenocarcinoma. Eligible pts must be adults (according to local regulations), with an ECOG performance status of 0 or 1, with documented GC or GEJ adenocarcinoma that has been previously treated in the metastatic first-line setting with a trastuzumab (tmab)-containing regimen. HER2-positivity (IHC3+ or IHC2+/ISH+) must be centrally confirmed on tumor biopsies obtained after progression on or after tmab. Pts must not have received anticancer therapy after a first-line tmab-containing regimen. Pts will be randomized 1:1 to receive T-DXd (6.4 mg/kg every 3 weeks) or ram (8 mg/kg on days 1 and 15 of a 28-day cycle) in combination with ptx (80 mg/m2 on days 1, 8, and 15 of a 28-day cycle). This study is actively enrolling with approximately 490 participants planned. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of T-DXd. NCT04704934. Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, of ApotheCom. Daiichi Sankyo, Inc., and AstraZeneca.

Pyrotinib Plus Vinorelbine Versus Lapatinib Plus Capecitabine in Patients With Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Retrospective Study.

BackgroundPyrotinib is a newly-developed irreversible pan-ErbB (erythroblastic leukemia viral oncogene homolog) receptor oral tyrosine kinase inhibitor (TKI) with promising efficacy in the human epidermal growth factor receptor-2 (HER2) positive breast cancer. The phase III PHOEBE study proved that pyrotinib plus capecitabine exceeded lapatinib plus capecitabine (LX) in PFS (p < 0.001). Oral vinorelbine is commonly used in combination with anti-HER2 treatment. However, no evidence was reported in terms of the real-world pattern, safety, and efficacy of pyrotinib plus vinorelbine (NP) compared with LX.MethodsMedical records were retrospectively evaluated for all HER2-positive metastatic breast cancer (MBC) patients who experienced progression on prior trastuzumab-containing regimens (advanced setting) and taxane (any setting) and received NP or LX therapy from 2015 to 2021 in five institutions.ResultsA total of 224 patients were enrolled and evaluated, of which 132 (58.9%) patients received LX and 92 (41.1%) patients received NP. The median progression-free survival (mPFS) of NP group was significantly longer than that in LX group (8.3 vs 5.0 months, HR = 0.47 95% CI 0.34–0.65, p < 0.001). The advantage of NP over LX was seen both in patients with trastuzumab resistance (p < 0.001) and refractoriness (p = 0.004). The NP group had more diarrhea cases (23.9%) compared to the LX group (8.3%). Discontinuation rates in the two groups were similar.ConclusionsThis trial revealed the clinical practice of NP and LX treatment among HER2+ MBC patients pretreated with trastuzumab in China. More patients received LX than NP in real-world while the efficacy of NP exceeded LX in terms of PFS regardless of resistant status of trastuzumab. Although the NP group had more diarrhea cases, toxicities in both groups were acceptable.