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Background Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. Methods Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. Results The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p  = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm ( p  = 0.0035). Adverse events were similar between the two arms. Conclusion In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. Trial registration Clinicaltrials.gov NCT02073487 , February 27, 2014.

Abstract Background Trastuzumab combined with chemotherapy is a standard treatment for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer in later lines. Lapatinib and trastuzumab have also demonstrated efficacy. This study assessed the efficacy, toxicity, and quality of life (QoL) of trastuzumab plus lapatinib (with endocrine therapy for hormone receptor-positive cases) versus trastuzumab with physician-selected chemotherapy in patients previously treated with at least 2 anti-HER2 regimens. Methods In this open-label, multicenter phase II trial, 59 patients were randomized 1:1 to receive either trastuzumab and lapatinib (arm A) or trastuzumab with chemotherapy (arm B). The primary endpoint was clinical benefit rate (CBR), defined as confirmed complete response, partial response, or stable disease for ≥24 weeks. Secondary endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), QoL, and safety. Results With a median follow-up of 57.5 months, the CBR was 20.7% in arm A and 26.7% in arm B (P = .76). The ORR was 13.8% versus 20.0% (P = .73), and median PFS was 3.6 months in arm A versus 6.1 months in arm B (HR 0.63; P = .08). Median OS was 29.9 versus 31.1 months (HR 1.07; P = .82). Adverse events occurred in 86.2% (arm A) and 66.7% (arm B) of patients, with grade 3–4 events in 24.1% and 13.3%, respectively. QoL favored arm A (P = .03). Due to early study closure and limited sample size, all results should be considered exploratory and not powered to assess definitive treatment effects. Conclusions While efficacy differences were not significant, trastuzumab with lapatinib showed better QoL despite higher adverse event rates, suggesting it may be a viable chemotherapy-free option for pretreated HER2-positive advanced breast cancer. EudraCT trial registration number 2013-005044-29

In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1–14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1–21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2–28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8–26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2–20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5–8·7] with trastuzumab; 4·6 months [2·1–8·9] with capecitabine; and 4·5 months [2·1–10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4–18·7] vs 5·9 months [4·3–7·9]; HR 0·5573 [0·4376–0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56–237) with trastuzumab deruxtecan versus 83 days (30–152) with treatment of physician's choice. Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. Daiichi Sankyo and AstraZeneca.

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20–60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient’s tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition. HER2-enriched breast cancers within the HER2-positive subtype are addicted to the HER2 pathway. Here, the authors analyse gene expression before, during, and after treatment with anti-HER2-based therapies in the phase II PAMELA clinical trial, finding phenotypic changes induced by treatment.

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer ( N  = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N  = 34), lapatinib (L; N  = 36), or both (TL; N  = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment ( N  = 110), after one cycle of HER2-targeted therapy alone ( N  = 89), and at time of surgery ( N  = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents. HER2+ breast cancer patients can often develop resistance to trastuzumab and therefore potential combination therapies need to be explored. Here, the authors report the results of a multi-center randomized phase II clinical trial evaluating the pathological and molecular responses associated with trastuzumab and/or lapatinib in combination with chemotherapy in HER2+ breast cancer patients.

Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand–foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Jiangsu Hengrui Medicine and National Key R&D Program of China. For the Chinese translation of the abstract see Supplementary Materials section.

Background Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. Methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. Results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68–1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4–11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54–6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25–2.75]), BMI > 30 kg/m 2 (vs < 25 mg/kg 2 , OR 2.21 [95% CI 1.40–3.49]), cumulative dose of doxorubicin ≥240 mg/m 2 (OR 1.36 [95% CI 1.01–1.82]) and of epirubicin≥ 480 mg/m 2 (OR 2.33 [95% CI 1.55–3.51]). Conclusions Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. Trial registration number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006–000562–36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2–06 /EGF106708/N063D.

BackgroundBiomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients.MethodsThis sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel.Results173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2.ConclusionThese results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.

Talazoparib (BMN673) is a new poly(ADP-ribose) polymerase inhibitor that has been FDA approved for patients suffering from metastatic breast cancer with germline BRCA mutations. In the current study, an accurate and efficient liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical methodology was developed for TZB estimation in addition to its metabolic stability assessment. TZB and lapatinib (LAP) (which is chosen as an internal standard; IS) were separated using reversed phase elution system (Hypersil C column) with an isocratic mobile phase. The linearity range of the established method was 5-500 ng/mL (r ≥ 0.999) in the human liver microsomes (HLMs) matrix. Different parameters were calculated to confirm the method sensitivity (limit of quantification was 2.0 ng/mL), and reproducibility (intra- and inter-day precision and accuracy were below 3.1%) of our methodology. For evaluation of TZB metabolic stability in HLM matrix, intrinsic clearance (9.59 µL/min/mg) and in vitro half-life (72.7 mins) were calculated. TZB treatment discontinuations were reported due to adverse events and dose accumulation, so in silico metabolic vulnerability (experimental and in silico) and toxicity assessment (in silico) of TZB were performed utilizing P450 Metabolism and DEREK modules of StarDrop software. TZB is slowly metabolized by the liver. TZB was reported to be minimally metabolized by the liver that approved our outcomes. We do recommend that plasma levels be monitored in cases when talazoparib is used for a long period of time, since it is possible for TZB to bioaccumulate after multiple doses to toxic levels. According to our knowledge, the current method is considered the first LC-MS/MS methodology for evaluating TZB metabolic stability. Further drug discovery studies can be done depending on this concept allowing the designing of new series of compounds with more safety profile through reducing side effects and improving metabolic behavior.

This phase III trial aimed to compare ARX788, a site-specific, construct-homogeneous antibody-drug conjugate, with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) who had progressed on one line of trastuzumab based regimen. Eligible patients were randomized (1:1) to receive ARX788 (1.5 mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC: lapatinib 1250 mg QD; capecitabine 1000 mg/m 2 BID, days 1–14, Q3W) and stratified by prior chemotherapy lines (0-1 versus >1) and visceral metastasis (yes versus no). The primary outcome was progression-free survival (PFS) assessed by a blinded independent central review (BICR). A total of 441 patients were randomly assigned to receive either ARX788 ( n  = 221) or LC ( n  = 220). The median PFS was 11.3 (95% confidence interval [CI], 8.4–13.8) months with ARX788 compared with 8.2 (95% CI, 6.9–8.7) months with LC, as per BICR (hazard ratio [HR] 0.64, p  = 0.0006). Frequencies of treatment-related adverse events (TRAEs) of any grade were 98.6% and 99.1% for ARX788 and LC, respectively. Grade ≥3 TRAEs were 41.4% and 40.0%, respectively, the most common adverse events were blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (ILD, 5.9%) with ARX788; hand-foot syndrome (18.1%) and hypokalemia (5.1%) with LC; all the hematological and gastrointestinal events of grade ≥3 with ARX788 were less than 3%. Six treatment-related deaths occurred, with three cases possibly related to ILD. ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile, supporting it as a potential treatment option.