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Trastuzumab emtansine (T-DM1) is widely utilized as a second-line and subsequent treatment for metastatic HER2+ breast cancer and has shown promise in early breast cancer treatment, particularly in adjuvant settings for residual disease after neoadjuvant chemotherapy. However, concerns have arisen regarding long-term hepatic adverse drug reactions (ADRs) not identified in clinical trials. We investigated potential safety signals of T-DM1 in hepatobiliary disorders and the time-to-onset of ADRs using the FDA Adverse Event Reporting System (FAERS) database. Suspected ADRs were extracted and divided into two groups: T-DM1 (N = 3387) and other drugs (N = 11,833,701). Potential signal for T-DM1 in hepatobiliary disorder were identified (reporting odds ratio [ROR] = 5.66, 95% confidence interval [CI] = 5.11–6.27; information component [IC] = 2.35, 95% Credibility Interval [Crl] = 2.18–2.51). A breast cancer indicated subgroup analysis (2519 T-DM1; 172,329 other drugs) also identified a potential safety signal (ROR = 3.28, 95% CI = 2.92–3.68; IC = 1.53, 95%CrI = 1.35–1.71). The median time-to-onset for T-DM1-associated hepatobiliary disorders was 41 days. For prolonged and chronic hepatobiliary disorders, median times were 322.5 and 301.5 days, respectively. These findings highlight the need for further research to inform clinical decisions on optimal T-DM1 treatment duration, balancing benefits with potential adverse reactions. [ABSTRACT FROM AUTHOR]

Purpose: The randomized phase 2 Neo-peaks study examined usefulness of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) following docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) as compared with the standard TCbHP regimen. We previously reported that pCR rate after neoadjuvant therapy tended to be higher with TCbHP followed by T-DM1 + P. We conducted an exploratory analysis of prognosis 5 years after surgery. Methods: Neoadjuvant treatment with TCbHP (6 cycles; group A), TCbHP (4 cycles) followed by T-DM1 + P (4 cycles; group B), and T-DM1 + P (4 cycles; group C, + 2 cycles in responders) were compared. Group C non-responders after 4 cycles were switched to an anthracycline-based regimen. We evaluated 5-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS). Results: Data from 203 patients (50, 52, and 101 in groups A–C, respectively) were analyzed. No significant intergroup differences were found for DFS, DDFS, or OS. The 5-year DFS rates (95% CI) were 91.8% (79.6–96.8%), 92.3% (80.8–97.0%), and 88.0% (79.9–93.0%) in groups A–C, respectively. TCbHP followed by T-DM1 + P and T-DM1 + P with response-guided addition of anthracycline therapy resulted in similar long-term prognosis to that of TCbHP. Conclusions: In patients who achieved pCR after neoadjuvant therapy with T-DM1 + P, omission of adjuvant anthracycline may be considered, whereas treatment should be adjusted for non-pCR patients with residual disease. T-DM1 + P with response-guided treatment adjustment may be useful for minimizing toxicity. Trial registration number and date of registration: UMIN-CTR, UMIN000014649, prospectively registered July 25, 2014. Some of the study results were presented as a Mini Oral session at the ESMO Breast Cancer 2023 (Berlin, Germany, 11–13 May 2023). [ABSTRACT FROM AUTHOR]

Abstract Trastuzumab emtansine (T-DM1) is widely utilized as a second-line and subsequent treatment for metastatic HER2+ breast cancer and has shown promise in early breast cancer treatment, particularly in adjuvant settings for residual disease after neoadjuvant chemotherapy. However, concerns have arisen regarding long-term hepatic adverse drug reactions (ADRs) not identified in clinical trials. We investigated potential safety signals of T-DM1 in hepatobiliary disorders and the time-to-onset of ADRs using the FDA Adverse Event Reporting System (FAERS) database. Suspected ADRs were extracted and divided into two groups: T-DM1 (N = 3387) and other drugs (N = 11,833,701). Potential signal for T-DM1 in hepatobiliary disorder were identified (reporting odds ratio [ROR] = 5.66, 95% confidence interval [CI] = 5.11–6.27; information component [IC] = 2.35, 95% Credibility Interval [Crl] = 2.18–2.51). A breast cancer indicated subgroup analysis (2519 T-DM1; 172,329 other drugs) also identified a potential safety signal (ROR = 3.28, 95% CI = 2.92–3.68; IC = 1.53, 95%CrI = 1.35–1.71). The median time-to-onset for T-DM1-associated hepatobiliary disorders was 41 days. For prolonged and chronic hepatobiliary disorders, median times were 322.5 and 301.5 days, respectively. These findings highlight the need for further research to inform clinical decisions on optimal T-DM1 treatment duration, balancing benefits with potential adverse reactions.

BackgroundThrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding.MethodsSubjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p

AbstractWe aimed to evaluate the efficacy and safety of trastuzumab emtansine in patients with metastatic breast cancer previously treated with pertuzumab plus trastuzumab and taxane. We reviewed the medical records of patients who were diagnosed with Human Epidermal Growth Factor Receptor 2 (HER-2) positive metastatic breast cancer and received pertuzumab and then TDM-1 between January 2014 and January 2021 from twenty- five cancer centers. The Kaplan- Meier method estimated progression-free survival (PFS) and overall survival (OS). Additionally, objective response rate (ORR), clinical benefit rate (CBR), and safety were evaluated. One hundred fifty-three patients were included,79.1% of the patients received TDM-1 in the second line, 90.8% had visceral metastasis, and 30.7% had central nervous system involvement. The PFS and OS of TDM-1 were evaluated according to the number of previous lines (on the 2nd line or more than two lines) metastatic sites (visceral and non-visceral) and the presence of central nervous metastasis. In TDM-1 therapy, PFS in second line therapy was ten months (95% CI: 7.7 − 12.2); this was statistically higher than later-line PFS, which was six months (95% CI: 3.3 to 8.6) (p = 0.004). The median OS time was 25 months (95% CI: 21.0 to 28.9) in patients treated with TDM-1 in the second line and 19 months (95% CI: 12.3 to 25.6) in patients who received later than the second line(p = 0.175). There were no significant differences in PFS time of patients with and without visceral and central nervous metastases. Our study showed that TDM-1 was also effective in patients using pertuzumab, contributes significantly to PFS when used in the second line compared to its use in the later line, and does not make any difference in OS. [ABSTRACT FROM AUTHOR]

Background: Antibody-drug conjugates have revolutionized cancer therapy due to their selectivity and efficacy. However, concerns have been raised regarding the potential effects of trastuzumab deruxtecan in interstitial lung diseases. Aim: This study aimed to investigate the safety signals and time to onset of antibody-drug conjugates induced interstitial lung disease. Method: We utilized the FDA Adverse Event Reporting System database (2004–2022) to identify interstitial lung disease safety signals in 13 FDA-approved antibody-drug conjugates. Disproportionality analysis was conducted to estimate the reporting odds ratios for interstitial lung disease. Results: Seven antibody-drug conjugates exhibited safety signals of interstitial lung disease: trastuzumab deruxtecan [reporting odds ratio, ROR (95% confidence intervals, CI) = 64.15 (57.07–72.10)], enfortumab vedotin [ROR (95% CI) = 5.24 (3.25–8.43)], trastuzumab emtansine [ROR (95% CI) = 3.62 (2.90–4.53)], brentuximab vedotin [ROR (95% CI) = 3.22 (2.49–4.17)], polatuzumab vedotin [ROR (95% CI) = 2.56 (1.59–4.12)], gemtuzumab ozogamicin [ROR (95% CI) = 2.53 (1.70–3.78)], and inotuzumab ozogamicin [ROR (95% CI) = 2.33 (1.21–4.49)]. Five antibody-drug conjugates with limited reports were excluded from further analysis: belantamab mafodotin, loncastuximab tesirine, mirvetuximab sorafenib, tisotumab vedotin, and moxetumomab pasudotox. Japan and the United States were the primary reporting countries. Conclusion: This real-world study highlights high safety signals of interstitial lung disease associated with antibody-drug conjugates. Clinicians should be aware of these safety concerns and risk factors and implement early identification measures for their patients. Future research should prioritize comprehensively exploring the relationship between antibody-drug conjugates and lung diseases. [ABSTRACT FROM AUTHOR]

Background and Objectives: Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo trastuzumab emtansine (T-DM1) therapy in subsequent lines. Combining endocrine therapy (ET) with T-DM1 can improve treatment outcomes in this subtype. Therefore, this study aimed to investigate the benefits of using T-DM1 with ET in HER2-positive and HR-positive MBC. This study was the first to investigate the benefits of combining ET with T-DM1. Material and Methods: This study analyzed the medical records of patients with HER2-positive and HR-positive MBC who were treated with T-DM1 from June 2010 to December 2021. The patients were divided into groups based on whether they received concomitant ET with T-DM1. The primary endpoint was to determine the progression-free survival (PFS), while the secondary endpoints were overall survival (OS), objective response rate, and safety of the treatment. Results: Our analysis examined 88 patients, of whom 32 (36.4%) were treated with T-DM1 in combination with ET. The combination therapy showed a significant improvement in median PFS (15.4 vs. 6.4 months; p = 0.00004) and median OS (35.0 vs. 23.1 months; p = 0.026) compared to T-DM1 alone. The ORR was also higher in the combination group (65.6% vs. 29.3%; p = 0.026). Patients treated with pertuzumab priorly had reduced median PFS on T-DM1 compared to those who were not treated with pertuzumab (11.7 vs. 5.4 months, respectively; p < 0.01). T-DM1 demonstrated better median PFS in HER2 3+ patients compared to HER2 2+ patients, with an amplification ratio of >2.0 (10.8 vs 5.8 months, respectively; p = 0.049). The safety profiles were consistent with previous T-DM1 studies. Conclusions: The combination of T-DM1 with ET can significantly improve PFS and OS in patients with HER2-positive and HR-positive MBC. Our study suggests that prior pertuzumab treatment plus trastuzumab treatment might decrease T-DM1 efficacy. [ABSTRACT FROM AUTHOR]

Trastuzumab (T) and tyrosine kinase inhibitors (TKIs) are among the first-line treatments recommended for HER2-positive breast cancer. More recently, antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) have been authorized, and they represent the second-line therapy in this type of cancer. The present study aimed to evaluate adverse drug reactions (ADRs) associated with T-based ADCs that were spontaneously reported in EudraVigilance—the European pharmacovigilance database. Out of 42,272 ADRs reported for currently approved ADCs on the market, 24% of ADRs were related to T-DM1, while 12% of ADRs were related to T-DXd. T-DM1 had a higher probability of reporting eye, ear and labyrinth, and cardiac and hepatobiliary ADRs, while T-DXd had a higher probability of reporting respiratory, thoracic and mediastinal, blood and lymphatic system, metabolism and nutrition, and gastrointestinal ADRs. The present research found that in terms of hematological disorders, T-DM1 and T-DXd had a higher probability of reporting ADRs than TKIs. Moreover, the data showed that T-DM1 seemed to have a higher risk of cardiotoxicity than T-DXd, while T-DXd had a higher probability of reporting metabolism and nutrition disorders than T-DM1. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer. [ABSTRACT FROM AUTHOR]

BackgroundKRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II-III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE.MethodsPatients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive.ResultsBiomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups.ConclusionsAlthough our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer.Trial registrationClinicalTrials.gov NCT02131064. Registered 06 May 2014.

Objective. We aimed to study the efficacy and safety of trastuzumab-emtansine (T-DM1) versus other anti-HER2 therapies in HER2+ breast cancer (BC). Materials and Methods. We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs). Our study focused on patients undergoing treatment for unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC), which included regimens involving trastuzumab and taxanes. Additionally, we considered cases within the first 6 months of treatment for HER2+ early breast cancer (EBC). Results. A total of 23 RCTs and 41 reports were included in our analysis. LABC and mBC showed no statistically significant difference in any of the comparisons of T-DM1 versus the other anti-HER2+ therapies. When assessing progression-free survival (PFS), trastuzumab-deruxtecan (T-DXd) and PyroCap demonstrated greater efficacy compared to other treatments (Hazard Ratio [HR]: 3.57; 95% confidence interval [CI]: 2.75-4.63 and HR: 1.82; 95% CI: 1.35-2.44; respectively), while T-DM1 alone exhibited superior effectiveness compared to LapCap (HR: 0.65; 95% CI: 0.55-0.77), TrasCap (HR: 0.65; 95% CI: 0.46-0.91), LapCapCitu (HR: 0.60; 95% CI: 0.33-1.10), Nera (HR: 0.55; 95% CI: 0.39-0.77), and Cap (HR: 0.37; 95% CI: 0.28-0.49). Conclusions. NMA allows a ranking based on the comparative efficacy and safety among the interventions available. Although superior to other schemes, T-DM1 showed a lower efficacy performance in PFS and overall response rate and a trend towards worse overall survival than T-DXd. [ABSTRACT FROM AUTHOR]

Purpose: Treating early-stage breast cancer (eBC) may delay or prevent subsequent metastatic breast cancer (mBC). In the phase 3 KATHERINE study, women with human epidermal growth factor receptor 2 (HER2)-positive eBC with residual disease following neoadjuvant therapy containing trastuzumab and a taxane experienced 50% reductions in disease recurrence or death when treated with adjuvant trastuzumab emtansine (T-DM1) vs adjuvant trastuzumab. We predicted the population-level impact of adjuvant T-DM1 on mBC occurrence in five European countries (EU5) and Canada from 2021–2030. Methods: An epidemiological prediction model using data from national cancer registries, observational studies, and clinical trials was developed. Assuming 80% population-level uptake of adjuvant treatment, KATHERINE data were extrapolated prospectively to model projections. Robustness was evaluated in alternative scenarios. Results: We projected an eligible population of 116,335 women in Canada and the EU5 who may be diagnosed with HER2-positive eBC and have residual disease following neoadjuvant therapy from 2021–2030. In EU5, the cumulative number of women projected to experience relapsed mBC over the 10-year study period was 36,009 vs 27,143 under adjuvant trastuzumab vs T-DM1, a difference of 8,866 women, equivalent to 25% fewer cases with the use of adjuvant T-DM1 in EU5 countries from 2021–2030. Findings were similar for Canada. Conclusion: Our models predicted greater reductions in the occurrence of relapsed mBC with adjuvant T-DM1 vs trastuzumab in the indicated populations in EU5 and Canada. Introduction of T-DM1 has the potential to reduce population-level disease burden of HER2-positive mBC in the geographies studied. [ABSTRACT FROM AUTHOR]

In recent decades, there has been a surge in the approval of monoclonal antibodies for treating a wide range of hematological and solid malignancies. These antibodies exhibit exceptional precision in targeting the surface antigens of tumors, heralding a groundbreaking approach to cancer therapy. Nevertheless, monoclonal antibodies alone do not show sufficient lethality against cancerous cells compared to chemotherapy. Consequently, a new class of anti-tumor medications, known as antibody-drug conjugates (ADCs), has been developed to bridge the divide between monoclonal antibodies and cytotoxic drugs, enhancing their therapeutic potential. ADCs are chemically synthesized by binding tumor-targeting monoclonal antibodies with cytotoxic payloads through linkers that are susceptible to cleavage by intracellular proteases. They combined the accurate targeting of monoclonal antibodies with the potent efficacy of cytotoxic chemotherapy drugs while circumventing systemic toxicity and boasting superior lethality over standalone targeted drugs. The human epidermal growth factor receptor (HER) family, which encompasses HER1 (also known as EGFR), HER2, HER3, and HER4, plays a key role in regulating cellular proliferation, survival, differentiation, and migration. HER2 overexpression in various tumors is one of the most frequently targeted antigens for ADC therapy in HER2-positive cancers. HER2-directed ADCs have emerged as highly promising treatment modalities for patients with HER2-positive cancers. This review focuses on three approved anti-HER2 ADCs (T-DM1, DS-8201a, and RC48) and reviews ongoing clinical trials and failed trials based on anti-HER2 ADCs. Finally, we address the notable challenges linked to ADC development and underscore potential future avenues for tackling these hurdles.

BackgroundTrastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population.Materials and methodsThis post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected.ResultsDuring the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101).ConclusionThis real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

Purpose: Trastuzumab deruxtecan (T-DXd) expressed substantial improvement in the progression-free survival and overall survival contrasted with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC), becoming the second-line standard of care, promisingly. We aim to estimate the cost–utility of T-DXd versus T-DM1 in HER2-positive mBC from the Chinese healthcare perspective. Methods: A partitioned survival model was applied to examine the cost–utility of T-DXd versus T-DM1. Clinical patients and outcome data were sourced from the DESTINY-Breast 03 trial. Costs and utilities were sourced in Chinese setting. Total costs, quality-adjusted life months (QALMs), and an incremental cost–utility ratios (ICUR) were calculated for cost–utility analysis. The willingness-to-pay threshold was set at $3188/QALM. Univariate, scenario, and probabilistic sensitivity analyses were performed. Results: T-DXd group gained ∆QALM of 7.09 months and ∆Cost of $304,503 compared with T-DM1 therapy, which caused an ICUR of $42,936/QALM. The results of sensitivity analyses confirmed the base-case findings. Furthermore, T-DXd must reduce the price to enter the Chinese mainland market. At least when the cycle cost of T-DXd is reduced to $2975, T-DXd has an 83.3% chance of becoming a better choice. Conclusions: T-DXd appears to be not cost effective compared with T-DM1 for HER2-positive mBC patients previously treated with trastuzumab and a taxane. [ABSTRACT FROM AUTHOR]

Anti HER2 therapy and left breast adjuvant radiation therapy (RT) can both result in cardiotoxicity. The aim of this study was to evaluate the influence of radiation dose on cardiac structures on the values of the early cardiotoxicity marker high-sensitivity cardiac troponin I (hscTnI) in patients with HER2-positive left breast cancer undergoing adjuvant concomitant antiHER2 therapy and radiotherapy, and to establish a correlation between the hscTnI values and cardiac radiation doses. Sixty-one patients underwent left breast hypofractionated radiotherapy in parallel with anti-HER2 therapy: trastuzumab, combined trastuzumab–pertuzumab or trastuzumab emtansine (T-DM1). The hscTnI values were measured prior to and upon completion of radiotherapy. A significant increase in hscTnI was defined as >30% from baseline, with the second value being 4 ng/L or higher. Dose volume histograms (DVH) were generated for the heart, left ventricle (LV) and left anterior descending artery (LAD). The hscTnI levels were corelated with radiation doses on cardiac structures. An increase in hscTnI values was observed in 17 patients (Group 1). These patients had significantly higher mean radiation doses for the heart (p = 0.02), LV (p = 0.03) and LAD (p = 0.04), and AUC for heart and LV (p = 0.01), than patients without hscTnI increase (Group 2). The patients in Group 1 also had larger volumes of heart and LV receiving 2 Gy (p = 0.01 for both) and 4 Gy (p = 0.02 for both). LAD differences were observed in volumes receiving 2 Gy (p = 0.03), 4 Gy (p = 0.02) and 5 Gy (p = 0.02). The increase in hscTnI observed in patients receiving anti-HER2 therapy after adjuvant RT was positively associated with radiation doses on the heart, LV and LAD. [ABSTRACT FROM AUTHOR]

Background Antibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after trastuzumab. Unfortunately, there is little data showing which ADCs should be chosen for those patients whose treatment with tyrosine kinase inhibitors (TKIs) failed. This study aims to analyze the efficacy and safety between novel anti-HER2 ADCs and trastuzumab emtansine (T-DM1) for those with TKIs failure. Materials and methods HER2-positive MBC using ADCs from January 2013 to June 2022 were included, and all of them were treated with TKIs. The primary study endpoint was progression-free survival (PFS), and the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety. Results A total of 144 patients with 73 patients in the novel anti-HER2 ADCs group and 71 patients in the T-DM1 group. In these novel ADCs, 30 patients received trastuzumab deruxtecan (T-Dxd), 43 patients receive other novel ADCs. The median PFS in the novel ADCs group and T-DM1 group were 7.0 months versus 4.0 months, respectively, and ORR was 54.8% versus 22.5%, CBR was 65.8% versus 47.9%, respectively. In subgroups analysis, the PFS were both significantly improved in patients receiving T-Dxd and other novel ADCs compared with T-DM1. The most common grades 3-4 adverse events in the novel anti-HER-2 ADCs group were neutropenia (20.5%) and thrombocytopenia (28.1%) in the T-DM1 group. Conclusions In patients with HER2-positive MBC previously treated with TKIs, both T-Dxd and other novel anti-HER2 ADCs yielded statistically significant better PFS than T-DM1 did, with tolerable toxicities. [ABSTRACT FROM AUTHOR]

Background and Objectives: Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo trastuzumab emtansine (T-DM1) therapy in subsequent lines. Combining endocrine therapy (ET) with T-DM1 can improve treatment outcomes in this subtype. Therefore, this study aimed to investigate the benefits of using T-DM1 with ET in HER2-positive and HR-positive MBC. This study was the first to investigate the benefits of combining ET with T-DM1. Material and Methods: This study analyzed the medical records of patients with HER2-positive and HR-positive MBC who were treated with T-DM1 from June 2010 to December 2021. The patients were divided into groups based on whether they received concomitant ET with T-DM1. The primary endpoint was to determine the progression-free survival (PFS), while the secondary endpoints were overall survival (OS), objective response rate, and safety of the treatment. Results: Our analysis examined 88 patients, of whom 32 (36.4%) were treated with T-DM1 in combination with ET. The combination therapy showed a significant improvement in median PFS (15.4 vs. 6.4 months; p = 0.00004) and median OS (35.0 vs. 23.1 months; p = 0.026) compared to T-DM1 alone. The ORR was also higher in the combination group (65.6% vs. 29.3%; p = 0.026). Patients treated with pertuzumab priorly had reduced median PFS on T-DM1 compared to those who were not treated with pertuzumab (11.7 vs. 5.4 months, respectively; p < 0.01). T-DM1 demonstrated better median PFS in HER2 3+ patients compared to HER2 2+ patients, with an amplification ratio of >2.0 (10.8 vs 5.8 months, respectively; p = 0.049). The safety profiles were consistent with previous T-DM1 studies. Conclusions: The combination of T-DM1 with ET can significantly improve PFS and OS in patients with HER2-positive and HR-positive MBC. Our study suggests that prior pertuzumab treatment plus trastuzumab treatment might decrease T-DM1 efficacy.

Trastuzumab (T) and tyrosine kinase inhibitors (TKIs) are among the first-line treatments recommended for HER2-positive breast cancer. More recently, antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) have been authorized, and they represent the second-line therapy in this type of cancer. The present study aimed to evaluate adverse drug reactions (ADRs) associated with T-based ADCs that were spontaneously reported in EudraVigilance—the European pharmacovigilance database. Out of 42,272 ADRs reported for currently approved ADCs on the market, 24% of ADRs were related to T-DM1, while 12% of ADRs were related to T-DXd. T-DM1 had a higher probability of reporting eye, ear and labyrinth, and cardiac and hepatobiliary ADRs, while T-DXd had a higher probability of reporting respiratory, thoracic and mediastinal, blood and lymphatic system, metabolism and nutrition, and gastrointestinal ADRs. The present research found that in terms of hematological disorders, T-DM1 and T-DXd had a higher probability of reporting ADRs than TKIs. Moreover, the data showed that T-DM1 seemed to have a higher risk of cardiotoxicity than T-DXd, while T-DXd had a higher probability of reporting metabolism and nutrition disorders than T-DM1.

Abstract The antibody‐drug conjugate trastuzumab emtansine (T‐DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)–positive breast cancer. We aimed to study tumor HER2 expression and its effects on T‐DM1 responses in patients with HER2‐positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non‐focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene‐protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker‐evaluable population, composed of screen‐failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2‐positive tumors. In a gene‐protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2‐positive UBC or PC can respond to T‐DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non‐breast tumor types.

Background: Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. Methods: This retrospective, observational study evaluated patients with HER2–positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). Results: A total of 214 patients were available for analysis (T-DM1, n = 161; LC, n = 53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34–0.89]; P=0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36–0.85]; P = 0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36–0.69]; P

Opinion statement: Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2+), conferring a particularly aggressive subtype of the disease with an increased risk for the development of systemic and brain metastases. However, the advent of trastuzumab and more recently several other HER2-targeting novel therapies has led to significant improvements in the prognosis, making the diagnosis a "double-edged sword." The current standard first-line therapy for patients with HER2+ metastatic breast cancer (MBC) is a taxane combined with trastuzumab and pertuzumab. Trastuzumab deruxtecan should be used preferentially in the second line, with the only caveat being patients with CNS involvement where the tucatinib, capecitabine, and trastuzumab regimen could be considered. In the third line setting, given the survival benefits demonstrated with the tucatinib regimen in patients with and without CNS metastases, this is the preferred strategy. In the fourth line and beyond, there is no clear standard. Options include margetuximab in combination with chemotherapy, neratinib + capecitabine, or trastuzumab + chemotherapy. There are several novel therapies under investigation reporting promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, with several active therapies being moved to the early-stage setting. Accordingly, it will be critical to identify biomarkers and mechanisms of resistance to optimize therapy selection and maximize patient outcomes and quality of life. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer and address the specific scenarios which may impact treatment selection including triple-positive breast cancer and the presence of brain metastases. Finally, we highlight promising novel treatments and ongoing trials that may impact future treatment sequencing. [ABSTRACT FROM AUTHOR]

Trastuzumab emtansine and trastuzumab deruxtecan are widely used in breast cancer and other solid tumor malignancies. Thrombocytopenia is a common adverse event associated with the use of these agents that can lead to a treatment delay, reduction in dose intensity, and discontinuation. The role of thrombopoietin receptor agonists (TPO-RA) remains unknown in this setting. We report a case series of 6 individuals with breast cancer that experienced dose-reductions and therapy delays due to thrombocytopenia secondary to trastuzumab emtansine or trastuzumab deruxtecan therapy and received intervention with TPO-RA. All 6 were able to resume therapy with TPO-RA support. Thrombopoietin receptor agonists (TPO-RA), such as eltrombopag, romiplostim, and avatrombopag, have shown efficacy in treating immune thrombocytopenia; however, their efficacy in improving platelet counts due to HER2-targeted antibody-drug conjugate therapy remains unknown. This article reports a series of cases in which TPO-RA were successfully utilized to treat such thrombocytopenia associated with ado-trastuzumab emtansine(T-DM1) and fam-trastuzumab deruxtecan (T-DXd) therapy. [ABSTRACT FROM AUTHOR]

In the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan (T-DXd) showed superior progression-free survival and overall survival versus trastuzumab emtansine (T-DM1) and manageable safety in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer. Here, patient-reported outcomes (PROs) are reported along with hospitalization data. Patients in DESTINY-Breast03 were assessed for prespecified PRO measures, including European Organization for Research and Treatment of Cancer quality of life (EORTC-QoL) questionnaires [the oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific EORTC QLQ-BR45] and the generic EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) visual analogue scale. Analyses included change from baseline, time to definitive deterioration (TDD), and hospitalization-related endpoints. EORTC QLQ-C30 baseline global health status (GHS) scores for T-DXd (n = 253) and T-DM1 (n = 260) were similar, with no clinically meaningful change (<10-point change from baseline) while on either treatment (median treatment duration: T-DXd, 14.3 months; T-DM1, 6.9 months). TDD analyses of QLQ-C30 GHS (primary PRO variable) and all other prespecified PROs (QLQ-C30 subscales, the QLQ-BR45 arm symptoms scale, and the EQ-5D-5L visual analogue scale) suggested T-DXd was numerically favored over T-DM1 based on TDD hazard ratios. Of all randomized patients, 18 (6.9%) receiving T-DXd versus 19 (7.2%) receiving T-DM1 were hospitalized, and the median time to first hospitalization was 219.5 versus 60.0 days, respectively. In DESTINY-Breast03, EORTC GHS/QoL was maintained on both therapies throughout treatment, indicating that despite the longer treatment duration with T-DXd versus T-DM1, health-related QoL did not worsen on T-DXd. Furthermore, TDD hazard ratios numerically favored T-DXd over T-DM1 in all prespecified variables of interest including pain, suggesting T-DXd may delay time until health-related QoL deterioration compared with T-DM1. Median time to first hospitalization was three times longer with T-DXd versus T-DM1. Together with reported improved efficacy and manageable toxicity, these results support the overall benefit of T-DXd for patients with HER2+ metastatic breast cancer. • Health-related QoL (HRQoL) data from DESTINY-Breast03 are reported for T-DXd in HER2+ metastatic breast cancer (mBC). • Overall HRQoL was maintained on T-DXd treatment in patients with HER2+ mBC. • Time to definitive deterioration across prespecified HRQoL measures was numerically longer with T-DXd versus T-DM1. • Findings were consistent with previously published efficacy results for DESTINY-Breast03 in patients with HER2+ mBC. [ABSTRACT FROM AUTHOR]

Abstract Background KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II–III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE. Methods Patients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive. Results Biomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups. Conclusions Although our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer. Trial Registration: ClinicalTrials.gov NCT02131064. Registered 06 May 2014.

The antibody‐drug conjugate trastuzumab emtansine (T‐DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)–positive breast cancer. We aimed to study tumor HER2 expression and its effects on T‐DM1 responses in patients with HER2‐positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non‐focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene‐protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker‐evaluable population, composed of screen‐failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2‐positive tumors. In a gene‐protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2‐positive UBC or PC can respond to T‐DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non‐breast tumor types. [ABSTRACT FROM AUTHOR]

Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. This retrospective, observational study evaluated patients with HER2–positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). A total of 214 patients were available for analysis (T-DM1, n = 161; LC, n = 53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34–0.89]; P= 0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36–0.85]; P = 0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36–0.69]; P < 0.001). These results support the superior effectiveness and clinical relevance of T-DM1 versus LC in patients with HER2-positive BCBM in the real world. • Breast cancer with brain metastases (BCBM) has been associated with lower survival. • T-DM1 improves survival vs lapatinib + capecitabine in real-world HER2+ BCBM patients. • Time to next treatment was also prolonged with T-DM1 vs lapatinib + capecitabine. • T-DM1 is an effective and clinically relevant option for patients with HER2+ BCBM. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

Background: DESTINY-Breast03 (NCT03529110) was the first global phase III study to assess the antitumor activity of trastuzumab deruxtecan (T-DXd) compared to trastuzumab emtansine (T-DM1) in 2022. However, the balance between efficacy and cost of T-DXd remains unclear. As a result, the present study's goal is to investigate the cost-effectiveness of T-DXd vs T-DM1 as a second-line treatment for patients with HER2-positive MBC from the US and Chinese payer's perspectives. Methods: A Markov model with a 20-year time horizon was developed to evaluate the overall cost of patient treatment, incremental cost-effectiveness ratio (ICER), quality-adjusted life-years (QALYs), and life-years (LYs) in the US and China at WTP levels of 150,000/QALY and 37,653/QALY, respectively (3 times GDP per capita in 2021). Key data were gathered from the US government's official website, the Xiangya Hospital of Central South University, and published literature. To determine the model's stability, a sensitivity analysis was performed. A subgroup analysis was also implemented. Results: Compared with T-DM1, treatment with T-DXd generated an additional 1.672 QALYs (2.796 LYs), resulting in an ICER of $13,342/QALY (US) and $186,017/QALY (China). The cost of drugs is the most influential factor in the American and Chinese models. Subgroup analysis revealed that the T-DXd and T-DM1 regimens were more cost-effective at reducing the risk of death in the US and Chinese HER2-positive MBC patients. Conclusion: T-DXd as second-line treatment could gain more health benefits for HER2-positive MBC patients in comparison with T-DM1, which is considered to be cost-effective in the US but not in China.

Introduction: Trastuzumab emtansine (T-DM1) is one of the effective treatment options in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. In this study, we aimed to find the effect of T-DM1 on survival, its tolerability and prognostic factors of T-DM1 treatment. Material and methods: The study was designed as a single-center, retrospective study that included patients treated in the oncology department of a university hospital in Turkey. HER2-positive patients with metastatic breast cancer who had a progression response to trastuzumab and taxane treatment and received T-DM1 treatment for at least 2 months between 2016-2022 were included in the study. Adverse events were defined according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Kaplan-Meier methodology and Cox proportional hazard modelling were used for survival analyses. Results: The median progression-free survival (mPFS) for T-DM1 was 10.4 months and the median overall survival (mOS) was 22 months. In the created univariate cox regression model, liver metastasis, ECOG performance status, and pre-treatment serum CA 15-3 were found to be factors associated with PFS. Liver metastasis (HR=2.54, p=0.019), ECOG performance status (HR=4.66, p=0.002), and serum CA 15-3 (HR= 2.55, p=0.041) maintained their statistical significance for PFS in the established multivariate analysis. In the regression analysis for OS, only ECOG performance status (HR= 2.61, p=0.023) was found to be prognostic. While toxicity occurred in 46 (82.1%) of the patients, grade 3-4 toxicity developed in 10 (17.9%) patients. The most common side effects were anemia, thrombocytopenia, fatigue and nausea. Conclusions: T-DM1 is a safe and tolerable agent that prolongs survival. Liver metastasis, ECOG performance status, and pre-treatment serum CA 15-3 levels are independent prognostic factors for patients using T-DM1.

Simple Summary: Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) represents a subgroup of breast cancer characterized by an aggressive behaviour and a particular sensitiveness to HER2-targeted agents. Because of the frequent occurrence of acquired resistance to anti-HER2 therapy, novel agents were investigated, including antibody-drug conjugates (ADCs). ADCs represent an emerging class of anticancer agents consisting of a humanized monoclonal antibody bounded to a cytotoxic drug by a molecular linker. HER2-positive mBC represents the first solid tumor in which ADCs, like Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), demonstrated to improve clinical outcomes compared to prior standards of care. Nonetheless, despite their effectiveness, resistance to T-DM1 and T-DXd still occurs in most of the patients treated with these ADCs, warranting an improved understanding of the mechanisms underlying resistance. This review aims to describe the emerging mechanisms of resistance to ADCs targeting HER2, highlighting the potential strategies to overcome resistance and further improve clinical outcomes of patients with metastatic breast cancer. The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the decrease of HER2 expression, the alteration of intracellular trafficking, the impairment of lysosome functions, the drug expulsion through efflux pumps and the activation of alternative signal pathways. Instead, the decrease of HER2 expression and SLX4 loss of function mutations represent the first evidences of mechanisms of resistance to T-DXd, according to the results of DAISY trial. Several strategies are under evaluation to overcome resistances to anti-HER2 ADCs and improve clinical outcomes in patients progressing on these agents: combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors and synthetic DNA-damaging agents are emerging as promising approaches. Furthermore, novel anti-HER2 ADCs with innovative structures and mechanisms of action are in development, in the attempt to further improve the activity and tolerability of currently available agents. [ABSTRACT FROM AUTHOR]

Abstract Background Current guidelines consider T-DM1 the standard 2nd line therapy for HER2 positive metastatic breast cancer (MBC) patients following trastuzumab (T) + pertuzumab (P) and taxane 1st line treatment. Despite this, there are no prospective studies supporting this sequence. Methods We performed a meta-analysis using real world data to determine the efficacy of T-DM1 after 1st line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the EMILIA phase III pivotal trial. Results Seven studies were eligible. The meta-analysis showed a combined 1-year PFS risk difference for T-DM1 efficacy after TP in 2nd or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p = 0.07), with low heterogeneity among studies (I2 0.01%, p = 0.836). Considering the four studies on T-DM1 in 2nd line setting, 1-year PFS risk was -0.034 (95% CI -0.207 – 0,139; p = 0.701) (I2 0.01%, p = 0.91). Conclusion Overall, the efficacy of T-DM1 after TP seems to be similar to that previously reported in the EMILIA trial. In the second line setting, data are not mature enough to confirm T-DM1 efficacy in TP pre-treated population.

Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), providing an actionable target for many different therapies. In the metastatic setting, prognosis has improved greatly with the use of anti-HER2 drugs such as trastuzumab, pertuzumab, and trastuzumab-emtansine. In the third line setting and beyond, several emerging treatments have shown benefits, including novel small molecule targeted agents and antibody-drug conjugates. Systemic treatment of brain metastases in HER2-positive patients and the role of endocrine-based treatment for patients with hormone receptor (HR) positive disease remain areas of research interest. This article will review the current approach to systemic management of metastatic HER2-positive breast cancer in Canada, and present novel treatments that may be available in the near future.

DESTINY-Breast03 (NCT03529110) was the first global phase III study to assess the antitumor activity of trastuzumab deruxtecan (T-DXd) compared to trastuzumab emtansine (T-DM1) in 2022. However, the balance between efficacy and cost of T-DXd remains unclear. As a result, the present study's goal is to investigate the cost-effectiveness of T-DXd vs T-DM1 as a second-line treatment for patients with HER2-positive MBC from the US and Chinese payer's perspectives. A Markov model with a 20-year time horizon was developed to evaluate the overall cost of patient treatment, incremental cost-effectiveness ratio (ICER), quality-adjusted life-years (QALYs), and life-years (LYs) in the US and China at WTP levels of 150,000/QALY and 37,653/QALY, respectively (3 times GDP per capita in 2021). Key data were gathered from the US government's official website, the Xiangya Hospital of Central South University, and published literature. To determine the model's stability, a sensitivity analysis was performed. A subgroup analysis was also implemented. Compared with T-DM1, treatment with T-DXd generated an additional 1.672 QALYs (2.796 LYs), resulting in an ICER of $13,342/QALY (US) and $186,017/QALY (China). The cost of drugs is the most influential factor in the American and Chinese models. Subgroup analysis revealed that the T-DXd and T-DM1 regimens were more cost-effective at reducing the risk of death in the US and Chinese HER2-positive MBC patients. T-DXd as second-line treatment could gain more health benefits for HER2-positive MBC patients in comparison with T-DM1, which is considered to be cost-effective in the US but not in China. • The Markov model was established based on the DESTINY-Breast03 trial. • To evaluate the cost-effectiveness of T-DXd and T-DM1 for HER2-positive MBC. • The ICER of T-DXd versus T-DM1 was $13,342/QALY (US) and $186,017/QALY (China). • The T-DXd was more cost-effective for patients with HER2-positive MBC in the US. • The T-DM1 was more cost-effective for patients with HER2-positive MBCin China. [ABSTRACT FROM AUTHOR]

Abstract: Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed across a broad range of histologies to allow the use of ADC biomarker-driven therapy irrespective of the primary tumor site. This suggests that the future efficacy of ADCs in multiple histologies may be similar to other classes of drugs that are considered histology-agnostic therapies nowadays. This review focuses on novel ADCs for the treatment of solid tumors, including topics such as their structure and mechanism of action, the latest indications of already US Food and Drug Administration-approved ADCs, and the outlook for new promising ADCs under development for the treatment of tumors of various histologies. [ABSTRACT FROM AUTHOR]

With an increase in the number of agents used concurrently with radiotherapy (RT), a new research area has emerged regarding toxicity. Here, we present a case of a 47-year-old woman presenting with radiation-induced lung injury (RILI) that occurred six months after the end of RT with concomitant and sequential use of trastuzumab-emtansine (T-DM1) with RT. The patient's T-DM1 treatment was discontinued because of RILI. Antibiotic and methylprednisolone treatments were started. The steroid dose was gradually tapered and completely discontinued after full recovery. If new agents are used concurrently with RT, the toxicity profile of new agents should be kept in mind. [ABSTRACT FROM AUTHOR]

Introduction: Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate targeting the human epidermal growth factor receptor 2, used in some recurrent metastatic cancers. It was linked to modest increases in serum aminotransferase elevations and bilirubin. More recently, some cases of noncirrhotic portal hypertension have been described in patients on long-term T-DM1. The underlying liver condition is usually nodular regenerative hyperplasia (NRH) with elements of sinusoidal obstruction. Case Report: We report the case of a 52-year-old woman who started T-DM1 therapy for recurrent metastatic lung adenocarcinoma. Although a progressive reduction in lung nodules was noticed, there was a new-onset cytocholestasis and elevation in bilirubin. A reduction in platelet count was also apparent over several months during the T-DM1 therapy. Liver biopsy revealed NRH and so the dose of T-DM1 was reduced. Thereafter, the patient had normalization of liver tests and platelet count. T-DM1 was continued for more than 9 months with no signs of portal hypertension or cancer progression. Conclusions: We presented a rare case of NRH induced by T-DM1 in a patient with lung adenocarcinoma. A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. This is the first report of a successful dose reduction in a patient with NRH induced by T-DM1, suggesting that it is possible to maintain the drug while it is being effective for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Interstitial lung disease (ILD) events associated with anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) have aroused wide attention. In meta-analysis, we systematically reviewed literatures, and the outcomes were the proportion and risk of ILD related to anti-HER2 ADCs. A disproportionality analysis based on data from VigiBase was conducted to characterize the main features of anti-HER2 ADC-related ILD/pneumonitis. Two hundred and forty-five all-grade and 47 grade ≥ 3 ILD events with the proportion of 4.4% (95% confidence interval (CI) [2.0%, 6.8%]) and 0.5% (95% CI [0.3%, 0.8%]) were observed for anti-HER2 ADCs, respectively. Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine significantly increased the risk of all-grade and grade ≥ 3 ILD events with Peto odd ratios of 2.62 (95% CI [1.71, 4.04], P < 0.0001) and 2.82 (95% CI [1.07, 7.42], P = 0.04), respectively. In VigiBase, 271 cases of ILD/pneumonitis related to trastuzumab emtansine and trastuzumab deruxtecan were extracted. The median time to the onset of event was 86 days and 54.95% of events occurred within 3 months. Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine increased the risk of ILD, which can lead to serious outcomes and tends to occur early. [ABSTRACT FROM AUTHOR]

Objectives: Trastuzumab emtansine(T-DM1) is more effective in some patients. However, predictive factors are not clear for T-DM1 efficacy. We attempt to explore prognostic importance of albumin to alkaline phosphotase ratio (AAPR) and prognostic nutritional index (PNI) importance in patients who used T-DM1. Methods: The present retrospective study included the sixty-one human epidermal growh factor-2 (HER-2) positive metastatic breast cancer patients who used T-DM1. The median values were used to analyze AAPR and PNI threshold. PNI and AAPR were measured at baseline and after one cycle. Survival analysis was performed by using Kaplan-Meier method and compared with log rank test. Univariate and multivariate analysis were performed to determine independent prognostic predictor of progression-free survival (PFS) and overall survival (OS). Results: The optimal cutoff value for AAPR and PNI were 0.41 and 45.0, respectively. OS and PFS were obviously inferior in patients with AAPR<0.41 compared to patients with AAPR=0.41 according to Kaplan-Meier curve (OS: p=0.028, PFS: p=0.047). Patients with PNI <45 prominently demonstrated poor OS and PFS than those with PNI=45 according to Kaplan-Meier curve (OS: p=0.033, PFS: p=0.071). Conclusion: Pretreatment PNI is reliable prognostic indicators in patients with mBC treated by T-DM1. [ABSTRACT FROM AUTHOR]

Introduction: Based on data from the DESTINY-Breast03 trial, we performed a cost-effectiveness analysis of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had been previously treated with trastuzumab and a taxane from the US payer perspective.Methods: We conducted a Markov model to assess the cost-effectiveness of T-DXd versus trastuzumab emtansine (T-DM1). The simulation time horizon for this model was the lifetime of patients. Transition probabilities were based on data from the DESTINY-Breast03 trial. Health utility data were derived from published studies. Outcome measures were costs (in 2022 US$), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses assessed the uncertainty of key model parameters and their joint impact on the base-case results.Results: The base-case results found that T-DXd provided an improvement of 3.90 QALYs compared with T-DM1, and the ICER was $220,533 per QALY. The one-way sensitivity analysis demonstrated that the utility value of progression-free survival, hazard ratios of T-Dxd versus T-DM1, and cost of T-Dxd contributed substantial uncertainty to the model. Probabilistic sensitivity analysis predicted T-DXd being cost-effective compared to T-DM1 was 0, 1, 16, and 46% at willingness-to-pay of $50,000, $100,000, $150,000, and 200,000 per QALY, respectively.Conclusion: T-DXd was unlikely to offer a reasonable value for the money spent compared to T-DM1 in a US payer setting. [ABSTRACT FROM AUTHOR]

The antitumor effect of antibody-drug conjugates (ADC) is the main factor in achieving cures. Although the mechanism of tumor resistance to treatment is multifaceted, tumor-derived extracellular vesicles (T-EVs) have been implicated as contributing to the attenuation of ADC therapeutic efficacy. Thus, strategies to eliminate T-EVs are highly promising for overcoming drug resistance. Here we demonstrate plasma exchange therapy to remove T-EVs, decreasing their amount in vitro by 75%. Although trastuzumab emtansine (T-DM1) treatment alone was effective in our rat tumor model, the combination therapy of T-DM1 and T-EV filtration achieved early tumor shrinkage. Our results indicate that T-EV filtration plus ADC is a promising strategy for overcoming drug resistance. [ABSTRACT FROM AUTHOR]

The widespread introduction of anti-HER2 agents has changed the natural course of Her2-positive breast cancer. The use of trastuzumab, and later dual anti-HER2 blockade with pertuzumab, in neoadjuvant regimens significantly increased the chances of complete cure. However, among patients with early and locally advanced forms of Her2-positive cancer, there is a cohort with an extremely unfavorable prognosis – tumors that have not achieved complete pathomorphological regression after neoadjuvant chemotherapy.The presence of a residual tumor in Her2-positive breast cancer has long been only a prognostically unfavorable factor without the potential to influence disease outcome. The results of the international phase III study KATHERINE, which demonstrated the high efficacy of post-adjuvant therapy with trastuzumab emtansine (T-DM1) in this patient cohort, have established a new standard of care. Due to T-DM1 adjuvant therapy, the possibility to significantly improve long-term results determined the predictive characteristics of the morphological response to the choice of treatment tactics, which became an important argument in favor of neoadjuvant therapy in patients with not only locally advanced but also primarily resectable Her2-positive breast cancer, followed by personalization of therapy.This article presents our own experience with post-neoadjuvant therapy with trastuzumab emtansine in a young patient with a residual tumor. The data of the main studies in early Her2-positive breast cancer are summarized.

Background: The DESTINY-Breast03 clinical trial demonstrated that trastuzumab deruxtecan (T-DXd) outperformed trastuzumab emtansine (T-DM1) in progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Considering the excessive cost of antibody-drug conjugates, the clinical value of T-DXd must be assessed by both its efficacy and cost. We compared the cost-effectiveness of T-DXd and T-DM1 for patients with HER2-positive mBC pretreated with anti-HER2 antibodies and a taxane from the perspectives of the United States (US) and China. Methods: A comprehensive Markov model based on the DESTINY-Breast03 phase III randomized clinical trial was used to compared the cost and effectiveness of T-DXd and T-DM1 for HER2-positive mBC. Data on direct medical cost and utilities were collected from published literatures. The recorded data included the costs, quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB). Sensitivity analysis was conducted to measure the potential uncertainty due to parameter variability. Additional subgroup cost-effectiveness analysis was performed. Results: Treatment of HER2-positive mBC with T-DXd gained 0.73 QALYs compared with T-DM1 strategy. The incremental cost was $59,942 in the US, with an ICER of $ 82,112/QALY and an INHB of 0.33 QALYs, respectively. In China, the incremental cost of T-DXd versus T-DM1 was $222,680, with an ICER of $305,041/QALY and a negative INHB of -5.18 QALYs. At willingness-topay (WTP) threshold of $150,000/QALY in the US and $37,653/QALY in China, the probability of T-DXd as the dominant option was 77.5 and 0.1%, respectively. The unit price of T-DXd greatly influenced the results according to one-way sensitivity analysis. To meet the 50% or 90% chance of being cost-effective, the estimated cost of T-DXd would need to be less than $17.24/mg and $12.06/mg in China, respectively. Conclusion: T-DXd is more cost-effective than T-DM1 for patients with HER2- positive mBC in the US, but not in China at current drug prices. [ABSTRACT FROM AUTHOR]

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Background: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor-2 targeted antibody-drug conjugate that contains a monoclonal antibody, trastuzumab, covalently linked to DM1, a small molecule cytotoxin.Methods: We conducted a systematic review and meta-analysis of published trials to examine the efficacy and safety of T-DM1 for patients with HER2-positive metastatic breast cancer. In addition, we systematically reviewed existing economic evaluations of T-DM1. An electronic literature search of online databases (Medline, CENTRAL, and Embase) was performed. Randomized controlled trials that compared T-DM1 with other active treatment agents were eligible for inclusion. In addition, studies that involved T-DM1 as one of the treatment comparators in an economic evaluation were included. Four trials with a total of 2462 participants were included in this meta-analysis.Results: Pooled results showed T-DM1 substantially improved overall survival (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.85; I2 = 0%) and progression-free survival (HR, 0.67; 95% CI, 0.52-0.85; I2 = 75%). In addition, T-DM1 showed greater association with severe thrombocytopenia and liver dysfunction than other regimens, but a lower rate of neutropenia, leukopenia, febrile neutropenia, asthenia, and diarrhea. All four trials included in the meta-analysis overall had a low risk of bias. Two cost-utility analyses involving T-DM1 were identified, and the overall quality was high.Conclusions: T-DM1 is effective for the treatment of patients with HER2-positive metastatic breast cancer, and it demonstrates a tolerable safety profile compared with other active controls. Little evidence was available regarding the cost-effectiveness of T-DM1 so no conclusions can be drawn. [ABSTRACT FROM AUTHOR]

Purpose of review: Summarizing the current preclinical and clinical evidence about bystander effect of antibody–drug conjugates (ADCs) in solid tumors. Recent findings: One of the main challenges of treating solid tumors with ADCs is the heterogeneous expression of the target antigen (Ag), which however may be overcome by the so-called bystander killing effect. This unique, but still debated, feature of certain ADCs is represented by the unintentional payload diffusion from Ag-positive tumor cells to adjacent Ag-negative tumor cells. Some pharmacological characteristics, such as a hydrophobic payload or a cleavable linker, seem to play a major role in this effect. Summary: Abundant preclinical evidence of the bystander effect has emerged, and the clinical activity of ADCs in tumors with a heterogeneous Ag expression suggests the relevance of this feature. Additional studies are required to investigate if the bystander effect is necessary for achieving a solid activity with ADCs. [ABSTRACT FROM AUTHOR]

Background: The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC., Methods: This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS)., Results: Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS., Conclusion: The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance., (© The Author(s) 2024. Published by Oxford University Press.)

The global phase 3 DESTINY-Breast03 study (ClinicalTrials.gov; NCT03529110) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan (T-DXd) over trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. Here, we report a subgroup analysis of Asian patients enrolled in DESTINY-Breast03. In total, 309 patients (149 in the T-DXd arm and 160 in the T-DM1 arm) from Asian countries and regions were randomized. At data cutoff (July 25, 2022), the median duration of follow-up in the Asian subpopulation was 29.0 months with T-DXd and 26.0 months with T-DM1. The PFS (determined by blinded independent central review) hazard ratio was 0.30 (95% confidence interval 0.22-0.41) favoring T-DXd over T-DM1 (median PFS 25.1 vs. 5.4 months). Median OS was not reached in the T-DXd arm and was 37.7 months in the T-DM1 arm. The median treatment duration was 15.4 months with T-DXd and 5.5 months with T-DM1. The incidence of grade ≥3 drug-related treatment-emergent adverse events was similar between both treatment arms (49.0% vs. 46.5%) and was consistent with the overall DESTINY-Breast03 population. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.9% of patients treated with T-DXd and 2.5% treated with T-DM1, with a higher incidence in Japanese patients; none of these were grade ≥4 events. These efficacy and safety data reinforce the favorable benefit-risk profile of T-DXd in HER2-positive mBC, including in the Asian subgroup., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)