T-DM1应用于乳腺癌的最新研究进展

T-DM1是由曲妥珠单抗、细胞毒药物DM1通过连接子偶联而成的抗体药物偶联物,具有靶向性和细胞毒杀伤双重抗肿瘤作用,是第4个被FDA批准上市的抗HER-2靶向治疗药物。在HER-2阳性晚期乳腺癌一线、二线以及多线治疗的临床研究中,T-DM1均显示出突出的抗肿瘤活性,且耐受性良好,NCCN指南推荐其作为曲妥珠单抗治疗失败后的二线首选治疗方案。目前正在进行的临床研究将明确T-DM1在早期乳腺癌治疗领域中的地位,以及与其他药物联合的疗效和安全性。本文综述了T-DM1的作用机制、疗效与安全性、与疗效相关的因素、克服耐药的策略以及应用前景,有助于指导T-DM1的临床应用。     

Combined chemotherapy with molecular-targeted agent for breast cancer

Molecular-targeted agents, trastuzumab, lapatinib or bevacizumab, demonstrated efficacy in patients with breast cancer. Trastuzumab exhibited efficacy and safety for HER2-positive metastatic breast cancer, in single usage or in combination with paclitaxel, docetaxel or vinorelbine. Trastuzumab is also useful in an adjuvant setting in HER2-positive early breast cancer. However, it is not clear whether concurrent or sequential treatment is superior. Lapatinib combined with capecitabine showed efficacy against HER2-positive metastatic breast cancer. It was suggested that the combination with lapatinib and paclitaxel was effective. Bevacizumab combined with paclitaxel revealed efficacy for metastatic breast cancer. These molecular-targeted agents play an important role in treatment of breast cancer.     

Lapatinib: A competitor or companion to trastuzumab?

Trastuzumab (Herceptin), a monoclonal antibody against HER2 has established itself as the treatment paradigm of HER2-overexpressing breast cancer. Its success, however, has been tempered by its sequelae. In particular, most tumours become resistant to trastuzumab through a variety of mechanisms. Furthermore, there is both an increased incidence of cardiac dysfunction and a worrying pattern of CNS metastasis associated with trastuzumab. To manage these concerns, many new treatments targeting HER2 have been developed. Of these emerging therapies, the dual tyrosine kinase receptor inhibitor against EGFR and HER2, lapatinib (Tyverb/Tykerb) has shown the most promise to date. Encouraging early results in vitro have now been reproduced in phase II/III clinical trials, both as lapatinib monotherapy and synergistically with other established therapeutic regimes, including trastuzumab itself. Trial results suggest it may be of considerable benefit to patients with trastuzumab-resistant tumours and may play a role in the reduction of CNS relapses. In addition, lapatinib is well-tolerated and unlike trastuzumab, minimal cardiac dysfunction has been documented. A number of trials are underway to assess whether lapatinib will oust trastuzumab from its pole position in the management of HER2-positive breast cancer or whether their combination will prove to be superior to either therapy alone.     

Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278)

Trastuzumab, a monoclonal antibody against the HER2 receptor, is currently approved as a part of adjuvant therapy for patients with HER2-overexpressing breast tumors. The Short-HER study is a phase III randomized, multicentric Italian trial aimed at testing the optimal duration of adjuvant trastuzumab. In this trial, 2500 patients with HER2-positive breast cancer will be randomized to receive the following: (arm A, long) 4 courses of anthracycline- based chemotherapy (doxorubicin/cyclophosphamide or epidoxorubicin/cyclophosphamide) followed by 4 courses of docetaxel or paclitaxel in combination with trastuzumab, followed by 14 additional courses of trastuzumab administered every 3 weeks (for a total of 18 3-weekly doses of trastuzumab); or (arm B, short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab (for a total of 9 weekly doses of trastuzumab) followed by 3 courses of 5-fluorouracil/epirubicin/cyclophosphamide. The primary objective is disease-free survival.     

A case report of trastuzumab dose in gastric cancer

Introduction

Trastuzumab (Herceptin®, F. Hoffman-La Roche) is now approved for the treatment of metastatic HER2-positive gastric cancer based on the improved survival observed on the phase III Trastuzumab for Gastric Adenocarcinoma (ToGA) study. Standard dosing of trastuzumab is currently extrapolated from breast cancer data: a 3-week schedule (8 mg/kg load, 6 mg/kg q 3 weeks) or a weekly schedule (4 mg/kg load, 2 mg/kg q week).

Case study

Our case study examines an HER2-positive metastatic gastric cancer patient that required a higher than currently recommended standard dose of trastuzumab to achieve treatment response.

Discussion

Several mechanisms may explain these findings and include higher clearance of trastuzumab, higher tumor burden, and pharmacologic resistance in metastatic gastric cancer versus breast cancer. The question of trastuzumab dosing in gastric cancer is currently being evaluated in a phase III clinical trial.Key Words: Trastuzumab, metastatic gastric cancer, pharmacokinetics     

Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.     

Les anticorps conjugués en oncologie : du concept au trastuzumab emtansine (T-DM1)

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) which associates the selective intracellular targeting of the cytotoxic agent, DM1 (maytansine derivative) to the antitumor activity of trastuzumab. T-DM1 targets the epidermal growth factor receptor 2 (HER2), highly expressed in the most aggressive forms of breast cancer. Current standard of care in HER2-positive advanced or metastatic breast cancers has its limitations, particularly after progression on HER2-targeted approved therapies. T-DM1 showed a significant antitumor activity in vitro and in vivo, and in experimental models resistant to HER2-targeted agents. Phase I and II studies showed that the maximum tolerated dose for T-DM1 is 3.6 mg/kg given intravenously every three weeks. At this recommended dose, T-DM1 provided objective tumor responses and favourable safety profile. A phase II randomised study, evaluating T-DM1 in first line vs trastuzumab plus docetaxel, the current standard of care in advanced or metastatic breast cancers, showed improved tolerability and efficacy. Recently, the results of EMILIA, a phase III randomised study assessing, after prior treatment with trastuzumab and a taxane, the efficacy and the safety of T-DM1 vs lapatinib plus capecitabine, confirmed the therapeutic benefit. T-DM1 appears to be an effective therapeutic option to treat patients with HER2-positive metastatic breast cancer.     

Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer

The development of antibody–drug conjugates composed of a cytotoxic agent and a monoclonal antibody carrier offers an important alternative to classic chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation antibody–drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, an exatecan derivative (DX-8951f). DS-8201a resulted in favorable outcomes in HER2-positive heavily pretreated breast cancer patients and also had a promising efficacy in patients with HER2-negative/low-expressing disease, whose options are limited. Interestingly, a recently published phase 2 trial (NCT03248492) reported 60% overall response and 97% disease control in patients with HER2-positive disease previously treated with multiple regimens, including trastuzumab emtansine. On the basis of recent clinical trials, the US Food and Drug Administration granted accelerated approval to DS-8201a in advanced or unresectable HER2-positive breast cancer pretreated with at least two HER2-targeting treatment lines. We review all preclinical and clinical data of DS-8201a regarding breast cancer.     

恩美曲妥珠单抗T-DM1在HER2阳性乳腺癌中的研究进展

T-DM1是由人源化单克隆抗体曲妥珠单抗通过连接子和细胞毒性药物DM1偶联形成的一种抗体-药物偶联物,综合了抗体的靶向性和细胞毒性药物的高效杀伤癌细胞特性,发挥双倍抗肿瘤效应的同时又降低了常规化疗药物的毒副反应。多项临床研究探索了T-DM1应用于晚期HER2阳性转移性乳腺癌的解救治疗以及早期HER2阳性乳腺癌的辅助化疗和新辅助化疗的有效性和耐受性,并展现出良好的临床应用前景。本文就T-DM1应用于HER2阳性乳腺癌的最新临床研究进展简要综述。     

Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer

Purpose

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6?mg/kg every 3?weeks (q3w) were assessed in aggregate.

Methods

Multiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.

Results

PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.

Conclusions

The PK profile of single-agent T-DM1 (3.6?mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.     

HER2-positive gastric cancer

Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis and poor outcomes of several types of cancer, including advanced gastric and gastroesophageal junction cancer. Molecular-targeted drugs, such as trastuzumab, which prolong overall survival and progression-free survival in HER2-positive breast cancer, may also be beneficial in patients with HER2-positive gastric cancer. Several studies have examined this possibility, such as the Trastuzumab for Gastric Cancer trial. In this context, the first part of this review provides an update on our knowledge of HER2 in breast and gastric cancer, including the detection and prognostic relevance of HER2 in gastric cancer. The second part of the review discusses the results of pivotal clinical trials that examined the potential for using trastuzumab to treat this disease. This section also summarizes the trials that have been conducted or that are underway to determine the optimal uses of trastuzumab in gastric cancer, including its use as monotherapy and continuation beyond disease progression. The final section discusses the future prospects of other anti-HER2 drugs, including lapatinib, trastuzumab emtansine, and pertuzumab, for the treatment of HER2-positive gastric cancer. The introduction of trastuzumab led to the establishment of a new disease entity, “HER2-positive gastric cancer,” similar to HER2-positive breast cancer. It is expected that more anti-HER2 drugs will be developed and introduced into clinical practice to treat HER2-positive cancers, including gastric cancer.     

Subcutaneous trastuzumab: a review of its use in HER2-positive breast cancer

Trastuzumab (Herceptin®) is a humanized IgG₁ monoclonal antibody that is an efficacious treatment for HER2-positive breast and gastric cancers. Subcutaneous trastuzumab is a new formulation approved in the European Union for use in patients with early or metastatic breast cancer. In the randomized, open-label, multinational HannaH (enHANced treatment with NeoAdjuvant Herceptin) study of neoadjuvant/adjuvant trastuzumab in patients with early HER2-positive breast cancer, the pharmacokinetics of neoadjuvant subcutaneous trastuzumab were similar to those after intravenous administration, meeting the noninferiority criterion for mean predose trough concentrations, as assessed prior to surgery (primary pharmacokinetic endpoint). Trastuzumab blood concentrations throughout the dosing interval remained above those considered necessary for anticancer activity. In this study, the pathologic complete response rates (primary efficacy endpoint) were 45.4 and 40.7 % in the subcutaneous and intravenous administration groups, respectively, meeting a study noninferiority criterion. In the randomized, open-label, crossover, multinational PrefHer study of neoadjuvant/adjuvant or adjuvant trastuzumab in early HER2-positive breast cancer, subcutaneous administration of trastuzumab was preferred over intravenous administration by >85 % of patients, most commonly because it was time saving and induced less pain and discomfort. In the HannaH study, the tolerability profile of subcutaneous trastuzumab was similar to that of intravenous trastuzumab, except that the rate of serious adverse events was 21 % (vs. 12 % with intravenous administration), partly because of more infections with subcutaneous administration. Whether this finding is of any clinical significance should emerge from ongoing studies. On the evidence, subcutaneous trastuzumab is an effective and generally well-tolerated treatment option that is preferred by patients over intravenous administration.     

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.     

The use of HER2 modulation in the adjuvant setting

Amplification of the her-2/neu gene is associated with poor prognosis in patients with early-stage and metastatic breast cancer. Trastuzumab is a humanized monoclonal antibody directed against the HER2 protein, which is overexpressed in approximately 25% of patients with primary invasive breast cancer. Randomized phase III clinical trials showed that administration of trastuzumab in combination with chemotherapy or following chemotherapy significantly improves disease-free and overall survival rates in patients with early-stage HER2-positive breast cancer. The integration of trastuzumab in the adjuvant setting is changing the natural history of HER2-driven breast cancer from one of the worst subtypes to one that is highly curable with available therapy.     

Acquired resistance to trastuzumab/pertuzumab or to T‐DM1 in vivo can be overcome by HER2 kinase inhibition with TAS0728

HER2‐targeting antibodies (trastuzumab, pertuzumab) and a HER2‐directed antibody‐drug conjugate (trastuzumab emtansine: T‐DM1) are used for the treatment of HER2‐overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small‐molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T‐DM1 for evaluating the effect of TAS0728 on HER2 antibody‐resistant populations. Treatment with trastuzumab and pertuzumab or with T‐DM1 initially induced tumor regression in NCI‐N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T‐DM1, HER2‐HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti‐tumor effect associated with HER2‐HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient‐derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T‐DM1, TAS0728 exerted a potent anti‐tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T‐DM1 are still dependent on oncogenic HER2‐HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti‐HER2 therapies.     

Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab

HER2 amplification in breast cancer is associated with a more aggressive disease, greater likelihood of recurrence, and decreased survival compared to women with HER2-negative breast cancer. Trastuzumab is a monoclonal antibody that inhibits HER2 activity, making this compound an important therapeutic option for patients with HER2-positive breast cancer. However, resistance to trastuzumab develops rapidly in a large number of breast cancer patients. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials for cancer treatment, can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. GRN163L was effective in inhibiting telomerase activity and shortening telomeres in HER2-positive breast cancer cells. We show that GRN163L acts synergistically with trastuzumab in inhibiting HER2-positive breast cancer cell growth. More importantly, we show that GRN163L can restore the sensitivity of therapeutic-resistant breast cancer cells to trastuzumab. These findings implicate that telomerase template antagonists have potential use in the treatment of cancers that have developed resistance to traditional cancer therapy.     

HER2-positive breast cancer: update on Breast Cancer International Research Group trials

HER2 gene amplification occurs in approximately 20% of primary breast cancers and is associated with a poor prognosis. Recently, trastuzumab, a humanized murine monoclonal antibody directed against the extracellular domain of HER2, was introduced for the treatment of patients with HER2-overexpressing advanced breast cancer. Trastuzumab has activity as both a single agent and in combination with chemotherapy. However, trastuzumab in conjunction with anthracyclines produces an unacceptably high rate of cardiac toxicity, which has prompted the search for alternative regimens. Docetaxel and the platinum salts are logical candidates to be combined with trastuzumab since these agents exhibit potent synergy with the antibody in preclinical experiments. Furthermore, the available phase II clinical data using the TCH (docetaxel/platinum/trastuzumab) regimen suggest this combination has significant activity. The Breast Cancer International Research Group (BCIRG) 006 trial is a 3-arm adjuvant study comparing doxorubicin/cyclophosphamide followed by docetaxel, the same regimen with trastuzumab administered with docetaxel (TH), and TCH in 3150 women with node-positive or high-risk node-negative, HER2-positive breast cancer. BCIRG 007 compares TH and TCH as first-line therapy in patients with HER2-positive metastatic breast cancer. In both trials, entry is restricted to patients whose tumors are positive for HER2 gene amplification as determined by fluorescence in situ hybridization. The data from these trials, in addition to the results from other ongoing randomized studies, will help define the optimal way to utilize trastuzumab in the management of patients with HER2-positive breast cancer.     

Trastuzumab emtansine: mechanisms of action and drug resistance

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.     

Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer

Increased understanding of the molecular mechanisms of tumorigenesis has led to the development of novel agents that target tumor cells with minimal effects on normal cells. The success of this approach is exemplified by the development of monoclonal antibodies directed toward antigens expressed selectively by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs has the potential to further improve efficacy while retaining a favorable safety profile. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) currently in clinical development. It combines the humanized antibody trastuzumab, which targets the human epidermal growth factor receptor 2 (HER2) receptor on cancer cells, and the potent antimicrotubule agent DM1 using a unique highly stable linker. When T-DM1 binds to HER2, a proportion of the receptors are thought to be internalized by the process of receptor endocytosis, followed by the intracellular release of an active form of DM1, which in turn kills the tumor cell. This review presents the rationale for the development of T-DM1 and summarizes the preclinical and clinical data for this novel agent for the treatment of breast cancer.