A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer

Masuda, Norikazu; Ohtani, Shoichiro; Takano, Toshimi; Inoue, Kentaro; Suzuki, Eiji; Nakamura, Rikiya; Bando, Hiroko; Ito, Yoshiaki; Ishida, Kazushige; Yamanaka, Takashi; Kuroi, Katsumasa; Yasojima, Hiroyuki; Kasai, Hideaki; Takasuka, Tsuyoshi; Sakurai, Takaki; Kataoka, Tatsuki R.; Morita, Satoshi; Ohno, Shinji; Toi, Masakazu

doi:10.1007/s10549-020-05524-6

Cited by 30 publications

(27 citation statements)

References 24 publications

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“…Finally, our study included 36 clinical trials published between 2007 and 2020, involving 89 treatment arms, focusing on neoadjuvant therapy for HER2-positive breast cancer, and involving a total of 10,379 patients ( Supplemental File 2 ). 6 , 8 , 9 , 11 , 22 – 56 Some of the studies compared chemotherapy with targeted therapy, and others compared dual-target therapy with single-target therapy. Five trials evaluated the efficacy of T-DM1 in neoadjuvant therapy, and another five focused on trastuzumab biosimilars.…”

Section: Resultsmentioning

confidence: 99%

“…As demonstrated in our study, T-DM1-containing regimens also show great efficacy, especially when combined with other targeted drugs or chemotherapies. 51 , 54 Compared with the traditional targeted therapy, the use of antibody drug conjugate (ADC) to increase the drug concentration in tumour cells may further enhance efficacy. However, we also noticed that ‘KAITLIN’, a phase III study directly comparing T-DM1 plus pertuzumab with taxane plus trastuzumab and pertuzumab after anthracycline as adjuvant therapy, did not meet its co-primary end point that T-DM1 is better than the control.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis

Zhang

Lin

et al. 2021

Ther Adv Med Oncol

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Aims: Currently, there are many approaches available for neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer that improve therapeutic efficacy but are also controversial. We conducted a two-step Bayesian network meta-analysis (NMA) to compare odds ratios (ORs) for pathologic complete response (PCR) and safety endpoints. Methods: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and online abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium were searched comprehensively and systematically. Phase II/III randomised clinical trials for targeted therapy in at least one arm were included. Results: A total of 9779 published manuscripts were identified, and 36 studies including 10,379 patients were finally included in our analysis. The NMA of PCR showed that dual-target therapy is better than single-target therapy and combination chemotherapy is better than monochemotherapy. However, anthracycline did not bring extra benefits, whether combined with dual-target therapy or single-target therapy. On the other hand, the addition of endocrine therapy in the HER2-positive, hormone receptor (HR)-positive subgroup might have additional beneficial effects but without significant statistical difference. By performing a conjoint analysis of the PCR rate and safety endpoints, we found that ‘trastuzumab plus pertuzumab’ and ‘T-DM1 containing regimens’ were well balanced in terms of efficacy and toxicity in all target regimens. Conclusion: In summary, trastuzumab plus pertuzumab-based dual-target therapy with combination chemotherapy regimens showed the highest efficacy of all optional regimens. They also achieved the best balance between efficacy and toxicity. As our study showed that anthracycline could be replaced by carboplatin, we strongly recommended TCbHP as the preferred choice for neoadjuvant treatment of HER2-positive breast cancer. We also look forward to the potential value of T-DM1 in improving outcomes, which needs further study in future trials.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis

Zhang

Lin

et al. 2021

Ther Adv Med Oncol

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“…In the JBCRG-20 trial, patients were randomly assigned to three treatment regimens: (I) docetaxel, carboplatin, and trastuzumab plus pertuzumab for six cycles; (II) docetaxel, carboplatin, and trastuzumab plus pertuzumab for four cycles followed by T-DM1 plus pertuzumab for four cycles; (III) T-DM1 plus pertuzumab for four cycles, followed by two cycles of same regimen for responders or four cycles of anthracycline-based regimen for non-responders (19). The pCR rates were 57%, 71%, and 57% for group A, group B, and group C, respectively.…”

Section: Increasing the Proportion Of Patients Who Achieve Pcr With Dual Her2 Blockadementioning

confidence: 99%

Neoadjuvant treatment for HER2-positive breast cancer

Takada

Toi

2020

Chin Clin Oncol

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Neoadjuvant therapy has become a standard clinical practice to downsize the tumor and increase the breast-conserving rate. The addition of trastuzumab to neoadjuvant chemotherapy roughly doubles the proportion of patients with HER2-positive breast cancer who achieve pathological complete response (pCR). Patients with pCR show better prognosis compared with those with residual disease after neoadjuvant therapy. Targeting the HER2 pathway with trastuzumab and pertuzumab can further increase the pCR rate.Several studies have shown that neoadjuvant chemotherapy with trastuzumab plus pertuzumab is tolerable, increases the pCR rate compared with trastuzumab alone, and results in about 50-70% pCR rate. One of the most important studies on neoadjuvant therapy is the KATHERINE trial, in which improved prognostic outcome for patients with residual disease after neoadjuvant therapy was observed. In the trial, improved invasive disease-free survival (DFS) was observed with the administration of postoperative trastuzumab emtansine in patients with HER2-positive breast cancer who had residual disease after neoadjuvant therapy.The indication of neoadjuvant therapy in patients with HER2-positive breast cancer may be changed because the opportunity for residual disease-guided approach, demonstrated in the KATHERINE trial, will be lost when patients had first undergone surgery. Translational studies are promising for further patient selection for HER2-targeted therapy and the development of a novel treatment strategy including PI3K-targeted therapy and immune checkpoint inhibitors. Feasibility studies to evaluate the ability of needle-biopsy to predict pCR after neoadjuvant therapy suggested that standardization and refinements in biopsy procedure (i.e., needle size, number of samples, etc.) are essential for the design of clinical trials of omitted surgery for patients with radiologic complete response.

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“…36 Ado-trastuzumab emtansine based neoadjuvant therapy may provide better quality of life for patients and minimize toxicity when compared to chemotherapy-based treatment, but thus far it has not shown to be the best agent for neoadjuvant phase. 37 It is hypothesized that inferiority of neoadjuvant ado-trastuzumab emtansine to chemotherapy-based treatment is likely due to lack of payload bystander effects in the setting of HER2 receptor heterogeneity, toxicity limited C max and slow rate of internalization. 5,7 HER2 receptor heterogeneity is also responsible for development of resistance to the ado-trastuzumab emtansine.…”

Section: Clinical Use Controversiesmentioning

confidence: 99%

“…36 The trial concluded while ado-trastuzumab emtansine based neoadjuvant therapy has fewer side-effects, it was inferior to neoadjuvant chemotherapy-based therapy. 37 Shortcomings of ado-trastuzumab emtansine that may explain ado-trastuzumab emtansine inferiority in the KRISTINE trial include toxicity limited C max , slow rate of internalization, and lack of payload bystander effects which decreases drug effectiveness with heterogenous HER2 receptor expression and a number of resistance mechanisms. 7 These shortcomings make for great research targets to enhance function of the drug.…”

Section: Perspective On Use (Summary Paragraph On How This Drug Fits mentioning

confidence: 99%

The role of ado-trastuzumab emtansine in current clinical practice

Turshudzhyan

2020

J Oncol Pharm Pract

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Objective This review reflects the literature from 2019 to 2020 on ado-trastuzumab emtansine’s (T-DM1) therapeutic use, clinical controversies, and newest perspectives on use. Data sources: PubMed was used as a database. Search “ado-trastuzumab emtansine” on June 11th, 2020 resulted in 57 publications: 20 clinical trials, two metanalysis, six randomized controlled studies, 13 reviews, and two systematic reviews. Of the 57 publications, 34 were descriptive of the topic in question and were used for this review. Data summary: T-DM1 is now used for patients with HER2 breast cancer who have residual disease post surgery after neoadjuvant chemotherapy (KATHERINE trial). Initial success prompted KRISTINE trial, which investigated whether T-DM1 can be used as a neoadjuvant therapy. While it did have fewer adverse events, T-DM1 was inferior to chemotherapy in treating early breast cancer. Noted shortcomings of the drug were toxicity limited Cmax, slow rate of internalization, lack of payload bystander effects, and number of resistance mechanisms. Proposed solutions were pre-treatment with metformin to augment drug internalization by the cell, use of second generation anti-HER2 antibody-drug conjugates to overcome developing resistance, payload swapping to increase bystander effect. Conclusions While T-DM1 has fewer side-effects, it is inferior to chemotherapy in early breast cancer treatment. More research should be done to overcome resistance pathways, identify rate-limiting intracellular processing pathways, improve bystander, and enhance internalization of the drug. Until more research is done, T-DM1 will continue to be used in HER2 positive breast cancer as well as a few other HER2 expressing tumors that fail to respond to neoadjuvant therapy.

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A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer

Cited by 30 publications

References 24 publications

Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis

Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis

Neoadjuvant treatment for HER2-positive breast cancer

The role of ado-trastuzumab emtansine in current clinical practice

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