Trastuzumab Emtansine In Patients Research Articles

P88-3 Effectiveness and safety of trastuzumab emtansine in patients with breast cancer: meta-analysis of clinical trials

P88-3 Effectiveness and safety of trastuzumab emtansine in patients with breast cancer: meta-analysis of clinical trials

Real-world data on the efficacy and safety of trastuzumab emtansine in patients with metastatic breast cancer previously treated with pertuzumab: Turkish oncology group multicenter study

We 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 CT265: Trastuzumab emtansine in patients (pts) with HER2 mutation-positive (HER2mut) tumors: TAPISTRY study

Abstract Background: HER2 point mutations are found in ~1.4% of solid tumors, but prevalence varies across tumor types. Trastuzumab emtansine is an antibody-drug conjugate approved in HER2-overexpressing metastatic breast cancer. Here we present efficacy and safety data of trastuzumab emtansine in pts with HER2mut advanced/metastatic solid tumors (excluding HER2 amplifications) from Cohort F of the TAPISTRY trial (NCT04589845). Methods: TAPISTRY is a phase II, global, open-label, multi-cohort basket trial evaluating the efficacy and safety of multiple therapies in pts with advanced/metastatic solid tumors. Pts in Cohort F were ≥12 years old, with tumors harboring an activating HER2 mutation identified by NGS, and measurable disease by RECIST v1.1. Trastuzumab emtansine 3.6 mg/kg IV was administered every 21 days; tumor assessments were performed at screening, every 6 weeks from day 1/cycle 1 for one year, and every 9 weeks thereafter. Primary endpoint: objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints: ORR by investigator; duration of response; progression-free survival; overall survival; safety. Results: At data cut-off (16 Jul 2023), 35 pts with 10 different tumor types were efficacy evaluable; the most common tumor type was non-small cell lung cancer (NSCLC; 31%). Baseline characteristics and key outcomes are presented in the Table. After a median follow-up of 7 months, ORR by IRC in efficacy-evaluable pts was 14.3% (n/N=5/35; 95% CI 4.8-30.3]). Responses were observed in 3 tumor types: NSCLC (n/N=1/11), breast (n/N=3/5), endometrial (n/N=1/1). The most frequent adverse events were decreased appetite, fatigue, and nausea (25.7% each). No new safety signals were identified. Conclusions: Trastuzumab emtansine in pts with HER2mut tumors (excluding HER2 amplifications) did not meet its primary endpoint. Trastuzumab emtansine was generally well tolerated and the safety profile was consistent with the known profile of the drug. TABLE 1. NAND Baseline characteristics Trastuzumab emtansine N=35 Median age, years (range) 67 (29-83) Female, n (%) 22 (62.9) Prior lines of therapy, n (%) - No prior lines of therapy/1 prior line of therapy/≥2 prior lines of therapy 1 (2.9)/8 (22.9)/26 (74.3) Efficacy N=35 Objective response rate by IRC, n (%) [95% CI] 5 (14.3)* [4.8-30.3] Complete response 0 Partial response 5 (14.3) Stable disease 14 (40.0) Progressive disease 10 (28.6) Missing† 6 (17.1) Clinical benefit rate by IRC, n (%)‡ 8 (22.9) Objective response rate by investigator, n (%) 2 (5.7) Median duration of response, months (95% CI) - By IRC/By investigator 9.4 (2.8-NE)/11.8 (8.3-NE) Median progression-free survival, months (95% CI) - By IRC/By investigator 3.3 (1.4-4.3)/2.7 (1.5-3.9) Median overall survival, months (95% CI) 10.0 (6.2-13.4) Safety, n (%) N=35 ≥1 AE 33 (94.3) Grade 3-5 AEs 19 (54.3) AE-related deaths 4 (11.4) Serious AEs 13 (37.1) AEs leading to withdrawal from study 4 (11.4) Treatment-related AEs 25 (71.4) Treatment-related AEs leading to withdrawal from study 1 (2.9) *By tumor type: non-small cell lung cancer (n=1), breast (n=3), and endometrial (n=1); †Six patients had missing data due to: death (n=4), clinical progression (n=1), or withdrawal of consent (n=1) prior to first scan; ‡Criteria for clinical benefit: either a response (confirmation not required) and/or stable disease or better for at least 24 weeks. AE, adverse event; CI, confidence interval; NE, not estimable. Citation Format: Jeong Eun Kim, David Thomas, Shirish Gadgeel, Marcelo Corassa, Tira J. Tan, Eugenia Girda, Donald Richards, Sabine Tejpar, David Chen, Junhan Fang, Sid Patel, Timothy R. Wilson, Fabrice Barlesi. Trastuzumab emtansine in patients (pts) with HER2 mutation-positive (HER2mut) tumors: TAPISTRY study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT265.

Abstract GS2-02: GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03

Abstract Background: Trastuzumab deruxtecan (T-DXd) is approved in the United States and European Union for use in patients (pts) with HER2+ unresectable/metastatic breast cancer (mBC) after ≥1 prior anti–HER2 regimen(s). Approval was based on the randomized, multicenter, open-label, phase 3 DESTINY-Breast03 study (NCT03529110), in which T-DXd demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1). At the primary interim analysis (data cutoff May 21, 2021), the risk of disease progression or death was reduced by 72% with T-DXd (P < 0.001; Cortes et al. N Engl J Med 2022). Overall survival (OS) data were immature for both treatment groups; although the prespecified cutoff for significance was not reached (NR), a trend toward benefit with T-DXd was observed. With further follow-up, we report results from the prespecified OS analysis of DESTINY-Breast03 (data cutoff July 25, 2022), including updated efficacy and safety. Methods: Pts with HER2+ mBC previously treated with trastuzumab and a taxane in either the metastatic setting or (neo)adjuvant setting with progression within 6 mo of therapy, who could have received pertuzumab, were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks (Q3W) or T-DM1 3.6 mg/kg Q3W until disease progression. The primary endpoint was PFS by blinded independent central review (BICR). The key secondary endpoint was OS (80% powered at 2-sided significance level of 5%); other secondary endpoints included objective response rate (ORR), duration of response (DoR), PFS based on investigator assessment, and safety. Results: 524 pts received either T-DXd (n = 261) or T-DM1 (n = 263). As of the updated data cutoff, median duration of study follow-up was 28.4 mo (range, 0.0-46.9 mo) for T-DXd and 26.5 mo (range, 0.0-45.0 mo) for T-DM1. Median treatment duration was 18.2 mo (range, 0.7-44.0 mo) for T DXd and 6.9 mo (range, 0.7-39.3 mo) for T-DM1. The risk of death was reduced by 36% (HR, 0.64; P = 0.0037) with T-DXd; median OS (mOS) was NR (95% CI, 40.5 mo-not evaluable [NE]), with 72 (27.6%) OS events, for T-DXd vs NR (95% CI, 34.0 mo-NE), with 97 (36.9%) OS events, for T-DM1. Landmark 12-mo OS rate was 94.1% (95% CI, 90.4-96.4) for T-DXd vs 86.0% (95% CI, 81.1-89.8) for T-DM1; 24-mo OS rate was 77.4% (95% CI, 71.7-82.1) for T-DXd vs 69.9% (95% CI, 63.7-75.2) for T-DM1. The P value for OS crossed the prespecified boundary (P = 0.013) and was statistically significant. mPFS by BICR was 28.8 mo (95% CI, 22.4-37.9 mo) with T-DXd, compared with 6.8 mo (95% CI, 5.6-8.2 mo) with T-DM1; HR, 0.33; nominal P < 0.000001. Key efficacy and safety results are shown in the table. Grade ≥3 treatment-emergent adverse events were experienced by 56.4% of T-DXd-treated pts and 51.7% of T DM1-treated pts. Drug-related interstitial lung disease/pneumonitis, as evaluated by an independent adjudication committee, was experienced by 39 pts (15.2%) in the T-DXd arm and 8 pts (3.1%) in the T DM1 arm; no adjudicated drug-related grade 4 or 5 events were observed in pts who received T-DXd. Conclusions: Updated results confirm the superiority of T-DXd compared with T-DM1 for pts with HER2+ mBC previously treated with an anti-HER2 therapy, with highly clinically meaningful and statistically significant benefit in OS and PFS and a manageable safety profile with longer treatment duration. Editorial Acknowledgment Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, and Rachel Hood, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy Results for T-DXd and T-DM1 Citation Format: Sara Hurvitz, Roberto Hegg, Wei-Pang Chung, Seock-Ah Im, William Jacot, Vinod Ganju, Joanne Win Yang Chiu, Binghe Xu, Erika Hamilton, Srinivasan Madhusudan, Hiroji Iwata, Sevilay Altintas, Jan-Willem Henning, Giuseppe Curigliano, José Manuel Pérez-García, Anton Egorov, Yali Liu, Jillian Cathcart, Shahid Ashfaque, Javier Cortés. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-02.

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial

An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. Daiichi Sankyo and AstraZeneca.

Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer

BackgroundKAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings.MethodsPatients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis.ResultsKAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines.ConclusionsCohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC.

Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer

BackgroundTrastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.MethodsWe conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody–drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety.ResultsAmong 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5.ConclusionsAmong patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.)

Abstract ES10-3: IO beyond TNBC

Abstract Hormone receptor-positive breast cancer is not considered an immunogenic tumor, since characterized by lower level of programmed death-ligand 1 (PD-L1) expression and tumor infiltrating lymphocytes. Despite being a cold tumor some studies are addressing the question on potential role of immune-checkpoint inhibitors in the adjuvant or metastatic setting. The phase II Checkmate7A8 trial (NCT04075604) is investigating the combination of nivolumab, anastrozole, and palbociclib versus anastrozole with palbociclib as neoadjuvant therapy for postmenopausal women with luminal BC. The phase II ImmunoADAPT trial (NCT03573648) is studying the combination of tamoxifen, palbociclib, and avelumab versus tamoxifen with avelumab for patients with early-stage luminal BC, expecting to show an improvement in the radiological complete response rates assessed after four cycles of treatment. A phase I safety study is also investigating the combination of durvalumab, abemaciclib, and anastrozole in a similar population (NCT04088032). The Phase 3 CA209-7FL trial is a randomized, multicenter, placebo-controlled phase 3 study of nivolumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy in patients with high-risk, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer. In the HER2 positive metastatic breast cancer the combination of pembrolizumab and trastuzumab administered upon progression on a trastuzumab-based regimen was investigated in the PANACEA study, which reported a response rate of 15%, restricted to PD-L1 positive tumors with a PFS benefit in the PD-L1 population. In the KATE2 trial, the addition of atezolizumab to trastuzumab emtansine in patients previously treated with trastuzumab demonstrated no significant benefit in PFS, although numerically higher PFS and response rates were observed in the PD-L1-positive population. A subsequent underpowered analysis (due to the small number of events) of the same trial suggested a possible OS benefit for patients with PD-L1-positive tumors. The combination of trastuzumab, pertuzumab, taxane, and atezolizumab is under investigation in the first-line setting (NCT03199885). The phase III IMpassion050 (NCT03726879) trial compares atezolizumab or placebo combined with neoadjuvant chemotherapy and dual anti-HER2 blockade for early-stage HER2-positive BC. This trial includes patients with PD-L1-positive and PD-L1-negative tumors and is considering pCR rates in the PD-L1-positive and ITT population as primary endpoints. In patients who do not achieve a pCR, TDM-1 is added in the adjuvant phase. The addition of atezolizumab to an anthracycline-free regimen of neoadjuvant chemotherapy and dual anti-HER2 blockade is the objective of the phase III APTneo trial (NCT035955592). In my presentation I will cover biological rational for IO studies beyond triple negative breast cancer in the attempt to provide an ideal immunogram for this population of patients. Citation Format: G Curigliano. IO beyond TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES10-3.

Current approaches to the treatment of HER2‑positive breast cancer with brain metastases

The article discusses modern approaches in the treatment of HER2-positive breast cancer (BC) with brain metastases (BM).The patients are subject to multidisciplinary, comprehensive and biologically – oriented treatment, with the involvement of a neurosurgeon and a radiation therapist to make a decision considering local treatment of BM, as well as a clinical oncologist to choose systemic drug therapy. Local treatment of HER2+ BC with BM patients includes surgical treatment and/or radiotherapy. Use of targeted anti-HER2 therapy changes “biology” of the disease from aggressive to indolent.In the prospective KAMILLA trial, clinically significant antitumor activity of trastuzumab emtansine was found for the first time both in patients with HER2+ BC with BM, who were previously treated with radiotherapy, and without radiotherapy in the anamnesis, which suggests the validity of further use of trastuzumab emtansine in this category of patients.The antitumor activity of trastuzumab emtansine in patients with HER2+ BC with BM was also confirmed in preclinical models. Despite the similar drug distribution in the tissues, trastuzumab emtansine, in contrast to trastuzumab, significantly slowed the growth of metastases, causing the induction of apoptosis in HER2+ BC models with BM in mice.

Economic evaluation of adjuvant trastuzumab emtansine in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment in Canada.

In the katherine trial, adjuvant trastuzumab emtansine [T-DM1, Kadcyla (Genentech, South San Francisco, CA, U.S.A.)], compared with trastuzumab, significantly reduced the risk of recurrence or death by 50% (unstratified hazard ratio: 0.50; 95% confidence interval: 0.39 to 0.64; p < 0.0001) in patients with her2-positive early breast cancer (ebc) and residual invasive disease after neoadjuvant systemic treatment. A cost-utility evaluation, with probabilistic analyses, was conducted to examine the incremental cost per quality-adjusted life-year (qaly) gained associated with T-DM1 relative to trastuzumab, given the higher per-cycle cost of T-DM1. A Markov model comprising a number of health states was used to examine clinical and economic outcomes over a lifetime horizon from the Canadian public payer perspective. Patients entered the model in the invasive disease-free survival (idfs) state, where they received either T-DM1 or trastuzumab. Transition probabilities between the health states were derived from the katherine trial, Canadian life tables, and published literature from other relevant clinical trials (emilia, cleopatra, and M77001). Resource use, costs, and utilities were derived from katherine, other clinical trials, published literature, provincial fee schedules, and clinical expert opinion. Sensitivity analyses were conducted for key assumptions and model parameters. Compared with trastuzumab, adjuvant T-DM1 was associated with a cost savings of $8,300 per patient and a 2.16 incremental qaly gain; thus T-DM1 dominated trastuzumab. Scenario analyses yielded similar results, with T-DM1 dominating trastuzumab or producing highly favourable incremental cost-utility ratios of less than $10,000 per qaly. Adjuvant T-DM1 monotherapy is a cost-effective strategy compared with trastuzumab alone in the treatment of patients with her2-positive ebc and residual invasive disease after neoadjuvant systemic treatment.

Neoadjuvant treatment for HER2-positive breast cancer.

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.

A Study Evaluating the Safety and Efficacy of Venetoclax in Combination With Trastuzumab Emtansine in Patients With Previously Treated HER2-Positive Locally Advanced or Metastatic Breast Cancer

A Study Evaluating the Safety and Efficacy of Venetoclax in Combination With Trastuzumab Emtansine in Patients With Previously Treated HER2-Positive Locally Advanced or Metastatic Breast Cancer

Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial

BackgroundHER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.MethodsHERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).ResultsThirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.ConclusionsHERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.Trial registration number2012-002128-33 and NCT03225937.

Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship. Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration-time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints. An apparent exposure-response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure-response relationship was observed for any safety endpoints. Exposure-response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C min showed the strongest exposure-response trend. The Q1 subgroup based on model-predicted cycle 1 C min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6mg/kg every 3weeks) has a positive benefit-risk ratio versus control, even for the T-DM1 Q1 subgroup.

Trastuzumab Emtansine in Patients with HER2-Positive Metastatic Breast Cancer: a Multicenter Japanese Retrospective Study

Trastuzumab Emtansine in Patients with HER2-Positive Metastatic Breast Cancer: a Multicenter Japanese Retrospective Study

Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study

Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1-23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2-18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7-9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1-11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87-1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. F Hoffmann-La Roche.

Semi-mechanistic Population Pharmacokinetic Model of Multivalent Trastuzumab Emtansine in Patients with Metastatic Breast Cancer

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.