Adjuvant T-DM1 Research Articles

193P - Impact of adjuvant trastuzumab emtansine (T-DM1) on incidence of metastatic breast cancer (mBC): An epidemiological model of patients with HER2-positive breast cancer (BC) who did not achieve pathological complete response (pCR) after neoadjuvant treatment (non-pCR)

BackgroundProgression from early BC (eBC) to mBC creates a substantial burden for pts and healthcare systems. The KATHERINE trial showed adjuvant T-DM1 reduced the risk of disease recurrence or death by 50% vs trastuzumab (T) in pts with HER2-positive eBC with residual disease after neoadjuvant tx. The population level impact of T-DM1 on preventing relapsed mBC cases of HER2-positive, non-pCR eBC in 5 European countries (EU5) was estimated. MethodsAn epidemiological model was developed and data from observational and clinical trial studies were used to inform BC variables (Table). Weighted averages of non-pCR rates by neoadjuvant tx and hormone receptor (HR) subtype were calculated and extrapolations from KATHERINE data were used to model disease progression and death.Table193P Epidemiology model variables and sources to determine prevented relapsed mBC cases over the time period 2020-2029TableVariableDefinitionSourceBC incidenceAll incident cases of BCNational Cancer Registries for EU5*eBC stage HER2/HR statusStage I–III HER2-positive, HR-positive, and HR-negativePublished literature, SEER dataHER2-positive neoadjuvant tx rateRate of tx with T or T + pertuzumabESMO guidelines, syndicated reports, and SEER dataHER2-positive neoadjuvant-treated non-pCRHER2-positive who do not achieve pCR after neoadjuvant tx by tx regimen and HR statusSystematic literature review of observational studies, NeoSphere and KRISTINE trialsRelapsed mBC incidenceExtrapolated disease-free survival and overall survival curvesKATHERINE trial*EU5 = France, Germany, Italy, Spain, United Kingdom (UK) ESMO, European Society for Medical Oncology; SEER, Surveillance, Epidemiology, and End Results. ResultsProjected incidence of HER2-positive eBC in EU5 increased from 36,966 to 39,039 pts between 2020 -2029. Annual population eligible for adjuvant T-DM1 tx was stable at approximately 10,000 pts over the study time period. Total cases of mBC prevented with adjuvant T-DM1 from 2020 -2029 is projected to increase from 46 to 1732 with a cumulative total of 10,139 or 27% of total projected incident-relapsed mBC cases among pts with HER2-positive, non-pCR eBC. At year 10 (2029), the model projects 3798 pts prevented from developing mBC with T, thus a 46% decrease with TDM-1 relative to T. Findings were similar across EU5. Modeling estimates may not consider shifts in incidence or reflect actual practice or events occurring outside of the study period. ConclusionsModel outputs show a reduction of mBC due to T-DM1 beyond the maximum impact of T in eBC in EU5, thereby changing the epidemiology of HER2-positive BC over time, illustrating an even further decrease in current clinical and economic burden of this disease in these high-risk pts. Editorial acknowledgementPurvi Shah, MD, of Ashfield Healthcare Communications (a UDG Healthcare plc company), supported by F Hoffmann-La Roche Ltd/Genentech, Inc. Legal entity responsible for the studyF Hoffmann-La Roche Ltd/Genentech, Inc. FundingF Hoffmann-La Roche Ltd/Genentech, Inc. DisclosureM.Y. Williamson: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann -La Roche Ltd. A. Tomar: Full / Part-time employment: ZS Associates International Inc. G.S. Jhuti: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann -La Roche Ltd. C. Revil: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann -La Roche Ltd. A. Kotzeva: Full / Part-time employment: F. Hoffmann -La Roche Ltd. K. Gururaj: Full / Part-time employment: ZS Associates International Inc.

Neoadjuvant trastuzumab (H), pertuzumab (P), and chemotherapy versus trastuzumab emtansine (T-DM1) and P in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC): Final outcome results from the phase III KRISTINE study.

500 Background: KRISTINE compared neoadjuvant chemotherapy plus dual HER2- blockade (HP) with T-DM1 plus P (T-DM1+P), a targeted regimen that omits standard chemotherapy. T-DM1+P resulted in a lower pathologic complete response (pCR) rate, but a more favorable safety profile. Here we present the final outcomes from KRISTINE. Methods: KRISTINE (NCT02131064) was a randomized study of T-DM1+P versus docetaxel, carboplatin, and H plus P (TCHP). Patients with HER2-positive stage II–III BC received 6 cycles of neoadjuvant T-DM1+P or TCHP q3w. Patients receiving T-DM1+P continued adjuvant T-DM1+P; patients receiving TCHP received adjuvant HP, for 12 cycles in each arm. Patients in the T-DM1+P arm without pCR were encouraged to receive standard adjuvant chemotherapy before adjuvant T-DM1+P. Secondary endpoints, analyzed with descriptive statistics, included event-free survival (EFS; all events pre- and post-surgery), invasive disease-free survival (IDFS; invasive events post-surgery), overall survival and safety. Results: At median follow-up of 37 months, EFS favored TCHP (HR = 2.61 [95% CI: 1.36–4.98]), due to more locoregional progression events in the T-DM1+P arm before surgery (6.7% vs 0; Table). pCR was associated with reduced risk of an IDFS event (HR = 0.24 [95% CI: 0.09– 0.60]) regardless of treatment arm. There were 5 deaths (2.3%) in the TCHP arm and 6 (2.7%) in the T-DM1+P arm. There were more grade ≥3 AEs with TCHP but a higher rate of AEs leading to treatment discontinuation with T-DM1+P. Conclusions: EFS numerically favors TCHP due to locoregional progression events with T-DM1+P prior to surgery. T-DM1+P was associated with fewer grade ≥3 AEs but increased treatment discontinuation. Clinical trial information: NCT02131064. [Table: see text]

Patient-reported outcomes (PROs) from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients (pts) with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer.

513 Background: The phase 3 KATHERINE (NCT01772472) study, met its primary endpoint by demonstrating significantly improved invasive disease-free survival with adjuvant T-DM1 compared to H in pts with residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. PROs are reported here. Methods: Eligible pts had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy (with/without anthracyclines) followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Pts were randomized to 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and adjuvant endocrine and radiation therapy per standard of care. The EORTC Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Breast Cancer (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6 and 12 months’ follow-up. Results: Of 1,486 pts randomized (T-DM1, n = 743; H, n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 post-baseline PRO assessments. During the study, pts in both arms had similar mean scores on the QLQ-C30 and QLQ-BR23 function and symptom scales. There was no clinically meaningful change (≥10 points) from baseline in the mean scores in either arm, including on symptoms similar to AEs seen with T-DM1 (eg, fatigue). While more pts in the T-DM1 arm reported clinically meaningful deterioration in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 61%), nausea/vomiting (39% vs. 30%), and systemic therapy side effects (49% vs 36%) at ≥1 assessment, the proportion reporting clinically meaningful change in functioning was similar between arms at any given assessment. Conclusions: Mean scores showed only small deterioration from baseline in patient-reported treatment-related symptoms in both study arms. While more pts in the T-DM1 arm reported deterioration at some point in several symptoms, baseline global health status and functioning were generally maintained in both arms over the treatment course. Clinical trial information: NCT01772472.

Abstract GS1-10: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE

Abstract Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed HER2-positive (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p<0.0124. The statistical plan stipulated an IA of OS if the IDFS IA boundary was crossed. Secondary endpoints include IDFS including second primary non-breast cancer, disease-free survival, distant recurrence-free interval, overall survival, and safety. Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p<0.0001). IDFS events occurred in 91 patients (12.2%) in the T-DM1 arm compared with 165 patients (22.2%) in the trastuzumab arm. T-DM1 treatment increased estimated three-year IDFS rates (88.3% vs 77.0% with trastuzumab). A consistent benefit was shown across all stratification subgroups. With 98 deaths reported, the OS analysis is immature (HR=0.70; 95% CI: 0.47 to 1.05; p=0.085). The safety data were consistent with the known safety profile of T-DM1, with expected increases in AEs associated with T-DM1 compared to trastuzumab alone. One grade 5 AE (0.1%) occurred in each arm. Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-10.

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

BackgroundPatients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)–targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.MethodsWe conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease–free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).ResultsAt the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.ConclusionsAmong patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann–La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.)

Academic and Community Cancer Research United (ACCRU) RU011301I: Adjuvant ado-trastuzumab emtansine (T-DM1) for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

TPS629Background: Receipt of adjuvant chemotherapy + trastuzumab is particularly important for pts with HER2+ breast cancers because of the significantly improved outcomes that trastuzumab-based chemotherapy regimens provide. However, many older pts do not receive HER2-directed therapy. T-DM1 has a favorable toxicity profile and proven efficacy in advanced disease, and is a promising therapy option for treating older pts. Methods: In this phase II, single-arm, multicenter, open-label protocol at 15 U.S. ACCRU centers, we will administer adjuvant T-DM1 to pts aged ≥ 65. T-DM1 will be administered at 3.6 mg/kg IV every 21 days for one year. Longitudinal geriatric assessments (GA), biomarkers of aging, and patient-reported outcomes (PRO-CTCAE) will be collected. Specific Aims: The primary endpoint is 5-year invasive disease-free survival (IDFS). Secondary endpoints include overall survival, toxicity, and site of first recurrence. Correlative endpoints include associations of toxicity and clinical endpoints w...

Abstract OT1-1-06: A phase 3, randomized, open-label trial comparing trastuzumab emtansine and trastuzumab as adjuvant therapy for HER2-positive primary breast cancer with residual invasive tumor in the breast or axillary lymph nodes following preoperative therapy (KATHERINE)

Abstract Background: HER2-positive patients (pts) who do not achieve pathologic complete response with preoperative chemotherapy and HER2 directed therapy (PST) are at increased risk of recurrence and mortality despite further anti-HER2-targeted and endocrine treatment. The antibody–drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab (H) with intracellular delivery of the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged progression-free survival (PFS) and overall survival (OS) in a phase 3 study in pts with previously treated HER2-positive metastatic breast cancer (MBC) compared with capecitabine and lapatinib. It also prolonged PFS compared with H and docetaxel in a phase 2 study in pts with previously untreated HER2-positive MBC. Trial design: KATHERINE (NCT01772472) is a phase 3, 2-arm, open-label trial in pts with HER2-positive primary breast cancer (BC) who have received PST, including H, and have residual invasive disease after surgery. Pts are randomly assigned 1:1 to adjuvant T-DM1 3.6 mg/kg IV q3w or H 6 mg/kg IV q3w for 14 cycles. Pts can receive concomitant radiotherapy and/or hormonal therapy if clinically indicated. Eligibility criteria: HER2-positive BC (centrally determined IHC 3+ and/or ISH ratio ≥2); clinical stage T1–4, N0–3, M0 (T1a/bN0 ineligible) prior to PST; ECOG PS 0 or 1; adequate surgical excision; ≥6 cycles of preoperative treatment (≥16 weeks total; ≥9 weeks of H and ≥9 weeks of taxane-based chemotherapy); residual invasive breast or axillary lymph node disease after preoperative therapy; ≤12 weeks from surgery to random assignment. Pts with anthracycline exposure equivalent to doxorubicin &amp;gt;240 mg/m2 or significant cardiopulmonary dysfunction are excluded. Specific aims: The primary efficacy endpoint is invasive disease-free survival (IDFS). Secondary endpoints include disease-free survival, OS, distant recurrence-free interval, quality of life, and pharmacokinetics. Safety assessments include all adverse events, abnormal laboratory values, cardiac events, and LVEF. Statistical methods: The log-rank test (stratified by clinical stage, hormone receptor status, preoperative HER2-directed therapy, and pathologic nodal status after preoperative therapy) will be used to compare IDFS between arms. The hazard ratio (HR) and its 95% confidence interval (CI) will be estimated using Cox proportional hazards model (also stratified). The Kaplan-Meier approach will be used to estimate 3-year IDFS rates and 95% CIs for each arm. The final IDFS analysis, which provides 80% power to detect a HR of 0.75 (a 6.5% improvement in 3-year IDFS from 70% in the control arm to 76.5% in the T-DM1 arm) at a 2-sided alpha level of 5%, will be performed after ∼384 IDFS events have occurred. The final OS analysis will be performed at the end of 10 years of follow-up. Interim analyses of IDFS and OS are planned. Current and target accrual: Enrollment to 342 sites in 28 countries began in April 2013, and target accrual is 1484 pts. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-06.