Faggen, Meredith

635 Background: Prospective data on efficacy, quality of life, and treatment-related toxicities in older adults with breast cancer are limited. The ATOP trial (NCT03587740) evaluated T-DM1 in older adults and demonstrated favorable 5-year invasive disease-free survival. Here, we report patient-reported adverse events (AEs) and health-related quality of life (HRQOL) findings from ATOP. Methods: ATOP was a single-arm, phase II, multicenter study of adjuvant T-DM1 for those aged 60 with stage I-III HER2+ breast cancer. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). PRO-CTCAE (assessing specific symptoms) and EQ-5D (a measure of HRQOL) surveys were administered electronically or on paper at baseline (pre-treatment), on Day 1 of each treatment cycle, and at a single 6–12-month post-treatment time point. Participants who responded to the baseline and at least one follow-up survey were included in the PRO analysis. EQ-5D changes from baseline were assessed using general linear mixed models. Summary statistics were used to assess PRO-CTCAE scores to evaluate which symptoms developed between baseline and 1 subsequent survey(s) and their severity. Results: Among the 111 patients enrolled on ATOP (median age=71, range 60-88 years), 98 responded to the baseline survey and 1 subsequent survey(s). 1435 surveys were returned that included at least one PRO-CTCAE response, and 1661 surveys were returned that included EQ-5D. The Table displays the % of participants who reported PRO-CTCAE symptoms that worsened from baseline to any severity level (scores >0) or to a severe level (scores ≥3). More than 60% of survey respondents reported new or increased dry mouth, fatigue, muscle aches, decreased appetite, nausea, pain, and/or numbness/tingling at some point during or after treatment, but these were usually not severe. EQ-5D scores did not change significantly from baseline at any time point. Conclusions: In this adjuvant trial for patients aged >60, participation rates for PRO data collection were high. Reassuringly, global HRQOL was not impacted by T-DM1, and though frequently reported, the vast majority of patient-reported symptoms were mild. Future analyses of this trial will focus on duration and predictors (clinical and biomarker-based) of severe AEs, agreement between patient-reported and clinician-reported AEs, and whether sharing PRO reports with clinicians impacted clinician-reported AE grades. Clinical trial information: NCT03587740 . Most common new or worsening symptoms reported via PRO-CTCAE in ATOP (n=95). Symptom % with score >0 n (%) with score 3+ Dry mouth 79% 26% Fatigue 71% 29% Muscle aches 69% 20% Decreased appetite 69% 12% Nausea 67% 6% Pain 66% 21% Numbness/tingling 65% 9% Blurry vision 60% 4% Mouth or throat sores 60% 5%

Abstract Purpose: There are limited prospective data on the efficacy, tolerability, and functional impact of treatments for older and frail adults with HER2+ early breast cancer. We report the first-ever, US-based adjuvant trial dedicated to this population. Methods: We conducted a single arm, phase II, multicenter, investigator-initiated study of adjuvant ado-trastuzumab emtansine (T-DM1) in patients aged 60 and older with stage I-III HER2+ breast cancer who either declined standard adjuvant therapy or were deemed by their physician not to be candidates for standard treatment for any reason. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). The primary endpoint was 5-year invasive disease-free survival (iDFS) with a 2-sided 90% confidence interval. Secondary endpoints presented here are toxicity and 3-year iDFS, invasive breast cancer-free survival (iBCFS), and overall survival (OS). All survival analyses were evaluated using Kaplan Meier methods and began at the time of C1D1 of T-DM1. Results: ATOP enrolled 111 evaluable patients during 2015-2020; median follow-up is 4.9 years (IQR 4.2-5.5). The median age was 71 (range 60-88); 50.4% were aged >70 and 11.7% were aged >80. Overall, 69.4% had stage I, 26.1% had stage II, and 4.5% had stage III disease; 70.3% had hormone receptor-positive tumors. The 5-year iDFS = 84.2% (90% CI 77.1-92.0%). The 3-year iDFS = 91.2% (90% CI 85.9%, 96.9%) and iBCFS = 94.1% (90% CI 89.7-98.8%) (see Table for event details); 3-year OS = 96.1% (90% CI 92.4-99.9%). In total, there were 3 distant recurrences and 2 breast cancer-related deaths. Overall, 82% reported grade 2+ toxicity during treatment; the most common grade 2+ events were fatigue (30.6%) and peripheral sensory neuropathy (19.8%). The most frequent grade 3 events were liver function abnormality, anemia, decreased neutrophil count, and neuropathy (<5% for each); one patient (0.9%) had grade 4 thrombocytopenia. Sixty-five (58.6%) completed all 17 cycles of protocol therapy; 27 (24.3%) completed 10-16 cycles, and 19 (17.1%) completed 1-9 cycles. Reasons for early treatment discontinuation in the remaining 41.4% included toxicity (28.8%), patient withdrawal (6.3%), other (3.6%), disease progression (0.9%), death on study (0.9%, deemed unrelated to treatment), and other complicating disease (0.9%). Conclusions: The ATOP trial demonstrated a favorable 5-year iDFS and manageable toxicity among older adults with early stage HER2+ breast cancer. Although iDFS was numerically worse than historical controls (i.e., 5-year iDFS in the ‘ATEMPT’ trial by Tolaney et al. J Clin Oncol, 2024 was 97% [95% 95.2-98.7]), ATOP’s participants had higher-risk cancers, advanced age, and more competing non-breast cancer events. Future endpoints will include in-depth analyses of patient-reported outcomes, biomarkers of aging, and longitudinal functional status. Citation Format: R. A. Freedman, H. Heiling, K. J. Ruddy, L. Rogak, M. Sedrak, A. Dueck, H. Liu, A. Fraettarelli, S. Atanasov, M. DeMeo, P. Lange, A. Perilla Glen, S. Sinclair, D. Dillon, J. Mortimer, M. Fenton, J. Walsh, L. Spring, H. Muss, N. Sinclair, E. Hamilton, C. Dang, S. Giordano, M. Faggen, S. Lo, C. Kuzma, S. Lemke, P. Stella, R. Mowat, M. Wilkinson, J. Rauch, N. Tayob, E. Winer. Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-04.

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [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 PD18-01.

Abstract Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

Abstract Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI&lt;3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-02.

102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.