Hope Rugo

Abstract This prospective, correlational study sought to identify a clini-cally feasible, valid measure of taxane-induced peripheral neuropathy that correlated with impairments in balance, physical performance, pain, and quality of life (QOL). In all, the study included 20 breast can-cer patients who completed taxane chemotherapy and 20 healthy women who were matched by age, height, and weight. All participants completed a testing session that included measures of peripheral neu-ropathy, balance, physical performance, pain, and QOL. Modified Total Neuropathy Scores (mTNS) discriminated between women in the breast cancer and control groups. Positive correlations were found between the mTNS and the Total Neuropathy Score (r = 0.99; P < 0.001) and physi-cal performance (r = 0.654; P = 0.002). Negative correlations were found between the mTNS and measures of balance (r = –0.638; P = 0.002) and QOL (r = –0.615; P = 0.004). Pain was experienced by 70% of the women with breast cancer. Pain intensity scores did not correlate with any mea-sure of peripheral neuropathy. The mTNS may be a valid clinical measure to monitor the severity of peripheral neuropathy in women receiving a taxane for breast cancer, because it correlated strongly with the TNS. In addition, because the mTNS was correlated with measures of balance, physical performance, and QOL, it may help clinicians to identify patients who may benefit from rehabilitative services. Pain and peripheral neu-ropathy may need to be assessed separately.Oncologists must monitor for taxane-induced peripheral neuropathy, because peripheral neu-ropathy has a negative impact on upper extrem-ity function, balance, physical performance, and quality of life (QOL) in other populations.

Abstract Background: For patients with stage II-III triple-negative breast cancer (TNBC), standard of care systemic therapy consists of neoadjuvant pembrolizumab with chemotherapy, followed by 27 weeks of adjuvant pembrolizumab based on the results of the phase III KEYNOTE-522 trial. This trial demonstrated that pathologic complete response (pCR) rates and event-free survival (EFS) were significantly better among patients who received neoadjuvant followed by adjuvant pembrolizumab in addition to chemotherapy compared to chemotherapy alone. An exploratory analysis from this study demonstrated better EFS among patients who experienced a pathologic complete response (pCR) to neoadjuvant therapy compared to those with residual disease. Additionally, other studies, including GeparNuevo, which did not include adjuvant checkpoint inhibition, demonstrated EFS benefit from the addition of preoperative checkpoint inhibitor therapy to chemotherapy. It is therefore unclear if adjuvant pembrolizumab improves outcomes for patients with early-stage TNBC who achieve a pCR after neoadjuvant pembrolizumab plus chemotherapy. OptimICE-pCR trial utilizes response to preoperative therapy to tailor adjuvant therapy, and the goal is to determine whether patients who achieve pCR to pembrolizumab plus chemotherapy can achieve a similar recurrence-free survival (RFS) with observation compared to adjuvant pembrolizumab monotherapy Methods: OptimICE-pCR is an open-label, multicenter, randomized phase III trial that is enrolling patients with stage T1cN1-2 or T2-4N0-2 TNBC. To be eligible, patients must have experienced a pCR after the completion of neoadjuvant therapy containing a minimum of six cycles of chemotherapy in combination with pembrolizumab. Participants are randomized 1:1 to receive either 27 weeks of adjuvant pembrolizumab or to observation. Participants on the pembrolizumab arm receive pembrolizumab 200 mg IV on day 1 of each 21-day cycle for 9 cycles, or 400 mg IV on day 1 of each 42-day cycle for 4 cycles, followed by one dose of 200 mg IV every 21 days. The primary objective is to evaluate whether observation results in non-inferior RFS compared to adjuvant pembrolizumab. Non-inferiority is defined as an estimated 3-year RFS of 91% or higher in the observation arm compared to 94% in the pembrolizumab arm. The total sample size will be 1,295 patients, which will provide 80% power at one-sided significance level of 0.05 to detect this difference, which corresponds to a non-inferiority hazard ratio of 1.52. Key secondary endpoints include overall survival, locoregional recurrence, quality of life, financial toxicity, work productivity impairment, cost-effectiveness, and safety and tolerability. Key correlative objectives include detection of ctDNA at baseline and association with RFS and association of key biomarkers (TILs, PDL1, immune gene expression) from the primary tumor with RFS. The trial is currently open and enrolling patients. Support: U10CA180821, U10CA180882; U24 CA196171; U10CA180820 (ECOG-ACRIN); U10CA180863 (CCTG); https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT05812807 Citation Format: Sara Tolaney, Karla Ballman, Charles M Perou, David Cescon, Margaret Gatti-Mays, Victoria Blinder, Shoshana Rosenberg, Elizabeth Mittendorf, Anna Weiss, Hope Rugo, Alice Ho, Dana Casey, Baljit Singh, Fabrice Smieliauskas, Yara Abdou, Vijay Damarla, Jane Meisel, Lisa Carey, Ann Partridge. OptimICE-pCR: De-escalation of therapy in early-stage TNBC patients who achieve pCR after neoadjuvant chemotherapy with checkpoint inhibitor therapy (Alliance A012103) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-05.

Abstract Background: Approximately 70% of all breast cancer (BC) cases are hormone receptor positive/human epidermal growth factor receptor 2-negative (HR+/HER2–), with ~65% of these being HR+/HER2-low (immunohistochemistry [IHC]1+, IHC2+/in situ hybridization [ISH]–). Despite an increasing number of available endocrine and targeted treatments for metastatic disease, tumors eventually develop resistance to endocrine therapy (ET). Chemotherapy, the standard of care for patients (pts) whose cancers no longer respond to ET, is associated with poor outcomes, representing a high unmet need in the first-line endocrine-resistant setting. Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate (ADC) that delivers SN-38 (the active metabolite of the topoisomerase inhibitor irinotecan) to tumor cells via internalization, and to the surrounding tumor microenvironment via the bystander effect. SG demonstrated a significant and clinically meaningful survival benefit in the phase 3, randomized TROPiCS-02 trial, and is approved in the US for inoperable, locally advanced, or metastatic HR+/HER2– BC after ET and ≥ 2 systemic therapies in the metastatic setting. ASCENT-07 will examine the efficacy and safety of SG in the first-line chemotherapy setting, ie, in patients with inoperable, locally advanced, or metastatic ET resistant HR+/HER2– BC. Study design: ASCENT-07 (NCT05840211) is a randomized, open-label, global study evaluating SG versus treatment of physician’s choice (TPC) chemotherapy in pts with HR+/HER2– inoperable, locally advanced, or metastatic BC who have received ET and are eligible for their first chemotherapy for advanced/metastatic disease. Pts aged ≥ 18 years with histologically confirmed HR+/HER2– (HER2 IHC0 or HER2-low [IHC1+, IHC2+/ISH–]) according to ASCO/CAP criteria, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be included. Pts are eligible if they meet ≥ 1 of the following criteria: progressive disease (PD) in the metastatic setting on ≥ 2 lines of ET (± targeted therapy) (disease recurrence within the first 24 months of starting adjuvant ET is considered a line of therapy), PD within 6 months of first-line ET (± CDK 4/6 inhibitor) in the metastatic setting, or disease recurrence within 24 months of adjuvant ET with CDK 4/6 inhibitor initiation and no longer a candidate for additional ET. PD on the most recent therapy will be documented by CT or MRI per RECIST v1.1. Key exclusion criteria include prior treatment targeting topoisomerase I. Pts will be randomized to SG 10 mg/kg IV on days 1 and 8 of a 21-day cycle or TPC (capecitabine, paclitaxel, nab-paclitaxel). The primary endpoint is progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1 criteria or death from any cause, whichever comes first. Secondary endpoints include PFS (assessed by the investigator), overall survival, objective response rate and duration of response per BICR and investigator, and quality of life (QoL) assessed using the EORTC QLQ-C30 cancer questionnaire (primarily change in the Physical Functioning domain at week 16 and time to deterioration in the Global Health Status/QoL domain). Pharmacokinetics and immunogenicity analyses will be undertaken in pts receiving SG. Incidence of adverse events and serious adverse events, including relationship to study drug(s), will be reported. Laboratory and vital signs will be monitored. ASCENT-07 is currently open for recruitment and requires ~654 eligible pts to provide adequate power for assessment of the primary and key secondary endpoints. Citation Format: Hope Rugo, Javier Cortés, Giuseppe Curigliano, Carlos Barrios, Kevin Punie, Yeon Park, Hiroji Iwata, Alex Young, Xuehan Ren, Pelin Cinar, Komal Jhaveri. ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-09.

Abstract Background: Circulating tumor DNA (ctDNA) testing in plasma offers the opportunity to identify early breast cancer (BC) recurrence in patients (pts) who, despite completion of definitive therapy, have molecular residual disease (MRD). ZEST is a randomized, phase 3, double-blind trial evaluating whether niraparib can enhance disease-free survival in pts with BC and ctDNA detection (ctDNA+) without evidence of radiographic recurrence after completion of curative intent therapy. Methods: Pts with stage I–III triple negative breast cancer (TNBC) or BRCA-mutated HER2− BC were eligible. A personalized, tumor-informed ctDNA assay (Signatera) was designed based on whole-exome sequencing of tumor tissue and matched normal blood. Testing for ctDNA-based MRD began any time after the end of definitive treatment (EODT); pts with HR+ disease were allowed concurrent endocrine therapy (stable regimen). Upon ctDNA+, radiographic staging was performed. Those without evidence of metastatic disease were randomized (1:1) to niraparib (200 or 300 mg/day, depending on weight and platelet count) or placebo (PBO). Imaging was performed every 12 weeks. The primary endpoint was safety of niraparib; disease-free survival (measured as time from randomization to recurrence or death from any cause) was also assessed. Results: As of May 8, 2024, a total of 2746 pts were prescreened; 1901 pts had ≥1 ctDNA test result (ctDNA+, 147 [8%]). Of the 1901 pts, median age was 52 (range, 22–88) years; 1683 pts (89%) had TNBC (ctDNA+, 135), and 218 (11%) had BRCA-mutated HR+ disease (ctDNA+, 12); 620 (33%) pts received neoadjuvant therapy, 643 (34%) received adjuvant therapy, and 593 (31%) received both neoadjuvant and adjuvant therapy. Due to low rates of ctDNA+, study enrollment was terminated early. ctDNA+ was 5.2% on first test of pts with ≥1 test, and 4.4% on second or subsequent test of pts with ≥2 tests. Of pts with ctDNA+ (n=147), 66% had ctDNA+ on the first test, 91% on the first or second test, and 59% were ≤6 months from EODT. Compared with pts with ctDNA undetected, pts with ctDNA+ tended to have positive lymph nodes, T3/T4 tumor size, stage III disease, residual disease after neoadjuvant therapy, and received both neoadjuvant and adjuvant therapy. Of the 147 pts with ctDNA+, 72 (49%) had radiographic recurrence upon initial staging before randomization. The rate of radiographic recurrence was 52% (51/98) at first ctDNA+ test and 44% (21/48) at second or later ctDNA+ test. Of pts with ctDNA+, 40 were enrolled and randomized (niraparib, 18; PBO, 22); 36 pts (90%) had TNBC, and 4 pts (10%) had BRCA-mutated HR+ disease. At data cutoff, 6 pts in the niraparib arm and 4 pts in the PBO arm remained on study without radiographic recurrence. Median disease-free survival was 11.4 (95% CI, 5.7–18.2) months for niraparib vs 5.4 (95% CI, 2.8–9.3) months for PBO (hazard ratio, 0.64; 95% CI, 0.30–1.39). No new safety signals were observed for niraparib. Conclusions: The ZEST study was terminated early because of infeasibility of completing enrollment due to a low rate of ctDNA+ and a high rate of metastatic disease at the time of ctDNA+. Although ctDNA testing began any time after EODT, ctDNA+ occurred most frequently on the first test and ≤6 months from EODT. Pts, predominantly those with TNBC, had a high rate of radiographic recurrence at time of ctDNA+, consistent with early recurrence typical of TNBC. These findings have implications for future trial design, emphasizing the importance of early ctDNA testing, and careful selection of criteria defining risk of recurrence. Updated survival data and on-treatment ctDNA dynamics will be presented. Citation Format: Nicholas Turner, Isabel Pimentel, David Cescon, Hiroji Iwata, Wolfgang Janni, Aleksandra Lacko, Sibylle Loibl, Hope Rugo, Gianfilippo Bertelli, Hiroshi Ishiguro, Sumainizah Sukor, Tytti Ahola, Christian Kurzeder, Erin Hofstatter, Laura Austin, Fotini Kouri, Magdalena Zajac, Cheynna Crowley, Yufei Wang, Jon Chung, Angela Silvestro, Melinda Telli. Circulating tumor DNA surveillance in ZEST, a randomized, phase 3, double-blind study of niraparib or placebo in patients w/ triple-negative breast cancer or HER2+ BRCA-mutated breast cancer with molecular residual disease after definitive therapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS3-01.