Alliance Foundation Trials

Abstract Background The PALLAS trial investigated the addition of palbociclib to standard adjuvant endocrine therapy reduces breast cancer recurrence. This pre-specified analysis was conducted to determine whether adjuvant palbociclib benefited patients diagnosed with lower risk stage IIA disease compared to those with higher stage disease. Methods PALLAS was an international, multicenter, randomized, open-label, phase III trial, representing a public-private partnership between Pfizer, the Austrian Breast Cancer Study Group and, the U.S. ALLIANCE Foundation. Patients diagnosed with stage II-III, hormone-receptor-positive, HER2/neu negative breast cancer who were within 12 months of diagnosis, and had completed all definitive therapy aside from endocrine therapy, which was started within 6 months prior to study entry. All patients were required to submit a formalin-fixed paraffin-embedded (FFPE) tumor block. Patients were randomly assigned 1:1 to receive standard adjuvant endocrine therapy (of physicians’ choice) for at least 5 years with or without 2 years of Palbociclib, administered orally at a starting dose of 125 mg daily, given for 21 days followed by a 7-day break. Results A total of 5,796 patients with HR+/HER2- early breast cancer (including 1,010 with stage IIA) were enrolled. Median follow-up was 50 months for stage IIA patients and 43.1 months overall. In the stage IIA cohort, four-year iDFS in the palbociclib arm was 92.9% versus 92.1% for ET alone (HR 0.75, 95%CI 0.48–1.19, p = 0.23). There was no differential benefit by histologic grade, chemotherapy receipt, age, or anatomic/clinical risk. Additionally, no benefit to palbociclib was seen in this cohort in invasive breast cancer-free survival (iBCFS), locoregional relapse-free survival (LRFS), distant relapse-free survival (DRFS), or overall survival (OS). For the stage IIB/III patients, 4-year iDFS was 85.3% for palbociclib + ET versus 83.6% for ET alone (HR 0.91, 95% CI 0.77–1.07, p = 0.24). Conclusions and Relevance: While there were substantial differences in outcome for stage IIA versus IIB/III patients at 4 years of follow-up, the addition of 2 years of palbociclib did not improve outcomes for patients, regardless of stage. Trial Registration: The study was registered on Clinicaltrials.gov on July 31, 2015, and was assigned the clinical trial number (NCT02513394).

Abstract Introduction: Analyses of multiple clinical trials have suggested racial and ethnic disparities in outcomes for early-stage, hormone receptor-positive and HER2-negative (HR+HER2-) breast cancer, however, none of these studies examined the use of adjuvant CDK4/6 inhibitors. The objective of this study was to explore racial and ethnic differences in toxicity, treatment duration, and disease outcomes in patients (pts) with early-stage HR+HER2- breast cancer treated with or without adjuvant palbociclib on the PALLAS trial. Methods: The PALLAS phase III, global, open-label trial randomized 5,796 pts with stage II-III HR+HER2- breast cancer to 2 years of palbociclib plus ongoing provider/patient choice adjuvant endocrine therapy (ET+palbo) vs. ET alone (ET). The analytic cohort was limited to pts enrolled in North America with known self-reported race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Asian or Pacific Islander). Descriptive statistics were used to examine treatment characteristics, early discontinuation, and toxicity by race and ethnicity. Kaplan-Meier curves were used to estimate 3-year locoregional recurrence-free survival (LRFS) and invasive disease-free survival (IDFS) stratified by racial and ethnic group. Cox proportional hazards models were used identify predictors of LRFS and IDFS. Results: 2,547 North American pts were randomized and included in the intent-to-treat population with a median follow-up of 59.8 months; 1,996 (78.4%) identified as Non-Hispanic White (NHW), 132 (5.2%) Non-Hispanic Black (NHB), 156 (6.1%) Hispanic, and 134 (5.3%) Asian or Pacific Islander (API). Stage, performance status, type of surgery, and prior radiation were similar across racial and ethnic groups. Age, body mass index, grade, and prior chemotherapy differed by race and ethnicity (p< 0.05). Median age was lowest in API pts and highest in NHW pts (47.5 vs 53.0 years, respectively). Median body mass index was lowest in API and highest in NHB pts (24.4 vs 30.9). NHB pts were most likely to have high-grade disease (40.9% vs 26.9-30.5% in other groups). NHW pts were least likely to have received prior chemotherapy (81.0% vs 87.1-91.0%). Palbociclib early discontinuation was lowest in NHB pts (50.7%) and highest in Hispanic pts (65.9%), p=0.14. ET early discontinuation was similar across all groups (p=0.35). Palbociclib grade 3-4 overall toxicity was variable across groups (NHW 71.6%, NHB 79.1%, Hispanic 69.5%, API 85.2%), but this variation did not reach statistical significance (p=0.07). Neutropenia was highest in API pts (90.0% vs 57.3% in NHW, 58.2% in NHB, and 51.2% in Hispanic pts, p< 0.01). Overall 3-year LRFS was 98% (95% CI 97-98%) and IDFS was 89% (95% CI 88-90%). LRFS and IDFS were statistically similar by race and ethnicity and within each study arm (Table). No differences in LRFS or IDFS were seen by race or ethnicity in adjusted models (p=0.95). Conclusions: In this clinical trial population of HR+HER2- breast cancer patients exposed to similar treatments, no racial/ethnic differences were seen in short-term LRFS or IDFS across study arms. Differences in palbociclib toxicity by racial and ethnic group, particularly neutropenia, were seen with the highest toxicity in API patients; however, this difference did not translate into early discontinuation of palbociclib or ET. Table: 3-year Kaplan-Meier Survival Outcomes Stratified by Race and Ethnicity Citation Format: Olga Kantor, Oluwadamilola (Lola) Fayanju, Amylou Dueck, Michael Gnant, Harold Burstein, Matthew Goetz, Claudine Isaacs, Lois Shepherd, Olwen Hahn, Daniel Anderson, Kathy Miller, Hope Rugo, Tiffany Traina, Zoneddy Dayao, Katherine Clifton, Eric Winer, Antonio Wolff, Norman Wolmark, Dongrui Lu, Patrick O'Brien, Sara Scovil, Angela DeMichele, Erica Mayer. Racial and Ethnic Differences in Clinical Outcomes among North American Patients with Hormone Receptor-Positive, HER2-negative, Early Breast Cancer in the PALLAS Trial (AFT-05) [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 PO3-02-05.

Abstract Background: Approximately 50,000 women in the U.S. are diagnosed with ductal carcinoma in situ (DCIS) annually. Without treatment, it is estimated that 20-30% of DCIS will lead to invasive breast cancer. Currently, more than 97% of women undergo surgery, with many also undergoing radiation. An alternative to surgery for low-risk DCIS is active monitoring (AM), an approach in which regularly scheduled mammography and physical exams are used to monitor breast changes and determine if, or when, surgery is needed. Trial design: COMET, a multicenter phase III prospective randomized trial, opened in the U.S. in June 2017 (clinicaltrials.gov reference: NCT02926911). The hypothesis is that management of low-risk DCIS using an AM approach does not yield inferior invasive breast cancer and/or quality of life outcomes compared to surgery. Eligibility criteria: Patients with a new diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS, or atypia verging on DCIS are eligible. Patients must be ≥40 years of age, have no contraindication for surgery, and pathologic confirmation of grade I/II DCIS. DCIS must be ER and/or PR≥ 10% and HER2-negative without invasion, diagnosed within 120 days of registration. Breast tissue, blood and imaging are collected at trial entry and if invasive cancer subsequently occurs, and are stored in central repositories. Specific aims: The primary aim is to assess whether the 2-yr ipsilateral invasive breast cancer rate for AM is non-inferior to surgery. Secondary aims include comparison of 2-, 5-, and 10-yr mastectomy rate, contralateral invasive breast cancer rate, overall survival and invasive breast cancer-specific survival, as well as 5- and 10-yr ipsilateral invasive breast cancer rate between groups. Patient reported outcomes (PRO) using validated tools are critical secondary endpoints, and will enable comparison of health-related quality of life and psychosocial outcomes between surgery and AM groups at prespecified time points over a period of 5 years. Statistical methods: An accrual goal of 1200 was estimated using a 2-group test of noninferiority of proportions, with the 2-yr invasive breast cancer rate in the surgery group assumed to be 0.10, including accounting for upstaging. The projected drop-out rate is 25%, for a total of 900 patients treated per allocation arm. The non-inferiority boundary was set at 0.05. Based on a 1-sided un-pooled z-test, with alpha=0.05, a sample size of n=446 per group will have 80% power to detect the specified noninferiority margin. Intention-to-treat analysis of the 2-yr invasive breast cancer rate will be conducted using all patients as randomized, and will be completed using Kaplan-Meier estimates, stratified by group, combined with Greenwood’s confidence interval. Several sensitivity analyses (per protocol, as-treated, and instrumental variable) are also planned to account for loss of follow-up, rejection of randomization allocation and withdrawals. Present and target accrual: Trial accrual as of 7/1/20 is 540 randomized patients from 84 activated Alliance for Clinical Trials in Oncology sites. Despite logistical challenges posed by the COVID-19 crisis, patients continue to be recruited to the COMET trial. Over 80% of patients have sample sets/images stored in the tissue and image repositories. This trial will provide definitive clinical, quality of life and biomarker evidence regarding the trade-offs of surgery vs AM in patients with low-risk DCIS. Support: CER-1503-29572; https://acknowledgments.alliancefound.org Contact: Thomas Lynch (Project Manager) - thomas.lynch2@duke.edu Citation Format: Thomas Lynch, Ann Partridge, Alastair Thompson, Elizabeth Frank, Donna Pinto, Deborah Collyar, Desiree Basila, Louise Davies, Jenny Donovan, Terry Hyslop, Linda McCall, Marc Ryser, Taylor O' Donnell, Anna Weiss, Shelley Hwang. Comparing an operation to monitoring, with or without endocrine therapy (COMET): A prospective randomized trial for low-risk DCIS (AFT-25) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-08-02.

Abstract Background Pre-clinical data and initial results from clinical studies point to the added benefit of CDK4/6 inhibition when combined with anti-HER2 tx. The current study is designed to evaluate the added benefit of palbociclib when given in combination with anti-HER2 and endocrine tx maintenance in the 1st†line setting of metastatic HER2+HR+ breast cancer. Trial design PATINA is an international, open-label, pivotal Phase III study. Primary objective is to demonstrate that the combination of palbociclib with anti-HER2 plus endocrine tx is superior to anti-HER2 plus endocrine tx in prolonging PFS. Sample size is 496 pts. The study starts after completion of 6-8 cycles of chemotherapy-containing anti-HER2 tx for metastatic breast cancer in the 1st line setting. Pts are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD). To account for the need for less intense tx regimens for a subset of pts diagnosed with HER2+ER+ disease, clinicians may recommend the combination of trastuzumab with either a taxane or vinorelbine prior to study initiation. Clinicians might also choose a non-pertuzumab option for pts previously treated with pertuzumab in the neo(adjuvant) setting. Secondary objectives include measures of tumor control (OR, CBR, DOR), OS, safety and QOL. The translational science main objective is to compare PFS estimates according to PIK3CA mutation status assessed by cfDNA analysis. Endocrine tx options are AI or fulvestrant. Premenopausal pts must receive ovarian suppression. The study has a 90% power to detect a hazard ratio of 0.667 in favor of the palbociclib arm. Pts approached to participate in AFT-38 will be asked to indicate on the informed consent forms whether remaining biospecimens and clinical data from the control arm of the study can be shared with the Mastering Breast Cancer (MBC) Initiative. The overarching purpose of the MBC is to create a mechanism for understanding the natural history of metastatic breast cancer by cataloguing longitudinally studied tumor-specific markers and treatment effects. ClinicalTrials.gov Identifier: NCT02947685 Citation Format: Metzger-Filho O, Mandrekar S, Loibl S, Ciruelos E, Gianni L, Lim E, Miller K, Huang C, Koehler M, Francis P, Valagussa P, Goel S, Prat A, Goetz M, Loi S, Krop I, Carey L, Lanzillotti J, Winer E, Tripathy D, DeMichele A. PATINA: A randomized open label phase III trial to evaluate the efficacy and safety of palbociclib + anti HER2 therapy + endocrine therapy vs anti HER2 therapy + endocrine therapy after induction treatment for hormone receptor positive, HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-07.