PALLAS Trial Research Articles

Abstract PO1-01-13: Clinical characterization, prognostic and predictive values of HER2-low in early breast cancer in the PALLAS trial

Abstract Background: Low levels of HER2 expression (HER2-low) have recently emerged as a therapeutic target in patients (pts) with breast cancer (BC). The aim of this study was to evaluate clinical and demographic variables associated with HER2 expression, as well as the value of HER2-low as a prognostic and predictive biomarker for palbociclib benefit in pts enrolled in the PALLAS trial. Methods: The phase III PALLAS trial investigated the addition of palbociclib to adjuvant endocrine therapy (ET) in pts with stage II-III hormone receptor-positive BC. The aims of this analysis are (1) to assess the association between the presence of low levels of HER2 expression with demographic and clinicopathological parameters, (2) to test the prognostic value of HER2-low status on invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) to assess the value of HER2 expression as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization; all pathologic evaluation was performed locally. Pts with HER2-0 and Her2-low BC were included in this analysis; those with HER2-positive BC or missing HER2 status were excluded. Association of HER2 with other baseline covariates were tested with Chi-squared tests. Prognostic and predictive power of HER2 were assessed with Cox Models. Multivariable models included age, T-stage, N-stage, grade and progesterone receptor (PR) expression. Hazard ratios (HR) and 95% Confidence intervals (CI) are reported. Results: From the original PALLAS intention-to-treat population (N = 5,753), 5304 pts (92.2%) were included in this analysis. Among these, 2,254 pts (42.5%) were classified as HER2 IHC 0 (HER2-0) and 3,050 (57.5%) as HER2-low (1,838 with IHC 1+ and 1,212 with IHC 2+). For this analysis, median follow-up was 59.8 months. Compared to HER2-0, pts with HER2-low tumors had statistically higher estrogen receptor expression levels (mean expression 89.2% vs 88.2%, p = 0.019), lower PR expression levels (65.9% vs 68.2%, p = 0.007). Importantly, HER2-low status varied significantly across 21 participating countries (range 16.7% to 75.6%; p< 0.001) and was more frequent in pts enrolled in North America (63.1%) than in Europe (53.4%) and other regions (53.4%) (p < 0.001). No differences in HER2 expression were observed according to anatomic stage, T-stage, N-stage, histological grade, age, menopausal status, primary surgery type, prior radiation, prior chemotherapy, or baseline performance status. There were no statistically significant differences in IDFS, DRFS or OS according to HER2 status in univariate or multivariable Cox models (prognostic value, HR provided in the Table). There was no significant interaction between the HER2 status and the benefit to palbociclib in IDFS, DRFS or OS (Table). Similar results were obtained when HER2-0 was compared to HER2 1+ and HER2 2+ separately. Conclusions: In this large, prospective and international cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib (predictive value) between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes. Support: AFT, Abbvie Pfizer; Clinicaltrials.gov: NCT02513394 https://acknowledgments.alliancefound.org Citation Format: Guilherme Nader-Marta, Christian F. Singer, Dominik Hlauschek, Angela DeMichele, Paolo Tarantino, Georg Pfeiler, Miguel Martín, Justin Balko, Zbigniew Nowecki, Marija Balic, Adam Brufsky, Arlene Chan, Patrick G. Morris, Tufia Haddad, Sibylle Loibl, Yuan Liu, Lidija Sölkner, Christian Fesl, Erica Mayer, Michael Gnant. Clinical characterization, prognostic and predictive values of HER2-low in early breast cancer in the PALLAS trial [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 PO1-01-13.

Abstract PO3-02-05: 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 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 PO1-01-08: The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study

Abstract Background: Data suggest that concomitant intake of proton pump inhibitors (PPI) may create drug-drug interactions, potentially impacting efficacy of agents including palbociclib, which is widely used in the treatment of metastatic hormone-receptor-positive/HER2-negative (HR+/HER2-) breast cancer. In the open label, randomized, phase 3 PALLAS trial, the addition of palbociclib for two years to standard adjuvant endocrine therapy (ET) in patients with HR+/HER2- early breast cancer (EBC) did not improve invasive disease-free survival (IDFS) compared to adjuvant ET alone. We explored whether concomitant use of PPIs could have affected clinical outcomes in patients treated with palbociclib in PALLAS. Methods: This is an exploratory, unplanned analysis of the PALLAS trial (AFT-05/ABCSG-42/PrE0109/BIG-14-13, NCT02513394), which enrolled 5796 patients with stage II-III HR+/HER2- EBC. Patients were randomized to receive either 2 years of palbociclib (125 mg oral capsules once daily on days 1-21 of a 28-day cycle) with adjuvant ET or ET alone. Primary endpoint was IDFS in the intention-to-treat population. The present exploratory analysis included patients who received at least one dose of palbociclib. Definitions of IDFS, distant relapse-free survival (DRFS) and overall survival (OS) were according to the PALLAS protocol (STEEP criteria), using first day of palbociclib intake as start date. Only PPI concomitant intake during palbociclib treatment was considered. To determine the association of concomitant PPI use with IDFS, DRFS, and OS, uni- and multivariable Cox models with time-dependent PPI (the latter adjusted for age, prior chemotherapy, progesterone receptor, grade, tumor stage, nodal stage, body mass index (BMI)) were used. Also, the association between PPI use and neutropenia was investigated in patients initiating PPI prior to randomization vs never. Odds ratios (OR) unadjusted and adjusted for age and BMI estimated with logistic regression models are reported. Results: Of 2840 patients treated with palbociclib + ET, 533 (18.8%) had concomitant PPI and palbociclib intake. Median duration of PPI intake was 10.8 months (interquartile range 2.3-22.3). Most patients received omeprazole as PPI (n=265, 49.7%). PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors as ET, higher BMI, and worse ECOG status (all p< 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (Table 1). Unadjusted all grade neutropenia rates were slightly lower in patients who initiated PPI prior study start vs patients never initiating (79% vs 85%, unadjusted OR 0.66, 95%CI 0.50-0.88). After adjustment for BMI and age, the difference between the groups decreased (adjusted OR = 0.77, 95%CI 0.57-1.04). Similar effect sizes were found for grade 3/4 neutropenia rates (54% vs 64%, unadjusted OR 0.66, 95%CI 0.52-0.83, adjusted OR 0.81, 95%CI 0.64-1.03). Conclusions: Our exploratory analysis did not demonstrate a statistically significant relationship between concomitant use of PPIs and palbociclib and survival outcomes of patients in the PALLAS trial. Nonetheless, careful consideration of concomitant medications and of drug-drug interactions is important when studying novel agents in the adjuvant breast cancer setting. Support: AFT, Pfizer; https://acknowledgments.alliancefound.org Table 1. Association between PPI intake and survival outcomes. Citation Format: Elisa Agostinetto, Georg Pfeiler, Dominik Hlauschek, Erica Mayer, Matteo Lambertini, Evandro de Azambuja, Meritxell Bellet- Ezquerra, Jane Meisel, Gabor Rubovszky, Nicholas Zdenkowski, Yelena Novik, Manuel Ruíz - Borrego, Karen Gelmon, Eleftherios Mamounas, Hiroji Iwata, Dongrui Lu, Lidija Sölkner, Christian Fesl, Michael Gnant, Angela DeMichele. The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study [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 PO1-01-08.

Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS Trial.

BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib. Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived. Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months). This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

Abstract PD17-05: Development and Validation of a Composite Biomarker Predictive of Palbociclib + Endocrine Treatment Benefit in Early Breast Cancer: PENELOPE-B and PALLAS Trials

Abstract Background: The PENELOPE-B (NCT01864746) and PALLAS (NCT02513394) trials are large prospective, randomized, phase III trials that evaluated adjuvant palbociclib (PAL) + endocrine treatment (ET) vs ET in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC). Both studies did not meet the primary endpoint of improving invasive disease-free survival (iDFS). We conducted biomarker analyses to identify patients who might benefit from PAL + ET in EBC. Methods: Resected tumor tissue was collected from consenting patients. Gene expression analyses were conducted using the HTG EdgeSeq Oncology Biomarker Panel including 2549 genes. Based on 91 genes from the HTG panel, the intrinsic molecular subtypes were calculated using Absolute Intrinsic Molecular Subtyping (AIMS). Potential predictive treatment biomarkers were established in PENELOPE-B (n=906 with resected tissue) as the development set using an outcome-oriented approach based on iDFS with a selection procedure that maximized the log-rank statistic to estimate a standard Z score–based optimal cutoff. Independent validation was conducted on PALLAS (n=2085; PENELOPE-B-like with resected tissue and HTG data). Hazard ratios and corresponding 95% CIs were calculated using the Cox proportional hazards model, and iDFS distributions between treatment arms were compared using the log-rank test. Interaction between treatment and biomarker status was assessed. Results: Patient baseline characteristics were well balanced, with no differences in iDFS between the intent-to-treat set and the biomarker set for both trials. Approximately 73% of patients (PENELOPE-B [n=663] and PALLAS [n=1516]) had luminal A subtypes whereas only 7.1 % (PENELOPE-B [n=64]) and 8.3 % (PALLAS [n=172]) had a luminal B subtype. AIMS subtypes showed overall similar prognostic patterns for iDFS between PENELOPE-B and PALLAS. The biomarker-defined subgroup found in PENELOPE-B with optimal cutoff demonstrated a preferential benefit from PAL + ET (n=364 [96 events]; hazard ratio [95% CI], 0.63 [0.42, 0.95]; P=0.025). Independent validation of the PALLAS subgroup using the pre-defined optimal cutoff confirmed a significant benefit from PAL + ET (n=916 [70 events]; 0.55 [0.34–0.90]; P=0.015) while not in the rest of the patients (interaction p=0.0025). Significant treatment effects remained (0.55 [0.34–0.89]; P=0.015) after adjusting for the randomization stratification factors of PALLAS. Conclusions: The composite predictive biomarker defined from PENELOPE-B was independently validated in a prospectively defined retrospective analysis of a subset of patients selected from PALLAS. The composite biomarker identified a subset of EBC patients deriving benefit from the addition of PAL to ET. This patient stratification approach can potentially be applied to future adjuvant clinical trials for treatment of hormone receptor–positive/HER2– EBC. Citation Format: Sibylle Loibl, Carsten Denkert, Yuan Liu, Erik S. Knudsen, Angela DeMichele, Zhe Zhang, Julia Teply-Szymanski, Martin Filipits, Peter A. Fasching, Michael Gnant, Shibing Deng, Marija Balic, Federico Rojo, Mark Watson, Chetan Deshpande, Nicholas Turner, Otto Metzger, Kathy Puyana Theall, Agnieszka Witkiewicz, Olga Valota, W. Fraser Symmans, Erica L. Mayer. Development and Validation of a Composite Biomarker Predictive of Palbociclib + Endocrine Treatment Benefit in Early Breast Cancer: PENELOPE-B and PALLAS Trials [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 PD17-05.

Adjuvant palbociclib for ER+ breast cancer (PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): A preplanned analysis of the stage IIA cohort

390216 Background: CDK4/6 inhibitors have become standard of care for advanced hormone receptor positive, HER2-negative (HR+/HER2-) breast cancer in combination with endocrine therapy (ET), with one approved for high-risk patients (pts) in the adjuvant setting. The PALLAS Trial investigated the addition of palbociclib to adjuvant ET in pts with stage II-III breast cancer. Stage IIA patients were specifically enrolled to evaluate the potential benefit of using palbociclib with adjuvant ET pts diagnosed at lower risk who may have more indolent disease. Methods: In the prospective, randomized, phase III PALLAS trial, pts with HR+/HER2- early breast cancer were randomly assigned to receive adjuvant ET for at least 5 years with or without 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle). ET was of provider’s choice. Stage IIA enrollment was capped at 1,000 patients. While the primary end point of the overall study was invasive disease-free survival (iDFS) for the entire cohort, there was a preplanned analysis of recurrence and survival endpoints in the stage IIA cohort. Outcomes were compared between arms using stratified log-rank tests and Cox models (stratification factors: chemotherapy and age ≤ 50). Results: Among 5,796 pts enrolled at 406 centers in 21 countries worldwide between 9/1/2015 and 11/30/2018, a total of 1,010 stage IIA pts were enrolled. The protocol-defined number of events occurred at a median follow-up of 50 months for this subgroup (43.1 months for the overall study). Median age within this subgroup was 54 (range 29-85 yrs), and 410 (40.6%) were pre/perimenopausal, 506 (50.1%) T2/N0 (vs T0-1/N1), 272 (26.9%) grade 3 (vs. grade1/2), and 561 (55.5%) received chemotherapy. iDFS events occurred in 31 of 503 (6.2%) pts who received palbociclib plus ET and in 45 of 507 (8.9%) pts who received ET alone, resulting in a statistically nonsignificant difference in iDFS at 4 years (92.9% vs. 92.1%; hazard ratio, 0.75; CI, 0.48 to 1.19; P = .23). Nonsignificant differences were also observed for invasive breast cancer-free, distant recurrence-free, and locoregional cancer-free survival. No significant differences in iDFS were observed in subgroups including age group, receipt of chemotherapy, tumor grade, and clinical risk (T1/N1 vs. T2/N0).Conclusions: In this preplanned analysis of the stage IIA cohort of the PALLAS trial, the addition of adjuvant palbociclib to standard ET did not improve outcomes over ET alone, suggesting no benefit from the agent in reducing the incidence of early relapse in pts with lower-stage HR+/HER2- breast cancer. Future analyses will incorporate genomic risk and other molecular patterns from the extensive transPALLAS correlative program. Additional follow-up (10-year minimum) is also underway to assess the impact of palbociclib exposure on late recurrence in HR+ disease. Clinical trial information: NCT02513394.

Abstract P4-12-01: Adherence with adjuvant endocrine therapy with or without Palbociclib in the PALLAS trial

Abstract Background: As the development and use of oral anticancer agents increases, it is critical to understand patient adherence to both standard and investigational agents. The open label, phase 3 multicenter PALLAS trial investigates whether adding 2 years of the CDK4/6 inhibitor palbociclib (P) to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) over adjuvant ET alone in patients (pts) with HR- positive, HR2-negative, stage II-III breast cancer. Pts were randomly assigned to either Palbociclib (125 mg/day, 3 weeks on, 1 week off, in a 28-day cycle) plus ongoing provider/patient-choice adjuvant ET (P+ET) versus ET alone. We examined patient-reported adherence to ET +/- P during the first two years of study treatment. Methods: Adherence outcomes were measured in English-speaking pts in the U.S., UK, Ireland and Australia, Spanish-speaking pts in Spain and Mexico, and German-speaking pts in Germany and Austria. Adherence measures included drug diaries completed at each cycle, pill counts (for P only) collected at each study visit, and the Morisky Medication Adherence Scale-4 item and the McHorney Adherence Estimator questionnaires completed at cycles 2, 3, 6, 12, 18, and 24 (22 months). Mean adherence for each cycle was defined as the average proportion of prescribed pills taken (via drug diary) across all patients who initiated that cycle. Persistence was defined as the duration of drug initiation to treatment cessation (via drug diary). Generalized estimating equations were used to model the “most adherent” pts on the Morisky (score = 5 vs score <5) and “low risk” for adherence problems on the McHorney (score=0 vs score >0) to compare the average difference between arms over time for ET, adjusting for baseline demographic and clinical variables. Results: 81% (N=4688) of PALLAS pts were included in this analysis. Median persistence to ET was 23.6 months in P + ET (n=2169), 23.7 months in ET alone (2136) and 20.4 months for P (n=2194). The number of pts who initiated each cycle for ET declined over time and was similar between arms; the decline was more marked for P (Table 1). Mean adherence range as measured by drug diary was 98.2-99.3% for ET in P+ET and 98.0 - 99.4% in ET alone; and for P, ranged from 93.4 - 98.8%. The adherence and persistence results were nearly identical whether measured by drug diary or pill count for P. The observed percent “most adherent” for P measured by the Morisky scale ranged from 71.9% - 79.6% and the percent “low risk” for adherence problems measured by the McHorney scale, 64.0% - 73.4%. The percent of pts “most adherent” and “low risk” for adherence problems to ET was higher, on average over time, in the P+ET group compared to ET alone (75% vs 68%, p<0.01; 75% vs 72%, p=.05, respectively). Conclusions: Self-reported mean adherence for both P + ET and ET alone was strikingly high for pts who remained on therapy; persistence was also high with ET during the 2-year treatment period. Current analyses suggest that nonadherence to either P or ET was likely not a major contributor to the iDFS results seen in the overall PALLAS trial. These results illustrate the importance of measuring and monitoring patient adherence to oral study agents. Support: AFT, Pfizer; ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). https://acknowledgments.alliancefound.org Table 1.Adherence and persistence in PALLAS over the 24 month treatment periodPalbocicilb + ETETPalbociclibETETTreatment cycleMean Adherence (SD)N*Mean Adherence (SD)NMean Adherence (SD)N193.4 (13.8)229098.7 (6.1)230999.0 (5.2)2343294.7 (13.3)218198.8 (6.4)220398.4 (7.1)2206397.4 (10.1)211298.7 (7.3)214298.8 (6.3)2168497.6 (10.2)203598.6 (7.8)211099.0 (5.7)2154597.6 (11.1)197598.3 (7.9)209398.1 (8.3)2148698.1 (8.7)189998.7 (6.6)203798.5 (8.2)2116798.1 (9.3)185599.0 (6.3)201298.6 (7.3)2102898.0 (9.1)181098.2 (8.2)199798.1 (8.2)2092998.4 (7.4)173399.0 (6.4)196298.8 (6.8)20511098.3 (8.6)171499.2 (4.9)194699.0 (5.5)20381198.3 (8.0)169198.5 (7.3)193798.2 (8.2)20311298.7 (6.2)161299.1 (5.3)191098.7 (7.5)19861398.5 (7.7)159698.9 (6.4)189398.8 (7.1)19691497.9 (9.3)157698.4 (7.3)188298.0 (9.1)19611598.5 (6.9)151499.2 (4.6)185499.0 (6.0)19281698.2 (8.7)148699.1 (4.6)183599.1 (5.7)19131798.1 (9.8)147998.3 (7.8)182698.5 (6.4)19031898.7 (6.8)141699.3 (4.1)176899.2 (5.3)18601998.7 (7.3)140899.3 (3.8)175699.4 (3.1)18482098.4 (8.9)139798.9 (5.3)174298.7 (5.8)18382198.5 (7.5)130199.0 (6.1)167698.8 (7.1)17842297.8 (9.7)124698.8 (6.2)164799.2 (5.7)17692398.1 (8.8)118098.2 (8.5)161998.4 (8.0)17552498.8 (7.2)108699.0 (6.3)146898.9 (7.1)16192598.8 (6.7)99699.2 (5.2)143298.8 (7.1)15892697.9 (11.2)84599.1 (5.7)140998.6 (8.8)1578ET=Endocrine therapy * Number of pts who initiated the treatment cycle. Citation Format: Eileen Shinn, David Zahrieh, Angela DeMichele, Nick Zdenkowski, Julie Lemieux, Jun Mao, Vesna Bjelic-Radisic, Michelle Naughton, Georg Pfeiler, Karen Gelmon, Ingrid Mayer, Daniel Egle, Gabriele Zoppoli, Tiffany Traina, Miguel Martin Jiménez, Silvia Antolin Novoa, Tufia Haddad, Arlene Chan, Alistair Edward Ring, Antonio Wolff, Jose JuanPonce Lorenzo, Dhanusha Sabanathan, Hal Burstein, Zbigniew Ireneusz Nowecki, Gunda Pristauz-Telsnigg, Adam Brufsky, Meritxell Bellet-Ezquerra, Theodoros Foukakis, Yelena Novik, Gabor Rubovszky, Karoline Muehlbacher, Otto Metzger, Theodora Goulioti, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Dominik Hlauschek, Christian Fesl, Erica Mayer, Michael Gnant. Adherence with adjuvant endocrine therapy with or without Palbociclib in the PALLAS trial [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 P4-12-01.

Abstract GS1-07: Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial

Abstract Background Advances in the multidisciplinary care of hormone-receptor positive (HR+) early breast cancer (eBC) have markedly improved clinical outcomes: however, disease recurrence may still occur, particularly in patients (pts) with moderate or high-risk cancers at the time of diagnosis. The use of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) is a standard of care for advanced breast cancer, supporting the rationale to study CDK4/6i in the eBC setting. Here we present the final protocol-planned analyses of the global phase III PALLAS trial investigating whether the addition of the CDK4/6i palbociclib (P) to adjuvant ET improves outcomes over ET alone for HR+/HER2- eBC. Methods PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III open-label trial in which pts with stage II-III HR+/HER2- eBC were randomized to receive either 2 years of P with adjuvant ET (P+ET) or ET alone. The primary endpoint is invasive disease-free survival (iDFS); secondary endpoints include distant recurrence-free survival (DRFS), locoregional recurrence-free survival (LRRFS), overall survival (OS), and safety. Mandatory biospecimen collection has supported the creation of an expansive translational science program, and long-term follow-up is planned. Revised sample size calculations required recruitment of 5600 pts in order to detect a 25% iDFS improvement in patients receiving P+ET with 85% power; this final protocol-planned analysis was planned after 469 iDFS events. Results From September 1, 2015 to November 30, 2018, 5,761 pts (median age 52 years, range 22-90) were randomized in 406 centers in 21 countries worldwide. 1,014 (17.6%) had stage IIA disease (capped) and 4,728 (82.1%) stages IIB/III. 4,754 (82.5%) had received prior (neo)adjuvant chemotherapy. After a protocol-planned 2nd interim analysis in May 2020 crossed the futility threshold, 349 P+ET pts still on active treatment stopped P and were transferred to follow-up. At the time of final analysis cutoff date (November 20, 2020), after a median follow-up of 31 months and 516 events recorded, iDFS was similar between the two arms, with 3-year iDFS of 89.3% (95% CI: 87.8-90.6%) for Palbo+ET, and 89.4% (88.0-90.7%) for ET alone (hazard ratio 0.96, 95% CI: 0.81-1.14). There was no statistically significant difference in secondary outcome endpoints. Subgroup analyses revealed no significant interactions between treatment effect and other factors (including risk category). The safety profile of P was as expected, with grade 3 or 4 neutropenia the most common side effect (safety population: 1759/2841 [61.9%] vs 11/2902 [0.4%]). Overall 42% of pts. discontinued P prior to the planned 2-year duration, 28.2% of Palbo+ET pts discontinued therapy due to adverse events, without an observed impact on survival outcomes. Conclusions Now with the full number of events, this analysis of the PALLAS trial shows that the addition of 2 years of P to ongoing adjuvant ET did not improve survival endpoints for pts with stage II-III HR+/HER2- eBC. Whether P is beneficial in the adjuvant setting for certain sub-groups of pts will be further evaluated with longer-term follow-up and by the ongoing translational science program. Support: ABCSG; AFT; Pfizer; ClinicalTrials.gov Identifier: NCT02513394; https://www.abcsg.org; https://acknowledgments.alliancefound.org Citation Format: Michael Gnant, Amylou C Dueck, Sophie Frantal, Miguel Martin, Hal Burstein, Richard Greil, Peter Fox, Antonio C Wolff, Arlene Chan, Eric Winer, Christian Singer, Kathy Miller, Marco Colleoni, Michelle Naughton, Gabor Rubovszky, Judith Bliss, Ingrid A Mayer, Guenther G Steger, Zbigniew Nowecki, Olwen Hahn, Norman Wolmark, Hope Rugo, Georg Pfeiler, Hannes Fohler, Otto Metzger, Céline Schurmans, Kathy P Theall, Dongrui R Lu, Kathleen Tenner, Christian Fesl, Angela DeMichele*, Erica L Mayer, *shared last authorship. Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial [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 GS1-07.

Physician Network Connections Associated With Faster De-Adoption of Dronedarone for Permanent Atrial Fibrillation.

Physicians' professional networks are an important source of new medical information and have been shown to influence the adoption of new treatments, but it is unknown how physician networks impact the de-adoption of harmful practices. We analyzed changes in physicians' use of dronedarone after the PALLAS trial (Palbociclib Collaborative Adjuvant Study; November 2011) showed that dronedarone increased the risk of death from cardiovascular events among patients with permanent atrial fibrillation. Deidentified administrative claims from the OptumLabs Data Warehouse were combined with physicians' demographic information from the Doximity database and publicly available data on physicians' patient-sharing relationships compiled by the Centers for Medicare and Medicaid Services. We used a linear probability model with an interrupted linear time trend specification to model the impact of the PALLAS trial on physicians' dronedarone usage between 2009 and 2014. Before the PALLAS trial, the use of dronedarone was increasing by 0.22 percentage points per quarter (95% CI, 0.19-0.25) in our Medicare Advantage sample (N=343 429 patient-quarter observations) and 0.63 percentage points per quarter (95% CI, 0.52-0.75) in our commercially insured sample (N=44 402 patient-quarter observations). After the PALLAS trial and subsequent United States Food and Drug Administration black box warning, physicians in the Medicare Advantage sample with an above-median number of network connections to other physicians decreased their quarterly usage of dronedarone by 0.12 percentage points more per quarter (95% CI, -0.20 to -0.04; P=0.031) than physicians with equal to or below the median number of network connections. Similar patterns existed in the commercially insured sample (P=0.0318). After controlling for a wide range of patient, physician, and geographic characteristics, physicians with a greater number of network connections were faster de-adopters of dronedarone for patients with permanent atrial fibrillation after the PALLAS trial and subsequent United States Food and Drug Administration black box warning detailed the harmfulness of dronedarone for these patients. Policies for improving physicians' responsiveness to new medical information should consider utilizing the influence of these important professional network relationships.

Abstract PD2-03: Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer

Abstract Background:Adherence to and tolerability of oral agents for the treatment of hormone receptor positive (HR+) breast cancer in the adjuvant setting may be challenging and can limit drug exposure. Palbociclib (P) is an oral CDK4/6 inhibitor; P in combination with endocrine therapy (ET) has demonstrated efficacy in HR+/HER-2 negative (HER2-) metastatic breast cancer (MBC). The global PALLAS study (NCT02513394) was designed to determine if the addition of P to adjuvant ET improves outcomes over ET alone in early breast cancer. The goal of this analysis is to describe P exposure and discontinuation in PALLAS, and explore any impact on study endpoints. Methods:Pts with stage II-III HR+/HER2- disease were randomized to receive 2 years of P (starting dose 125 mg daily, 3 weeks on, 1 week off) in combination with adjuvant ET (Arm A) or ET alone (Arm B). The primary objective was to compare invasive disease-free survival (iDFS) between arms; secondary endpoints included safety, quality of life, adherence, and translational science. Dose adjustments were defined per protocol in the setting of emergent toxicity. Continuous monitoring of toxicity, dose modifications, and early discontinuations was performed throughout the trial. Statistical analysis included tabulation of dose levels/reductions and reasons for treatment discontinuation, as well as landmark analysis comparing iDFS between those receiving > 12 months (mo) vs < 12 mo of P. Ongoing analyses include exploration of relative dose intensity and modeling of P dose intensity/duration and impact on iDFS. Results:A total of 5760 pts were randomized; 83% had received prior chemotherapy; 68% initiated aromatase inhibitor and 33% tamoxifen, with or without ovarian suppression. Grade 3/4 neutropenia was more common in Arm A vs B (62% vs 0.4%); febrile neutropenia was uncommon (1%). Other all-grade adverse events (AEs) more common in Arm A included other hematologic toxicity, fatigue, upper respiratory infection, nausea, diarrhea, and alopecia. A total of 55% of pts required P dose reduction to 100mg, and 34% to 75 mg, at some point during treatment. At a median follow-up of 23.7 mo at the second interim analysis, no significant difference in iDFS was observed between the arms (3-year iDFS of 87.9% vs 88.4%, HR 0.93, 95% CI 0.76, 1.15); consequently, pts in Arm A stopped P, and all pts moved to long-term follow-up. At time of data cut-off, 32% had completed the planned 2 years of P, 26% were still receiving P, and 42% had discontinued P prematurely. P discontinuation was 18% at 6 mo, 30% at 12 mo, 38% at 18 mo, and 45% projected at 24 mo. A total of 27% of Arm A pts (770 of 2840) discontinued therapy due to AEs, primarily neutropenia (460, 16%) and fatigue (71, 3%). Other reasons for P discontinuation included non-compliance (128, 5%), recurrent disease or second malignancy (104, 4%), or withdrawal of consent (100, 3%). Last observed dose level was 125mg, 100mg, and 75mg for 45%, 22%, and 33% pts, respectively. Among those discontinuing due to AEs, dose level at time of discontinuation was 75mg for 62%, suggesting some discontinuations occurred without maximum dose reduction. Pts who received > 12 mo of P had a 2-year iDFS of 96.6%; those receiving <12 mo had 2-year iDFS of 95.7% (HR 0.86, 95% CI 0.55-1.34). Conclusions:An early analysis of PALLAS has demonstrated that 2 years of adjuvant P in combination with adjuvant ET did not improve iDFS when compared with ET alone in pts with HR+/HER2- breast cancer. While 2 years of adjuvant P was feasible for the majority of pts, 42% discontinued P early, primarily for AEs. Further data examining drug discontinuations and relationships between drug exposure and clinical outcomes will be presented, expanding upon initial point estimates suggestive of a possible explanation of trial results. Citation Format: Erica L. Mayer, Christian Fesl, Amylou Dueck, Michael Gnant, Angela DeMichele, on behalf of the PALLAS study team. Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer [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 PD2-03.

Patient and provider-level factors associated with changes in utilization of treatments in response to evidence on ineffectiveness or harm

High-quality health care not only includes timely access to effective new therapies but timely abandonment of therapies when they are found to be ineffective or unsafe. Little is known about changes in use of medications after they are shown to be ineffective or unsafe. In this study, we examine changes in use of two medications: fenofibrate, which was found to be ineffective when used with statins among patients with Type 2 diabetes (ACCORD lipid trial); and dronedarone, which was found to be unsafe in patients with permanent atrial fibrillation (PALLAS trial). We examine the patient and provider characteristics associated with a decline in use of these medications. Using Medicare fee-for-service claims from 2008 to 2013, we identified two cohorts: patients with Type 2 diabetes using statins (7 million patient-quarters), and patients with permanent atrial fibrillation (83 thousand patient-quarters). We used interrupted time-series regression models to identify the patient- and provider-level characteristics associated with changes in medication use after new evidence emerged for each case. After new evidence of ineffectiveness emerged, fenofibrate use declined by 0.01 percentage points per quarter (95% CI - 0.02 to - 0.01) from a baseline of 6.9 percent of all diabetes patients receiving fenofibrate; dronedarone use declined by 0.13 percentage points per quarter (95% CI - 0.15 to - 0.10) from a baseline of 3.8 percent of permanent atrial fibrillation patients receiving dronedarone. For dronedarone, use declined more quickly among patients dually-enrolled in Medicare and Medicaid compared to Medicare-only patients (P < 0.001), among patients seen by male providers compared to female providers (P = 0.01), and among patients seen by cardiologists compared to primary care providers (P < 0.001).

Abstract PD5-06: Adjuvant palbociclib plus endocrine therapy for hormone receptor positive/HER2 negative breast cancer: A phase II feasibility study

Abstract Background: The CDK4/6 inhibitor palbociclib (P) combined with endocrine therapy (ET) prolongs progression-free survival in previously untreated and treated hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC). The most common toxicity with P is neutropenia, typically non-cumulative and uncomplicated. Given observed benefits of P in metastatic BC, this single arm phase II trial was designed to determine the feasibility and toxicity of combination adjuvant P and ET for HR+/HER2- early BC (EBC). Methods: Eligible patients (pts) had HR+/HER2- stage II (not T2N0)-III EBC, with prior completion of 3-24 mo of ET (either AI or tamoxifen) without significant adverse events (AE). Pts received P at 125 mg daily, 3 wk on/1 wk off in a 28d cycle, plus continuous ET, for planned duration 2 yrs. Pts were removed from study for toxicity, non-adherence, or other events related to tolerability; pts who recurred or completed 2 yrs of therapy were censored for the primary endpoint. The primary objective was to evaluate the treatment discontinuation rate at 2 yrs; a rate of &amp;gt;50%, would indicated a non-feasible treatment duration (null hypothesis). Discontinuation rates at 2 yrs are estimated by Kaplan Meier with 95% confidence bands. A sample size of 160 pts provided 92% power to reject the null hypothesis using a one-sided alpha = 0.025 if the true rate of discontinuation is &amp;lt;33.3%, and accounting for a censoring rate of up to 20% over the 2 yrs. Secondary endpoints include toxicity, adherence, QOL, and pharmacogenomics. Results: Between 3/2014 and 11/2015, 162 pts initiated P; the majority had stage III EBC (52%) and received prior chemotherapy (63%). As of 05/2017, 120 (74%) have completed at least 1 yr of P + ET, and 50 (31%) have completed 2 yrs of P + ET. Early discontinuation of protocol treatment was reported for 59 pts (36%), including 49 events (30%) related to protocol-mandated (9%) and non-mandated (21%) tolerability. The cumulative rate of all discontinuations was 15.1% at 6 mos, 20.9% at 12 mos and 27.8% at 18 mos. Half of all non-mandated discontinuations occurred within the first 6 mos of initiation of therapy, and the rate decreased with greater provider and pt education. Median duration of pts still on treatment is 20 mos (inter-quartile range: 18 to 21 mos). The rate of grade 3/4 neutropenia was 77%, with 0 cases of febrile neutropenia. Other common all-grade P-related AE &amp;gt; 20% included fatigue 65%, alopecia 25%, mucositis 24%, and anemia 24%. 32% of pts required one dose reduction, 16% required two. There have been 2 BC recurrence events and 1 chemotherapy-related AML. Updated data for the primary analysis of feasibility and tolerability, as well as pharmacogenomics, QOL, and adherence, will be presented. Conclusions: In this single arm phase II trial, the majority of pts have completed at least 1 year of adjuvant P + ET therapy, with no new toxicity signals. Non-protocol discontinuations have decreased with education. Updated results for the primary analysis will be presented. As in the MBC setting, extended duration palbociclib appears feasible and tolerable for most pts. The efficacy of 2 years of P and ET will be addressed by the phase III PALLAS trial (NCT NCT02513394). Citation Format: Mayer EL, DeMichele AM, Guo H, Miller KD, Rugo HS, Schneider B, Waks AG, Come SE, Mulvey T, Huang Bartlett C, Koehler M, Barry W, Winer EP, Burstein HJ. Adjuvant palbociclib plus endocrine therapy for hormone receptor positive/HER2 negative breast cancer: A phase II feasibility study [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 PD5-06.

Management of ventricular and atrial arrhythmias in humans: towards a patient-specific approach

The strategy of sudden cardiac death prevention by implantable cardioverter defibrillator, in primary prevention, is mainly based on the value of ejection fraction. That means that the approach is not really patient specific. A lot of implanted patients will not receive any shock. The implantation of large categories of patients is interesting on a global therapeutical point of view but, when considering the economical aspects, it would be more useful to have better selection criteria in order to obtain a more patient-specific approach, avoiding implanting patients who will never receive shocks. The parameters commonly used to select patients for implantations have a good negative predictive value but a low positive predictive value. Concerning atrial fibrillation the approach is quite different. Antiarrhythmic drug treatment has shown many limitations. Antiarrhythmic drugs are useful and safe in atrial fibrillation patients only if the contra-indications are strictly respected. The main difficulty concerns patients with both heart failure and atrial fibrillation. The story of Dronedarone development is illustrative of the necessity of a patient-specific approach in the treatment strategy of atrial fibrillation. The ATHENA trial made with Dronedarone showed a benefit in patients with underlying heart disease but no patient with advanced cardiopathy was included in the study. On the contrary, the PALLAS trial has clearly shown that the drug is contra-indicated in patients with any type of heart failure. In atrial fibrillation, a patient-specific approach is mandatory. This review illustrates the dichotomy of the two different approaches.

Effective Alternatives

Primary care physicians are confronted with this problem on an almost daily basis and have to make decisions in the acute setting as well as for patients’ long term care. Professor Trappe’s article is thus enormously important and worth reading. However, I think a few additional comments are warranted: It seems worth discussing, and readers did not receive a sufficiently clear answer, whether the available and reported study results even justify medical treatment of cardiac arrhythmia. The author’s explanations regarding dronedarone are euphemistic when he says that the current state of the evidence, after a relatively short period of observation of the effects of dronedarone, does not justify the prominent position accorded to this drug in the published guidelines. After the PALLAS trial was stopped (clinicaltrials.org), it seems obvious that this drug, which was initially provocatively advertised, does not provide a further, potential treatment option for permanent atrial fibrillation. I would have wished for a specialist cardiological assessment of the use of pulmonary vein isolation. I wonder which ethics committee gave approval for a substance such as vernakalant to be tested in at least three studies versus placebo (!) when effective alternative therapeutics are available, for which conversion rates of 40–60% in the acute setting have been described and confirmed. This expensive new drug cannot achieve any more than that, and it remains unclear whether it offers any additional advantages compared with flecainide or propafenone. In my opinion, it would have been important to mention for dabigatran the significantly increased risk of provoking myocardial infarction (Uchino K, Hernandez AV: Circulation 2011; 124: Abstract 15500), which should be an additional factor in the decision-making process.

Highlights of the American Heart Association Scientific Sessions 2011: a focus on ATLAS–TIMI 51, TRACER and PALLAS

Several key reports from the American Heart Association meeting, held in Orlando (FL, USA) in November 2011, are presented related to anti-thrombotic therapy in acute coronary syndrome and the use of dronedarone in permanent atrial fibrillation is discussed in this brief (and selective) overview of this meeting. A summary of the ATLAS-TIMI-51, TRACER and PALLAS trials is provided.