Dueck, Amylou

Abstract Background This secondary analysis of a phase I clinical trial illustrates integrated summary and visualization of Common Terminology Criteria for Adverse Events (CTCAE) data and Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) data at baseline and through the first cycle of treatment for tolerability review during dose-cohort evaluation in a phase I trial. Methods This study uses data from a phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Through iterative feedback from clinicians and statisticians, we developed a summary of cycle 1 PRO-CTCAE and CTCAE data for the first dose-level cohort. This summary is intended to demonstrate reporting that would be reviewed to inform a decision about proceeding to the next dose level in a dose escalation trial. Results Cycle 1 CTCAE and PRO-CTCAE data for 4 patients enrolled in the first dose cohort are summarized as narrative and tabular summaries and visualized using swimmer and butterfly plots. In this cohort, 3/4 (75%) patients had at least one CTCAE grade 3 or higher adverse event, and all 4 (100%) patients had at least one PRO-CTCAE composite score of 3 during cycle 1. All 4 (100%) patients had at least one symptom for which PRO-CTCAE suggested greater symptom burden than was reflected in CTCAE. Conclusions In this illustrative summary of a dose cohort, PRO-CTCAE complemented CTCAE reporting by capturing patient-reported symptomatic burden that was not always fully reflected by clinician-graded adverse events. Reviewing PRO-CTCAE and CTCAE data together during dose-cohort evaluation may enrich discussions on safety and tolerability in phase I trials.

Abstract Background Patients’ self-report of their symptoms can provide important data for the evaluation of treatment benefit and tolerability of oncology drugs. Contemporary treatment approaches, including immunotherapy and molecular targeted therapies, have unique toxicities based on their novel mechanisms of action. This scoping review aimed to summarize evidence from existing reviews and clinical practice guidelines to examine the type and prevalence of toxicities including symptomatic adverse events (sympAEs) for adult cancer patients to inform clinical care and therapeutic trials. Methods A systematic search of PubMed, Web of Science, and Embase was performed using predefined eligibility criteria. Thirty-one literature reviews and 3 clinical practice guidelines met inclusion criteria and were selected for review and data abstraction. Results Findings from this scoping review demonstrated several leading sympAEs that were reported across immunotherapy and targeted therapy drugs, including fatigue, diarrhea, and rash. In addition to these more prevalent sympAEs, there were some less frequently reported class-specific sympAEs, which had potential for significant harm or disability to the patient if not properly identified and treated. Many studies reported toxicities as AEs or syndromes solely using data reported by clinicians without additional self-report from patients. Conclusion We identified several core sympAEs experienced by patients participating in oncology trials using immunotherapy and targeted therapy agents, which has implications for future trial design and drug labeling. Future cancer trials should assess patient-reported sympAEs based on the identified drug mechanism to inform the tolerability of these newer agents and enhance patient safety during trial participation and clinical care.

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: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.

523 Background: Adjuvant trastuzumab (Herceptin [H]) with chemotherapy improves outcome in HER2+ breast cancer (BC). Preclinical studies suggest H may enhance RT. We herein assess if H given with adjuvant RT increases adverse events (AE) after breast conserving surgery or mastectomy. Methods: N9831 randomized 3505 women with pT1–3N1–2M0, pT2–3N0M0, or pT1cN0M0 (ER/PR negative) HER2+ BC to doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T), AC→T→H, or AC→TH→H. Post-lumpectomy breast ± nodal RT was recommended, as was post-mastectomy chest wall + nodal RT (>3 nodes +); internal mammary RT was prohibited. RT started within 5 weeks of completion of T and allowed concurrently with H. 2324 eligible patients were enrolled on study prior to April 25, 2004: 1460 patients receiving RT are available for analysis of RT-associated AEs. Also, 1286 patients on +H arms who completed T (908 +RT and 378 -RT) are available for analysis of clinical cardiac events (CE). Rates of RT-associated AEs were compared across treatment arms, and rates of CE were compared for +RT vs -RT patients within +H arms. All reported p-values are for chi-squared statistics. Results: With a median follow-up of 1.5 years, significant differences among arms in RT-associated AEs were not identified. No significant differences across arms in +RT patients existed in the incidence of skin reaction (p=0.78), pneumonitis (p=0.78), dyspnea (p=0.87), cough (p=0.54), esophageal dysphagia (p=0.26), or neutropenia (p=0.16). There was a significant difference in +RT patients in the incidence of leukopenia (p=0.02) with higher incidence rates in the arms receiving H. RT did not increase the frequency of CE. In the AC→T→H arm, the incidence of CE was 2.2% in +RT patients versus 2.9% in -RT patients. In the AC→TH→H arm, the incidence of CE was 1.5% in +RT patients versus 6.3% in -RT patients. No difference in CE was seen between left- and right-sided RT fields in +RT patients in either +H arm. Conclusion: Concurrent administration of adjuvant RT with H in early stage breast cancer patients is not associated with an increased incidence of acute RT AEs. Further follow-up is required to assess late AEs. No significant financial relationships to disclose.

Abstract Introduction: The programmed cell death-1 (PD-1) immune checkpoint is a normal regulator of the autoimmune response to inflammatory stimuli. Several cancers have taken advantage of this mechanism by harboring its ligand (PD-L1), thus activating the checkpoint to evade immune destruction. Increased expression of PD-L1 on tumor cells has been linked with worse outcomes in several cancers, including breast cancer. In triple-negative breast cancer (TNBC), expression of PD-L1 is increased compared to luminal cancers and as such, has become a favorable target for anti-tumor therapies. However, few studies evaluate the impact of PD-1 and PD-L1 expression on overall survival (OS) in TNBC. The aim of this study was to assess OS based on PD-1 and PD-L1 positivity and distribution in the tumor microenvironment. Methods: All patients with newly diagnosed TNBC from 1999 to 2015 with adequate pathologic specimen were identified for evaluation. Surgical pathology specimens were stained by immunohistochemistry (IHC) for PD-1 and PD-L1. Those considered PD-1+ or PD-L1+ had a staining score of 3, 4, or 5. Patient and clinical characteristics of the adjuvant group were compared by PD-1 and PD-L1 status with Chi-Square and ANOVA, as appropriate; characteristics of the neoadjuvant population were described. OS was calculated using Kaplan-Meier method and compared by Log Rank test for PD-1, PD-L1 positivity and tumor microenvironment status. Results: Fifty-two patients met inclusion; 38 had surgery prior to chemotherapy while 14 had neoadjuvant chemotherapy. There were 15 PD-1+ patients (39%) and 21 PD-L1+ (55%) patients in the treatment naive cohort. No significant difference was found in the treatment naive group between age, race, postmenopausal status, final stage, or pathologic characteristics (e.g. tumor size, mitotic rate, and grade) for all PD-1+ and PD-L1+ patients. Of the 21 PD-L1+ patients, staining was present in the tumor, tumor/non-tumor (mixed), and non-tumor microenvironment 42.9%, 33.3%, and 23.8% of the time, respectively (p=0.008). No significant difference was found in OS between PD-1+ and PD-1- patients (p=0.509) or PD-L1+ and PD-L1- patients (p=0.240). However, distribution of PD-L1 staining significantly associated with OS. Those demonstrating PD-L1 staining in the tumor had a significantly higher OS than those with PD-L1 staining in the non-tumor microenvironment (p=0.008). In the subset of PD-L1+ patients, those with staining in the tumor show a 10-year OS of 100% versus 60% for those with staining in non-tumor (p=0.006). In the neoadjuvant cohort, 14.3% of patients expressed PD-1 positivity, while 42.9% had PD-L1 positivity; the distribution of the PD-L1 staining in tumor 14%, mixed 29%, and non-tumor 50%. No difference in OS was found based on PD-1 or PD-L1 (p=0.660) positivity in the neoadjuvant cohort. Conclusion: A large number of TNBC stain for PD-1 and/or PD-L1. The implications of this are yet to be determined. In this small cohort, pattern of staining had a significant impact on overall survival in treatment naïve patients. This finding will need to be validated on a larger cohort but may have important implications for treatment by defining patients who may benefit by checkpoint inhibitor therapy. Citation Format: Linnaus ME, Kosiorek H, Barrett MT, Dueck A, Anderson KS, Ocal IT, McCullough AE, Annamalai L, Yearley JH, Pockaj BA. Effect of PD-1 and PD-L1 in the tumor microenvironment on overall survival of triple-negative breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-03.