Clifton, Katherine

PURPOSE Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Early-stage, high-risk patients with TNBC are treated with chemotherapy and pembrolizumab per the KEYNOTE-522 regimen. This report examines real-world clinical effectiveness and toxicity of this regimen. METHODS This 19-site retrospective analysis included all patients who received at least one dose of the KEYNOTE-522 regimen. Safety, efficacy, and health care encounters were collected. RESULTS 675 patients from 19 sites in the United States who received chemotherapy and pembrolizumab for early-stage TNBC were included. 547 (81.0%) patients underwent surgery and 250 (54.7%) patients had a pathologic complete response (pCR). No baseline characteristics were predictive of pCR status. 224 patients (33.2%) had an adverse drug event resulting in ≥1 dose reduction of chemotherapy and were significantly more likely to have residual disease. Immune-related adverse events (irAEs) were observed in 388 (57.5%) patients and grade 3+ irAEs were observed in 176 (26.1%) patients. There was no difference in pCR status between provider's choice chemotherapy schedules. There was no difference of pCR rate between Black and White patients (55.6% v 51.6%, P = .489). White patients were significantly more likely to have any grade and grade 3+ irAEs. Older patients (age ≥65 years) had similar pCR rates compared with younger patients; however, older patients were significantly more likely to have grade 3+ irAEs. CONCLUSIONS In this multi-institutional real-world cohort, we observed a lower pCR rate, higher rates of toxicity, frequent emergency health care utilization, and the reporting of rare irAEs at higher frequency than the KEYNOTE-522 regimen. These findings have important implications for clinical management of patients with early-stage TNBC and warrant further validation with real-world data sets.

Abstract Background: We have identified two potentially predictive signatures of palbociclib resistance: the RBsig, composed of E2F1/E2F2 dependent genes, which is associated with genetic loss of RB1, and the ratio between the gene expression levels of CCNE1 to RB1 (CCNE1/RB1). Both signatures have been previously analyzed in vitro and in neoadjuvant and metastatic studies with palbociclib. The present analysis aims to explore the role of RBsig and CCNE1/RB1 in the phase III adjuvant PALLAS trial, which randomized patients to palbociclib plus endocrine therapy, versus endocrine therapy alone. Materials and methods: Gene expression data from PALLAS were generated using the HTG EdgeSeq Oncology BM Panel. Of the 87 genes composing RBsig, 46 were available within the EdgeSeq dataset and were used for the analyses; CCNE1 and RB1 were both available. RBsig was calculated as the mean of the Z-score scaled gene expression (log) of the 46 genes; CCNE1/RB1 was computed as the log ratio between the mRNA expression of CCNE1 and RB1. The prognostic/predictive effect of the continuous signatures in terms of invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), and overall survival (OS) was evaluated using Cox proportional hazard models. Results: HTG data were available from 2,587 of 5,748 patients from the entire PALLAS intention-to-treat (ITT) cohort. As RBsig and CCNE1/RB1 levels are affected by pre-surgical treatments, we limited the analyses to 1612 pre-treatment samples (530 core biopsies and 1082 surgical specimens) (analysis population). Compared with the entire PALLAS ITT cohort, the analysis population was significantly enriched for patients with low clinical risk (41.3% vs 59.4%) who did not receive prior chemotherapy (17.5% vs 55.9%). In keeping with the PALLAS ITT cohort, no significant benefit from the addition of palbociclib was observed in the analysis population. Higher baseline RBsig or CCNE/RB1 values were significantly and independently associated with worse IDFS (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.3-2.0; HR 1.22, 95%CI 1.1-1.3, respectively), DRFS (HR 1.94, 95%CI 1.5-2.5; HR 1.26, 95%CI 1.1-1.4, respectively) and OS (HR 1.79, 95% CI 1.3-2.4; HR 1.26, 95%CI 1.1-1.4, respectively) in the analysis population. No predictive effect of palbociclib benefit was observed for either signature in the analysis population, nor according to clinical risk or chemotherapy receipt. Interestingly, higher RBsig was strongly prognostic in patients who did not receive adjuvant chemotherapy (HR 1.83, 95%CI 1.4-2.3) but not in those who received it (HR 1.01, 95%CI 0.6-1.6) (interaction p=0.02) suggesting a potential predictive role of RBsig for chemotherapy benefit. Conclusions: In the PALLAS trial, higher baseline RBsig or CCNE1/RB1 values are associated with worse prognosis, but are not predictive of benefit from palbociclib in the adjuvant setting. RBsig might be associated with differential benefit from chemotherapy. Further study of these biomarkers may strengthen their role in risk stratification.https://acknowledgments.alliancefound.org Citation Format: L. Malorni, D. Hlauschek, E. Mayer, M. Benelli, L. Biganzoli, I. Migliaccio, A. Kermanidis, G. Pfeiler, E. P. Mamounas, A. M. Brufsky, M. Bellet-Ezquerra, K. Clifton, G. Rubovszky, T. Foukakis, M. Goetz, S. Lee, M. Ruiz-Borrego, W. Symmans, K. V. Ballman, F. Liu, J. Machacek-Link, C. Denkert, A. DeMichele, M. Gnant. Prognostic and predictive role of RBsig and CCNE1/RB1 gene-expression signatures for patients with early breast cancer treated with endocrine therapy with or without palbociclib in the PALLAS trial (ABCSG-42, AFT-05, BIG 14-03) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-13.

Abstract Abstract Title: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Despite the significant improvement in pathological complete response (pCR) and event-free survival rates across all patients, the landmark trial included only 4.5% Black patients. It is essential to assess outcomes in representative treatment populations. We assessed real-world toxicity and treatment outcomes across Black and White patients who received standard-of-care treatment per KEYNOTE-522. Methods: In this retrospective, multicenter study, we examined patients with early-stage TNBC who received planned treatment per KEYNOTE-522 as standard-of-care (SOC) therapy. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment-related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: Of the 577 patients who initiated treatment with chemotherapy and immunotherapy, 534 patients were included in this analysis with 105 patients who self-identified as Black (19.7%) and 429 who self-identified as White (80.3%). There were no statistically significant differences in clinical and pathological characteristics between the two groups. White women were more likely to have grade 3+ immune-related adverse events (irAEs) compared to Black women (33.8% vs 20.9%, P=0.011). There was no significant difference across Black and White patients with respect to grade 3+ chemotherapy-related adverse events. Out of the 444 patients who have completed surgery, no difference in pCR rate was observed between Black and White women (45/86 52.3% vs 200/358 55.9%) (p = 0.6). The authors also saw no difference in the rates of hospitalizations between Black and White women (39% vs 36% p = 0.5), and rates of acute care utilization (38% vs 38% p = 0.9). Conclusions: We report safety and efficacy across Black and White women in a real-world analysis of patients who received treatment per KEYNOTE-522. Notably, White patients had a significantly higher frequency of grade 3+ irAEs, although the reason for this finding is unclear based on this analysis. Black patients had similar pCR rates and rates of treatment-related hospitalizations compared to White patients. Assessment of outcomes and toxicity by race in clinical trials and real-world analyses are critical in drug development. Citation Format: Mara Hofherr, Andrew Davis, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Wiliam Adler, Traci White, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Katherine Clifton. Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 [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 PS14-02.

Abstract Title: Real-world analysis of adverse events in patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients (pts) with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Given the improvement in pathological complete response (pCR) and event-free survival rates, this regimen has emerged as standard-of-care (SOC) therapy. To date, real world outcome analyses are limited. Methods: In this retrospective, multicenter study, we examined pts with early-stage TNBC who received planned treatment per KEYNOTE-522 as SOC. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: 577 pts were included in this analysis. The median age of the cohort was 52 [range 27-77]. 457 pts had T1-2 disease and 139 had T3-4 disease. 316 pts had N0 disease and 261 had N1-3 disease. 506 pts had baseline ECOG 0, 62 had ECOG 1, and 9 had ECOG 2-3. Of the 482 patients who had surgery at the time of this analysis, 219 patients had pCR (54.5%) and 192 pts were still receiving treatment. 217 patients (37%) had an adverse drug event (ADE) causing dose reductions and 228 patients (39.5%) had to discontinue treatment early. There were 360 unplanned care visits, with 91 patients having 2+ visits. 66 patients had hospitalizations due to the regimen with 102 total hospitalizations. 179 (31%) of patients had grade 3+ immune related adverse events (irAEs), including many that are rare and potentially serious. 317 (54%) had an immune related adverse effect (see Table 1). There was no significant difference in the frequency of grade 3+ irAE based on age or body mass index. We observed no difference in residual disease between patients who discontinued treatment early and those who did not. However, if patients had an ADR causing a dose reduction, pts were significantly more likely to have residual disease (P=0.039) Conclusions: In a multicenter real-world analysis, the KEYNOTE-522 regimen was associated with a high frequency of dose reductions, early treatment discontinuations, ER visits, and hospitalizations. This may have accounted for a lower pCR rate than observed in the landmark clinical trial. Most grade 3+ irAEs occurred at greater frequency in our real-world analysis. Providers should carefully monitor for toxicity to ensure optimal patient outcomes. Table 1 Citation Format: Mara Hofherr, Katherine Clifton, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Traci White, William Adler, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Andrew Davis. Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522 [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 PS14-06.

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 Patients (pts) with ER+ HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after neoadjuvant chemotherapy with dual HER2 blockade than pts with ER- HER2+ BC. Endocrine therapy (ET) plus trastuzumab is effective in advanced ER+ HER2+ BC, but pCR rate is low in the neoadjuvant setting. Inhibition of CDK4/6 and HER2 results in synergistic reduction in cell proliferation in preclinical studies. We therefore combined ET with CDK4/6 inhibition and trastuzumab in ER+ HER2+ BC as a chemotherapy-sparing regimen. Methods We evaluated the efficacy of palbociclib, letrozole, trastuzumab (PLT) in the neoadjuvant setting for pts with stages II or III ER+ HER2+ BC. Primary endpoint was pCR after 16 weeks of therapy. We assumed null of 15% pCR and pCR ≥ 30% warrants further investigation. To achieve 80% power at 1-sided 0.05 significance, 48 pts were to be enrolled. Evaluable population included pts who completed Cycle (C) 1 unless discontinued due to treatment-emergent adverse events (TEAEs) prior to completing C1. All who received one dose on study were considered evaluable for toxicity. Biopsies were collected at baseline (BL), C1 day 15 (C1D15), and surgery for RNA sequencing and central Ki67 assessment, for PAM50 subtype distribution, complete cell cycle arrest (CCCA: Ki67 ≤2.7%) at C1D15 and surgery, and treatment induced signaling changes. Results Accrual stopped early due to futility. 26 pts accrued were evaluable for efficacy and toxicity. pCR (residual cancer burden- [RCB] 0) was 7.7% (95% CI 0.9 - 25.1%) and RCB 0/I was 38.5% (95% CI 20.2 - 59.4%). TEAEs (n= 337) were seen in all pts (71.5% grade [G] 1, 19.3% G2, 8.6% G3, 0.6% G4); the most common were leukopenia (7.7%), neutropenia (7.1%), anemia (5.9%). G3/4 TEAEs occurred in 19 pts (73.1%). Among the 19, incidence of G3/4 neutropenia was 50%, hypertension 26.9%, leucopenia 7.7%. TEAEs (hypertension, ventricular tachycardia, pulmonary edema) leading to treatment discontinuation were reported in 1 pt. Two pts had at least one SAE. No treatment-related deaths occurred. Pt reported outcomes using NCI PRO-CTCAE revealed no differences in appetite, nausea, respiratory symptoms, edema, palpitations, rashes and dry skin, or concentration from BL to end of C4. Pts had worsening hair loss from BL to end of C4. Ki67 analysis indicated CCCA in 78% at C1D15, compared to 18% at surgery after only P had been discontinued approximately 4 weeks prior to surgery. RNA sequencing was performed on available biopsies collected at BL (N=16), C1D15 (N=5), and surgery (N=2) from 16 pts. Among 16 BL samples, PAM50 subtyping identified 5 (31.3%) basal-like, 2 (12.5%) HER2-E, 6 (37.5%) Lum B, and 3 (18.8%) normal. Subtype switching to Lum A at C1D15 (N=3, 1 each with HER2-E, Lum B, and normal at BL) or normal (N=2, 1 basal and 1 HER2-E at BL) was observed. 161 genes were differentially expressed (FDR p<0.05); 145 downregulated and 16 upregulated comparing C1D15 to BL. MKI67, TK1, CCNB1, AURKB, PLK1 were among the downregulated genes, consistent with CCCA for majority of the samples at C1D15 by Ki67. Analysis of the Molecular Signatures Database Hallmark gene-sets comparing C1D15 and BL samples demonstrated downregulated biological processes involved in proliferation (E2F targets, G2M checkpoint, MYC targets, mitotic spindle), signaling (Estrogen response, mTORC1 signaling), and DNA damage (DNA repair) at C1D15, consistent with the mechanisms of action of the study drugs. E2F targets were higher in BL samples of RCB II/III, compared to RCB I (FDR p=0.042). Conclusions PALTAN did not meet its primary endpoint of pCR. Neoadjuvant PLT showed a pCR of 7.7% but was well tolerated. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments, despite significant heterogeneity of intrinsic subtypes. Clinical trial information: NCT02907918. Citation Format: Foluso O Ademuyiwa, Donald Northfelt, Tracey O'Connor, Ellis Levine, Jingqin Luo, Yu Tao, Jeremy Hoog, Marie Laury, Tracy Summa, Trish Hammerschmidt, Zhanfang Guo, Ashley Frith, Katherine Weilbaecher, Mateusz Opyrchal, Rebecca Aft, Katherine Clifton, Rama Suresh, Nusayba Bagegni, Ian S Hagemann, Cynthia X Ma. Phase 2 study of neoadjuvant palbociclib, letrozole, and trastuzumab in patients with ER+ HER2+ breast cancer (PALTAN) [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 P2-13-01.

The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.