Haddad, T. C.

Abstract Background: The PALLAS trial (ABCSG-42, AFT-05, BIG-14-03) investigates adjuvant palbociclib plus endocrine therapy (ET) versus ET alone in patients (pts) with HR+/HER2− early breast cancer. While palbociclib improves outcomes in metastatic settings, final analysis from PALLAS did not demonstrate benefit in survival outcomes from the addition of palbociclib to ET. A number of pts discontinued palbociclib before the planned 2 year duration though degree of palbociclib exposure was not associated with clinical outcomes. This analysis explores factors predictive of palbociclib early discontinuation and dose reductions, including baseline characteristics, toxicities, and patient-reported outcomes (PROs). Methods: Using the safety population of 5736 pts (2840 receiving palbociclib + ET), we assessed early palbociclib discontinuation within a competing-risks framework (competing events: progression, death). Cumulative incidence curves (Aalen-Johansen estimates) and cause-specific hazard models were used to explore associations with clinical and demographic factors (age, menopausal status, stage, race, endocrine therapy type), key toxicities (neutropenia, anemia, nausea), and baseline PROs (patient assessed quality of life [QoL], anxiety, fatigue, pain, frailty/ dependency, depression, and low income. financial difficulties). An automated model selection based on the Akaike information criterion (AIC) starting from the cause-specific hazard model incorporating all considered predictors including PROs. Results: Early discontinuation of palbociclib not due to progression or death occurred in 1171 pts (41.3%); an additional 343 pts (12.1%) stopped due to results of a futility analysis. In 108 (3.8%) and 2 (0.1%) pts treatment was discontinued due to progression or death. Median time to early discontinuation was 7.7 months in pts that discontinued treatment (median interquartile range 3.45-13.60). Very early discontinuation (≤3 months) occurred in 261 pts (9.2%). Dose reductions to 100mg and 75mg occurred in 1566 pts (55.2%) and 951 pts (33.6%) of 2840 pts, respectively. In univariable analyses, higher age, lower N-stage, and specific baseline PROs (baseline QoL, fatigue, anxiety, depression, frailty/ dependency and financial difficulties) were linked with increased risk of discontinuation. The best-fitting multivariable model identified age, nodal stage (N-stage), low quality of life (QoL), and low income as key predictors of early treatment discontinuation. Conclusions: In the PALLAS trial, our findings highlight the importance of integrating PROs into risk prediction of early treatment discontinuation. Additionally, when starting pts on oral targeted therapies in the adjuvant setting, symptom control, social work and financial counseling resources may support pts at higher risk of non-adherence. This is in line with findings from the ESMO Breast QoL analysis (Bjelic-Radisic et al.), which emphasized the added value of subjective patient-reported outcomes alongside objective clinical parameters in understanding treatment burden and adherence. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT02513394. Citation Format: M. Vetter, A. Wiencierz, M. Gnant, D. Hlauschek, C. Kurzeder, C. Grasic Kuhar, N. Zdenkowski, E. Shinn, J. Suga, D. Egle, J. Meisel, S. Antolin-Novoa, E. Munzone, T. Haddad, S. Loibl, A. Holynskyj, C. Fesl, A. Dueck, A. DeMichele, E. Mayer, on behalf of the PALLAS groups and investigators (ABCSG, AFT, BIG,PReCOG, GBG, NSABP). Predictors of early discontinuation of adjuvant palbociclib in early HR+/ HER2- breast cancer: final analysis of the PALLAS trial integrating patient-reported outcomes [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 PS3-07-14.

Abstract Background: Fatty Acid Synthase (FASN) is a key lipogenic enzyme co-regulated with HER2 and highly expressed in ER+ and HER2+ BC. Its targeting downregulates HER2 expression. Our preclinical studies revealed that FASN inhibition can sensitize or restore sensitivity to trastuzumab, paclitaxel and ET in HER2+ BC models. Denifanstat (deni, formerly TVB-2640) is a novel FASN inhibitor that demonstrated promising clinical activity and safety in a prior phase I trial as either monotherapy or in combination with paclitaxel. The primary objective of this study was to evaluate the objective tumor response rate (ORR) of deni plus trastuzumab (H) in combination with paclitaxel (T) or ET. Methods: Two independent, phase II clinical trials were initiated to assess the efficacy and safety of deni plus H in combination with T (Cohort A) or ET (Cohort B). Key inclusion criteria included HER2+ MBC resistant to HER2-directed therapy, measurable disease, unlimited ET, ≤6 prior chemotherapy or antibody drug conjugate regimens, and confirmation of HER2+ MBC on a pre-registration biopsy. Deni was administered 100 mg/m2 orally once daily. HP or H plus ET (fulvestrant or aromatase inhibitor) was administered at standard dose and schedule. Blood was collected on Cycle 1 Day 1 (C1D1), C1D8 and C2D1 for serum FASN analysis. An additional MBC tumor biopsy was collected on C2D1 for correlative studies. A 2-stage Simon design with a safety-run in was used to test the null hypothesis that the true ORR is at most 5% against the alternative it is at least 20%. With a sample size of 32 patients (pts) per cohort, if ≥4 responses are seen, this design has a 90% chance of rejecting the true ORR is <5% when the true ORR is ≥20% at a 0.10 level of significance. The decision to close both trials to enrollment early was multifactorial. Results: From August 2017 - February 2024, 33 pts with HER2+ MBC pre-registered, among which 17 were eligible and 16 were evaluable (15 pts in Cohort A and 1 pt in Cohort B). The most common reason for ineligibility was HER2-negative status on central review of the pre-registration biopsy. Median age was 57 years (range 35-80). All pts were non-Hispanic and 13 (81.3%) were White. Median prior lines of therapy was 5 (range 0 - 11). In Cohort A, there were 5 partial responses; thus, the primary endpoint was met with the ORR estimated to be 33.3% (90% CI: 14.2-57.7%). The median PFS time was 7.0 months (95 %CI: 3.7 - 11.3), and median OS was 25.7 months (95%CI: 10.2 - NE). No dose limiting toxicities were observed during the C1 safety run-in (6 pts). In Cohort A, 7 (46.7%) developed a grade 3 or 4 adverse event (AE) attributed to combination therapy. Grade ≥2 AEs regardless of attribution occurring in ≥20% of all pts included anemia, fatigue, neutropenia, palmar plantar erythrodysesthesia (PPE), and peripheral neuropathy. Treatment was discontinued due to progression (12; 80%) or AE (3; 20% - pneumonitis; neuropathy; PPE). In Cohort B, the pt maintained stable disease through 8 cycles with grade 3 ALT increase, and she remained alive 31.2 months post-registration. Median C1D1 FASN level was 32.7 ng/mL (IQR: 18.7 - 49.6 ng/mL). There was minimal association between C1D8 and C2D1 FASN levels and time to disease progression (C1D8 n=9, Spearman rank correlation coefficient (r s) = 0.040; C2D1 n=13, r s = -0.019). Analyses of changes in MBC tumor expression of FASN, phospho-AKT, and phospho-S6 are in progress. Conclusion: Deni combined with HP provided clinical antitumor activity in pts with HER2+ MBC resistant to trastuzumab. Expected paclitaxel-associated AEs were observed. Nearly half of pts experienced a grade 3 or 4 AE attributed to the combination therapy, and 20% stopped treatment due to AE. Further study of deni, H plus ET is necessary to draw safety and efficacy conclusions. Citation Format: T. C. Haddad, V. J. Suman, R. R. Roa, B. J. Ernst, R. Lupu, T. Vander Steen, M. H. Solanki, M. Keeney, D. W. Northfelt, K. S. Anderson, T. J. Hobday, S. Chumsri, J. E. Hoppenworth, J. L. Carroll, K. V. Giridhar, C. C. O’Sullivan, R. A. Leon-Ferre, M. P. Goetz. Phase II Trial of the FASN Inhibitor, Denifanstat (TVB-2640), Plus Trastuzumab in Combination with Paclitaxel or Endocrine Therapy (ET) in Patients with HER2+ Metastatic Breast Cancer (MBC) Resistant to Trastuzumab [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 PS5-01-16.

Abstract As shown by the TAILORx and RxPONDER trials, recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, it also identifies certain subsets of premenopausal pts who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, we question whether the noted ACT benefit in TAILORx/RxPONDER may have been the result of chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET v ACT+OFS+ET. We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. The HRQOL substudy will assess differences between arms in severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS). Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ∼95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ∼11 yrs after study initiation. Accrual is 292/3,960 (from 8/2023 to 5/2025). Among 148 pts with OFS data available, 79 (53.4%) were prescribed goserelin and 69 (46.6%) leuprolide. A monthly dosing schedule was prescribed for 86.1% of pts receiving goserelin and 73.5% of those receiving leuprolide; the remaining received a 3-monthly schedule. NCT05879926 Support: U10 CA180868, -80822, UG1 CA189867, U24 CA196067 Citation Format: S. Swain, G. Tang, S. L. Puhalla, P. A. Ganz, N. L. Henry, R. S. Cecchini, S. A. Reid, P. Rastogi, C. E. Geyer, Jr., J. R. White, A. S. Clark, T. C. Haddad, G. A. Vidal, N. Wolmark, E. P. Mamounas. NRG-BR009: A phase III trial evaluating addition of adjuvant chemotherapy to Ovarian Function Suppression + Endocrine Therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer and recurrence score ≤25 (OFSET) [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 PS5-07-04.

Abstract Background: Tumor-infiltrating lymphocytes (TILs) in HER2+ and triple-negative breast cancer (BC) are prognostic and associated with therapy response; however, there are few data regarding distribution and significance of TIL values in ER+ HER2-negative (HER2-) MBC patients (pts) treated with CDK4/6 inhibitors (CDK4/6i). CDK4/6 inhibition may promote antitumor immunity by production of type III interferons and tumor antigen presentation, and by inhibition of regulatory T cells (Goel, Nature 2017). Further, the addition of immune checkpoint therapy to palbociclib numerically prolonged PFS in the 2nd line (2L) setting (Mayer, JCO 2024). We aimed to investigate the prognostic role of TILs derived from fresh metastatic tumor biopsies in pts with ER+HER2- MBC prior to starting CDK4/6i and endocrine therapy (ET) in the first line (1L) and 2L setting. Methods: PROMISE (NCT0281902) is a multicenter, prospective study that enrolled women commencing the CDK4/6i palbociclib (Pb) with letrozole (1L) or fulvestrant (2L) for HR+HER2- MBC. The primary goal was to identify novel genomic variants and pathways associated with PFS. Here, we performed a secondary analysis to quantitate stromal TILs using protocol mandated pretreatment tumor biopsies and determine their association with PFS. Using the Kaplan-Meier method, we reported median PFS (mPFS) and 3-year PFS percentage (%) (95% confidence intervals [CIs]) by TILs [≥20% vs <20%] separately within 1L and 2L. As sample TIL values were generally concentrated at zero (27/58 = 46.6%), coupled with wide spread of sample TIL values ≥20% [range: 20%- 80%], we applied a ≥20% threshold for PFS analysis (high vs low TIL group) as described by Luen, Salgado et al. Lancet Oncol 2017. Statistical significance was based on the Wilcoxon test of the null hypothesis that there was no difference in the PFS curves by TILs. PFS is reported at median follow-up of 21 months. Results: Pretreatment tumor biopsies from 58/68 (85.3 %) pts were evaluable (42 in 1L and 16 in 2L). Median [Q1, Q2] TIL values were higher in 1L (5% [0, 10]) vs 2L (0% [0, 15]). The most common biopsy sites were bone (44.8%), lymph node (17.2%), liver (17.2%) and breast (12%). Overall, TILs frequency (>20%) by the 4 most common biopsy sites were bone (2/20, 10%), lymph node (4/7, 57%), liver (2/6, 33%), and breast (1/7, 14%). In 1L, although PFS was not significantly different (P = 0.237), mPFS (44 vs 34 months) and 3-year PFS 75.0%, [95% CI: 50.3%, 100%] vs 46.4% [95% CI: 31.0%, 69.5%]) were longer in pts with high versus low TILS, respectively. In 2L, the 3-year PFS was numerically similar comparing high and low TILs groups, (25.0%, [95% CI: 4.6%, 100%] vs 22.5% [95% CI: 6.7%, 76.1%]) with no significant difference in PFS (P = 0.761). Conclusions: In pts with ER+HER2- MBC treated with Pb and ET, PFS was numerically longer comparing high vs low TIL values in 1L but not 2L settings. Future studies evaluating TILs in larger datasets are needed to validate these findings. Genomic analysis (DNA/RNA) and its association with TIL levels is underway and will be presented at the meeting. Funding: The Center for Individualized Medicine, Mayo Clinic; Mayo Clinic Breast Specialized Program of Research Excellence (SPORE P50CA116201); Mayo Clinic Cancer Center (CA15083-40A2); TEMPUS (https://www.tempus.com/) and Conquer Cancer Foundation of ASCO (Career Development Award 2018, Dr. O’Sullivan) Citation Format: C. C. O'Sullivan, A. M. Moyer, A. Nassar, D. M. Zahrieh, V. Suman, X. Tang, K. J. Thompson, R. C. Hentz, J. J. Harrington, A. Moreno-Aspitia, D. W. Northfelt, T. C. Haddad, S. Chumsri, P. P. Peethambaram, K. J. Ruddy, K. V. Giridhar, R. A. Leon-Ferre, R. Weinshilboum, L. Wang, K. R. Kalari, M. P. Goetz. Tumor-infiltrating lymphocytes in advanced ER-positive, HER2-negative breast cancer prior to treatment with palbociclib and endocrine therapy: a retrospective analysis of the PROMISE study [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 PS1-10-22.

Abstract Background: Aurora kinase A (AURKA) plays an integral role in the mitotic cell cycle, regulating spindle assembly, centrosome function, chromosome alignment, and mitotic entry. In addition to its mitotic role, activated AURKA has been shown to induce epithelial-mesenchymal transition reprogramming and contribute to endocrine resistance in ER+ breast cancer (BC) models. Amplification/overexpression of AURKA is linked to poor prognosis across multiple tumor types, including ER+/HER2- BC. Alisertib is a selective, reversible, ATP-competitive AURKA inhibitor that has been shown to disrupt spindle formation, leading to mitotic defects and cell death. In xenografts, the potent inhibition of AURKA by alisertib led to antitumor activity across a variety of tumor types. Preliminary clinical data with alisertib have shown significant antitumor activity and a manageable safety profile in patients with various cancers, including ER+/HER2- BC. This study aims to better characterize the role of alisertib in patients with BC to provide a rationale for future clinical studies. Methods: Three studies evaluating alisertib in patients with ER+/HER2- MBC have been completed, including a phase I study of alisertib + fulvestrant (Haddad 2018), a phase II alisertib monotherapy study (Melichar 2015), and a phase II study of alisertib ± fulvestrant (TBCRC 041; Haddad 2023). Descriptive summary statistics were utilized for patient characteristics, as well as clinical safety and efficacy data. Results: A total of 126 patients were enrolled and evaluable in the 3 clinical studies, as per Table 1. All patients had MBC and received prior endocrine therapy and chemotherapy. All patients in TBCRC 041 also received a prior CDK4/6 inhibitor (CDK 4/6i). In these heavily pretreated patients, tumor objective response rates (ORR) were ∼20%, and 6-month clinical benefit rates (CBRs) were 29-78%. The most common grade 3/4 adverse events (AEs) across studies were hematologic AEs (neutropenia, leukopenia, and anemia), and fatigue. In TBCRC 041, ctDNA- and tumor-derived RNA-Seq-based biomarker assessments are ongoing to investigate associations with clinical benefit from alisertib alone or combined with fulvestrant. Conclusions: Alisertib has shown efficacy and safety across multiple clinical studies in patients with ER+/HER2- MBC and could provide a novel option for treating those who have progressed on endocrine therapy and a CDK 4/6i. These findings provide a strong rationale for further development of alisertib in this patient population. The ongoing phase II ALISCA-Breast1 study (NCT06369285) is investigating the optimal dose of alisertib in combination with standard endocrine therapies in this setting. Citation Format: T. C. Haddad, K. McCann, P. Advani. The Aurora Kinase A Inhibitor Alisertib Alone or in Combination with Endocrine Therapy for Patients with Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Metastatic Breast Cancer (MBC) [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 PS1-10-03.