Abstract PS12-02: Safety and efficacy of an alternative schedule of palbociclib (PAL) in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) and the utility of serum thymidine kinase 1 (sTK1) activity in predicting PAL response
Authors: Krishnamurthy Jairam , Luo Jingqin , Suresh Rama , Ademuyiwa Foluso , Rigden Caron , Reardon Timothy , Clifton Katherine , Weilbaecher Katherine , Frith Ashley , Roshal Anna , Tandra Pavan , Cherian Mathew , Summa Tracy , Thomas Shana , Hernandez-Aya Leonel , Bergqvist Mattias , Peterson Lindsay , Ma Cynthia X 
Published: February 2021

Background: The approved 3 weeks (wks) on/1 wk off schedule of PAL results in grade (G)3+ neutropenia (ANC) up to 66%. We hypothesized that an alternative schedule (Alt Dose Pal), 5 on/2 off every 7 days, reduces the rate of G3+ ANC, allowing continued weekly dosing. In addition, based on our previous study supporting sTK1, an E2F-dependent enzyme critical for DNA synthesis, as a pharmacodynamic indicator of CDK4/6 inhibition, we hypothesized that Alt Dose Pal inhibits sTK1 and sTK1 dynamics predicts PAL response. Methods: A single arm phase II trial was conducted in HR+ HER2- MBC, ≤1 prior endocrine therapy (ET) for MBC (NCT03007979). Pts received PAL 125 mg daily, 5 on/2 off weekly, plus letrozole (LET) or fulvestrant (FUL) per physician choice, on a 28-day cycle (C). Goserelin was added if premenopausal. Complete blood count and chemistry panel were done at baseline (BL), C1&2D15, and D1 of C2+. The primary objective was to determine the rate of G3+ ANC in C1 D1-D29. Secondary objectives were to assess the rate of all cycle G3+ ANC, PAL dose reduction/discontinuation, adverse events (AE) per CTCAE v5, progression free survival (PFS), objective response rate (ORR: CR+PR (complete and partial responses)) and clinical benefit rate (CBR: no progression (PD) in 24 wks) by RECIST 1.1. The sample size of 47 provides 90% power, 1-sample binomial exact test, 5% alpha, to test the 1-sided null hypothesis of G3+ ANC rate &gt;62% vs the alternative of &lt;40%. Serial sTK1 was analyzed at BL, C1D15, C2D1, every 3 cycles with tumor imaging, and at PD, using the DiviTum™ assay. Results: From July 2017 to Feb 2020, 54 pts were enrolled. 3 pts went off in C1, unrelated to study, leaving 51 pts (38 LET, 13 FUL), median age of 62 (range 34-87) years, 8 (16%) premenopausal, 26 (51%) with visceral mets. 22 (43%) and 29 (57%) had adjuvant chemo or ET, respectively. 4 (8%) had 1 prior ET for MBC. 22 (43%) had primary or secondary ET resistance defined by ESMO. 17 (33%) had de novo MBC. The median follow up was 12 months (mo). Treatment is ongoing for 23 (45%) pts. Among 47 evaluable pts, 10 (21.3%, 95% CI: 11.2%-36.1%) had G3 ANC in C1 D1-29, with no G4 AE. 22 of 54 (40.7%; 95% CI: 27.9%-54.9%) had G3 (n=21) or G4 (n=1) ANC in all cycles. 37 pts in C1 and 32 pts in all cycles, were without G3+ ANC, exceeding the predefined boundary for better tolerability. PAL was dose reduced in 11 (20.3%) pts and discontinued in 3 (4.8%) due to AE. Table 1 lists treatment related AEs of &gt;10% or G3+. The ORR was 50% (2 CR, 13 PR, 95% CI: 33.15%-66.85%) in 30 pts with measurable disease (n=29) or non-measurable but CR (n=1). The CBR was 81.63% (95% CI: 67.5%-90.76%) in 40 (2CR, 13 PR, 25 SD ≥24 wks) of 49 evaluable pts. The median PFS (mPFS) was 24.3 mo (95% CI 15~not reached (NR)) overall. The mPFS was 33.5 mo (95% CI 17.3~NR) and 12 mo (95% CI: 10.4~NR), in ET sensitive and resistant population, respectively. sTK1 was significantly reduced, 80% down to undetectable, as early as C1D15 (p=7.77E-07). BL sTK1 levels correlated with PD vs non-PD (p=0.003) as best response and negatively correlated with PFS (p=0.002). sTK1 rose significantly at PD (p=0.0003). A median lead time of 80.6 (IQ range 6.8-189.2) days was observed for rising TK before RECIST PD. Conclusion: The Alt Dose Pal trial met its primary endpoint with reduced G3+ ANC. The efficacy data is comparable to prior reports. sTK1 shows promise for PAL response prediction and monitoring.

Table 1 AEAEG1G2G3G4TotalC1 D1-29 (n=47)Leukopenia13 (27.6%)22 (46.8%)7 (14.9%)042 (89%)Neutropenia6 (12.8%)18 (38.3%)10 (21.3%)034 (72%)Anemia18 (38.3%)5 (10.6%)0023 (49%)Lymphopenia6 (12.8%)8 (17%)2 (4.3%)016 (34%)Fatigue13 (27.7%)00013 (28%)Hot flashes7 (14.9%)0007 (15%)Nausea6 (12.8%)1 (2.1%)007 (15%)Thrombocytopenia5 (10.6%)1 (2.1%)006 (13%)Alopecia5 (10.6%)0005 (11%)Dizziness1 (2.1%)01 (2.1%)02 (4%)All cycles (n=54)Leukopenia10 (18.5%)22 (40.7%)21 (38.9%)053 (98%)Neutropenia4 (7.4%)21 (38.9%)21 (38.9%)1 (1.9%)47 (87%)Anemia29 (53.7%)12 (22.2%)3 (5.6%)044 (82%)Lymphopenia8 (14.8%)16 (29.6%)10 (18.5%)034 (63%)Fatigue19 (35.2%)4 (7.4%)0023 (43%)Nausea19 (35.2%)3 (5.6%)0022 (41%)Alopecia18 (33.3%)00018 (33%)Thrombocytopenia15 (27.8%)01 (1.9%) *016 (30%)ALT elevated3 (5.6%)02 (3.7%)05 (9%)AST elevated4 (7.4%)01 (1.9%)05 (9%)*pt died from subdural hematoma (G5)

Citation Format: Jairam Krishnamurthy, Jingqin Luo, Rama Suresh, Foluso Ademuyiwa, Caron Rigden, Timothy Reardon, Katherine Clifton, Katherine Weilbaecher, Ashley Frith, Anna Roshal, Pavan Tandra, Mathew Cherian, Tracy Summa, Shana Thomas, Leonel Hernandez-Aya, Mattias Bergqvist, Lindsay Peterson, Cynthia X Ma. Safety and efficacy of an alternative schedule of palbociclib (PAL) in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) and the utility of serum thymidine kinase 1 (sTK1) activity in predicting PAL response [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 PS12-02.