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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

2021; American Association for Cancer Research; Volume: 81; Issue: 4_Supplement Linguagem: Inglês

10.1158/1538-7445.sabcs20-ps12-02

1538-7445

Jairam Krishnamurthy, Jingqin Luo, Rama Suresh, Foluso O. Ademuyiwa, Caron Rigden, Timothy Reardon, Katherine Clifton, Katherine N. Weilbaecher, Ashley Frith, Anna Roshal, Pavan K. Tandra, Mathew Cherian, Tracy Summa, Shana Thomas, Leonel F. Hernandez‐Aya, Mattias Bergqvist, Lindsay L. Peterson, X. Cynthia,

Chronic Lymphocytic Leukemia Research

Abstract 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 >62% vs the alternative of <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 >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.