292P - Serum thymidine kinase 1 activity in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first-line with ribociclib (R) and letrozole (L) in the BioItaLEE trial

Background

Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis and cell proliferation. We assessed serum TK1 activity (TKa) as a prognostic and predictive biomarker of response to R+L.

Methods

287 postmenopausal patients (pts) were enrolled in the BioItaLEE trial (NCT03439046). Sera were collected at baseline (D0; n=263), day 15 of cycle 1 (D15; n=245), day 1 of cycle 2 (C2D1; n=241), and at first imaging (FI; n=203). TKa was measured with DiviTum®, an ELISA-based assay, with a limit of detection (LOD) of 20 DiviTum units (Du)/L. The predictive role of TKa dynamics was explored by defining three patterns (P): P1, TKa LOD at C2D1; P3, TKa >LOD at D15 and C2D1. Multivariate Cox models assessed the association between biomarkers and progression-free survival (PFS).

Results

Median follow-up was 26.9 months. High TKa (>median) at D0 was associated with poor prognosis (HR for disease progression 2.21; 95% CI 1.45,3.37; p=0.0002), whereas only 4% of pts with low TKa at FI had concomitant disease progression. Robust and complex TKa dynamics were observed, with a decrease below LOD seen in 85%, 29% and 40% of pts at D15, C2D1 and FI, respectively; 65% of pts with TKa LOD at C2D1 (P2). TKa dynamics were strongly predictive of PFS: P2 indicated a worse outcome vs P1 (HR 2.89; 95% CI 1.57,5.31; p=0.0006), while P3 was associated with shortest PFS (HR 5.65; CI 2.84,11.2; p<0.0001). For pts in P2, low TKa (

Conclusions

TKa appears to be a new promising prognostic, predictive and monitoring biomarker in pts with HR+/HER2- aBC treated with R+L as first-line therapy. Baseline and dynamic TKa changes provided independent information. Lack of TKa suppression at D15, as seen in P3, may indicate enrichment for primary resistance and poor prognosis. TKa rebound at C2D1, as seen in P2, may indicate early adaptation to R+L, while persistent suppression as observed in P1 may identify pts with sustained inhibition and excellent prognosis.

Clinical trial identification

NCT03439046. Actual Study Start Date: February 2, 2018.

Editorial acknowledgement

Medical writing and editorial assistance were provided by Vanesa Martinez Lopez of Novartis Pharmaceuticals Ireland, and supported by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals.

Funding

Novartis Pharmaceuticals.

Disclosure

L. Malorni: Financial Interests, Personal and Institutional, Other, Personal fees and grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Lilly. M. De Laurentiis: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Roche. G. Bianchini: Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Sanofi; Financial Interests, Personal, Other: Exact Science; Financial Interests, Personal, Other: Chugai; Financial Interests, Personal, Other: EISAI. A. Zambelli: Financial Interests, Personal, Other, Advisory board/Consultancy: AstraZeneca; Financial Interests, Personal, Other, Advisory board/Consultancy: Roche; Financial Interests, Personal, Other, Advisory board/Consultancy: Eli Lilly; Financial Interests, Personal, Other, Advisory board/Consultancy: Novartis; Financial Interests, Personal, Other, Advisory board/Consultancy: Pfizer; Financial Interests, Personal, Other, Advisory board/Consultancy: Daiichi Sankyo; Financial Interests, Personal, Other, Advisory board/Consultancy: Merck; Financial Interests, Personal, Other, Advisory board/Consultancy: Exact Sciences. F. Puglisi: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Other, Research grant and personal fees: Roche; Financial Interests, Personal, Other: Eli Lilly; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Ipsen; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Takeda; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Pfizer. G.V. Bianchi: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Eli Lilly. L. Del Mastro: Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Eli Lilly; Financial Interests, Personal, Other: Ipsen; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other, Supporting meetings/Travel: Celgene; Financial Interests, Personal, Advisory Board: Genomic Health; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca. F. Montemurro: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Pierre Fabre. M.A. Colleoni: Financial Interests, Institutional, Research Grant: Roche. C. Zamagni: Financial Interests, Personal and Institutional, Other, Advisory, travel, accommodation, research funding: Roche; Financial Interests, Personal, Other, Advisory: Eisai; Financial Interests, Personal and Institutional, Other, Advisory, travel, accommodation, research funding: Novartis; Financial Interests, Personal and Institutional, Other, Advisory, research funding: AstraZeneca; Financial Interests, Personal and Institutional, Other, Advisory, travel, accommodation, research funding: Pfizer; Financial Interests, Personal, Other, Advisory, travel, accommodation: PharmaMar; Financial Interests, Personal, Other, Advisory, travel, accommodation: Celgene; Financial Interests, Personal, Other, Advisory: Lilly; Financial Interests, Personal and Institutional, Other, Advisory: Amgen; Financial Interests, Personal and Institutional, Other, Advisory, travel, accommodation, research funding: Tesaro; Financial Interests, Personal, Other, Advisory: QuintikesIMS; Financial Interests, Personal and Institutional, Other, Travel, accommodation, research funding: Pierre Fabre; Financial Interests, Personal and Institutional, Invited Speaker, Travel, accomodation, research funding: Istituto Gentili; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: TEVA; Financial Interests, Institutional, Research Grant: Medivation; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Array BioPharma; Financial Interests, Institutional, Research Grant: Morphotek; Financial Interests, Institutional, Research Grant: Synthon; Financial Interests, Institutional, Research Grant: Seattle Genetics. M.E. Cazzaniga: Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Eli Lilly; Financial Interests, Personal, Other, Consulting fees: Pierre Fabre; Financial Interests, Personal, Other, Consulting fees: Novartis; Financial Interests, Personal, Other, Consulting fees: Eisai; Financial Interests, Personal, Other, Consulting fees: Roche. V. Guarneri: Financial Interests, Personal, Other: Eli Lilly; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Roche. D. Castelletti: Financial Interests, Personal, Full or part-time Employment: Novartis. M. Benelli: Financial Interests, Personal, Other: Novartis. M. Di Marino: Financial Interests, Personal, Full or part-time Employment: Novartis. G. Arpino: Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal and Institutional, Other: Eisai; Financial Interests, Personal and Institutional, Other: Pfizer; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: MSD. All other authors have declared no conflicts of interest.