Serum thymidine kinase activity (TKa) as a potential biomarker in the sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma (SECOMBIT) trial.

Abstract

9522 Background: In melanoma, there is a need for biomarkers for predicting treatment efficacy. Thymidine kinase 1 (TK) is a cytosolic enzyme that plays a pivotal role in DNA synthesis and repair as it is part of the reaction chain to introduce thymidine into the DNA strand. Dividing cells release TK during mitotic exit and TK can be measured in blood as a biomarker of cell proliferation. Elevated levels of TK enzyme activity (TKa) have been detected in blood samples from patients with several tumor types and correlated with disease stage, prognosis, and treatment efficacy. This study is the first to evaluate the role of TKa as a biomarker in a prospective clinical trial in patients with metastatic melanoma, the SECOMBIT study (NCT02631447). Methods: SECOMBIT was a randomized, three-arm, phase II trial where melanoma patients received, in ARM A: BRAF+MEK inhibitors (encorafenib (E) + binimetinib (B)) and at progressive disease (PD), immune checkpoint inhibitors (ICI) (ipimumab (I) + nivolumab (N), in ARM B: I+N and at PD E+B, and in ARM C: 8-week induction of E+B before a planned switch to I+N, and at PD E+B. Serum TKa was analyzed as DiviTum Unit of Activity (DuA) by the FDA cleared and CE-labelled assay (Biovica). Results: Baseline serum TKa was available from 81 (38.8%) of the patients in SECOMBIT, 25, 27 and 29 in ARM A, B and C, respectively. Patients were divided into TKa-HIGH (n=41) and TKa-LOW (n=40) by the median TKa value 110 DuA (range 39-2343, IQR 74-183). The median total progression-free survival (tPFS) was 17 months (95% CI 12 to 22), and the median overall survival (OS) was 19 months (95% CI: 12 to 26) in TKa-HIGH, while the median tPFS and OS were not reached at 76 months in the TKa-LOW group (tPFS: p=0.004 and OS: p<0.001). In ARM A and B, TKa-HIGH patients had significantly worse tPFS and OS while the survival difference between TKa-HIGH and TKa-LOW was not statistically significant in ARM C (Table 1). TKa predicts prognosis independently of LDH in multivariate analysis. Conclusions: Baseline serum TKa levels efficiently predicted the outcome of patients with BRAF V600 mutated metastatic melanoma treated with different sequences of ICI and BRAF+MEK inhibitors. Patients with elevated TKa is an evident poor prognosis group and appears to benefit from the regime received in ARM C, with an 8-week induction of BRAF-MEK inhibitors, before ICI (sandwich approach). TKa merits further study as a potential biomarker in metastatic melanoma. Clinical trial information: NCT02631447 . Survival according to study arm and TKa level. ARM A ARM B ARM C tPFS at 5 years, (rate, 95% CI) TKa-HIGH 10.0 (0-28.6) 38.5 (12.0-65.0) 47.1 (23.4-70.8) TKa-LOW 52.5 (26.8-78.2) 78.6 (57.0-100) 44.4 (4.6-84.2) P value 0.010 0.019 0.51 OS, at 5 years, (rate, 95% CI) TKa-HIGH 20.0 (0-44.7) 38.5 (12.0-65.0) 46.3 (22.2-70.4) TKa-LOW 60.0 (35.3-84.7) 78.6 (57.0-100) 75.0 (50.0-99.5) P value 0.030 0.015 0.11