Serum TKa Could Guide Sequencing in BRAF-Mutated Melanoma

Baseline circulating thymidine kinase activity (TKa) can independently predict progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600–mutated metastatic melanoma and identified which patients benefited most from a specific treatment sequence, according to a biomarker substudy of the phase 2 SECOMBIT trial (NCT02631447) published in Clinical Cancer Research.¹

In the randomized 3-arm noncomparative phase 2 SECOMBIT trial, investigators previously found evidence supporting immune checkpoint inhibitors (ICIs) followed by BRAF/MEK inhibition. When looking at those with low vs high serum TKa levels, first PFS at 5 years, total PFS (time from randomization to progression after receiving the second line of treatment in the trial), and OS were improved in the low-TKa group. The TKa-low patients had longer PFS and OS outcomes when receiving ICIs followed by BRAK/MEK or vice versa, but the TKa-high group had improved outcomes with the “sandwich” strategy of BRAF/MEK, then ICI, then BRAF/MEK again at progression vs the other 2 strategies.

Trial Design and Biomarker Analysis

The 3 arms in SECOMBIT consisted of encorafenib (Braftovi) and binimetinib (Mektovi) BRAF/MEK inhibition followed by ipilimumab (Yervoy) plus nivolumab (Opdivo) ICI therapy at progression in arm A, ipilimumab plus nivolumab followed by encorafenib/binimetinib at progression in arm B, and short-term BRAF/MEK-targeted induction therapy followed by ICI, then BRAF/MEK at progression in arm C.² The findings from SECOMBIT as well as DREAMseq (NCT02224781) led to the preference for ICI followed by BRAK/MEK inhibition in patients with BRAF-mutated advanced melanoma.

TKa is a blood-based marker of cellular proliferation released by dividing cells during mitotic exit.¹ It was measured using the DiviTum TKa assay from serum samples collected at baseline, within 4 months of treatment start, and at disease progression. TKa analysis was not a prespecified end point of SECOMBIT; this substudy included 81 patients (38.8% of the SECOMBIT cohort) with baseline serum available for TKa testing using the DiviTum TKa assay. Patients were stratified by median baseline TKa (110 DiviTum units of activity) into TKa-low (n = 41) and TKa-high (n = 40) groups.

Baseline characteristics, including sex, age, tumor stage, and number of metastatic sites, did not differ significantly between the TKa-low and TKa-high groups, though elevated lactate dehydrogenase (LDH) was more common among TKa-high patients (46.2% vs 22.5%; P = .027).

Survival Findings

At a median follow-up of 61 months, TKa-low patients had numerically higher first PFS at 5 years than TKa-high patients (43.3% vs 27.5%; HR, 1.68; 95% CI, 0.97-2.91; P = .062). Total PFS (60.8% vs 35.0%; HR, 2.47; 95% CI, 1.31-4.68; P = .004) and OS (70.7% vs 36.9%; HR, 3.08; 95% CI, 1.54-6.15; P < .001) were both significantly longer in the TKa-low group. In multivariable analysis adjusting for age, sex, tumor stage, number of metastatic sites, and LDH, TKa remained the only baseline factor independently predictive of both total PFS (HR, 2.54; 95% CI, 1.28-5.01; P = .007) and OS (HR, 3.31; 95% CI, 1.57-6.94; P = .002).

TKa and Treatment Sequencing

TKa-low patients had significantly better total PFS and OS than TKa-high patients in arms A and B, with absolute differences at 60 months ranging from 30% to 43%. In arm A, TKa-high patients had a particularly poor outcome, with a total PFS rate of only 10% at 60 months. By contrast, TKa-high patients in arm C, who received short-term BRAF/MEK induction before switching to ICI, had comparatively favorable outcomes relative to TKa-high patients in the other arms; there were no statistically significant differences between TKa-low and TKa-high patients within arm C. The study authors noted this pattern suggests brief targeted therapy induction may temporarily suppress tumor proliferation in patients with aggressive, TKa-high disease, potentially enhancing subsequent benefit from ICI, whereas the ‘sandwich’ approach did not appear to benefit TKa-low patients, for whom upfront ICI produced the best outcomes.

TKa Dynamics Over Time

Longitudinal sampling showed that TKa-low patients tended to have an initial increase in TKa levels early in treatment that leveled off by the time of progression, while TKa-high patients showed a sharp increase in TKa specifically at the time of progression rather than earlier. Among 19 patients with paired baseline and progression samples, 12 (63.2%) had higher TKa at progression than at baseline. The study authors reported that an early TKa increase was more common among patients starting ICI therapy, particularly those with longer first PFS, and proposed this pattern may reflect TKa release from activated, proliferating immune cells rather than solely from dying tumor cells.

Study Limitations and Potential Biomarker Use

The study authors identified the modest cohort size and available serum samples as the main limitation; TKa data were available for only 38.8% of the overall SECOMBIT population, with sequential sampling available in an even smaller subset of 16% at the second time point and 9.2% at the third. The authors characterized the sequential TKa findings as exploratory and hypothesis generating, and they stated that additional research is warranted before TKa can be broadly applied for risk stratification and sequencing of ICI and BRAF/MEK therapy.

A news release from Biovica, the developer of the DiviTum assay for TKa, described the potential of this biomarker to identify patients with more aggressive disease and assist in sequencing, with chief executive officer Theis Kipling, MBA, stating that the publication “highlights the potential of DiviTum TKa to support key decisions in oncology drug development, including patient selection, treatment sequencing and response monitoring.”³

REFERENCES

1. Helgadottir H, Capone M, Ridolfi L, et al. Circulating thymidine kinase activity predicts survival and optimal treatment sequencing in BRAF-mutated metastatic melanoma in the SECOMBIT trial. Clin Cancer Res. Published online August 24, 2026. doi:10.1158/1078-0432.CCR-26-1402

2. Ascierto PA, Casula M, Bulgarelli J, et al. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nat Commun. 2024;15(1):146. Published 2024 Jan 2. doi:10.1038/s41467-023-44475-6

3. New publication broadens the potential of DiviTum TKa in immuno-oncology. News release. Biovica International AB. August 25, 2026. Accessed August 25, 2026. https://tinyurl.com/3kdmj9su