Debbie G. J. Robbrecht

CUPISCO (ClinicalTrials.gov identifier: NCT03498521 ) demonstrated longer progression-free survival (PFS) with comprehensive genomic profiling (CGP) and subsequent molecularly guided therapies (MGTs), versus standard platinum-based chemotherapy, in patients with previously untreated, unfavorable cancer of unknown primary (CUP) who reached disease control after induction chemotherapy (three cycles). We report efficacy and safety after >1 year of additional follow-up. Eligible patients were randomly assigned (3:1) to MGT (investigator-chosen after discussion in a molecular tumor board) or three further cycles of chemotherapy. The primary end point was PFS. Secondary end points included overall survival (OS) and safety. At data cutoff (December 6, 2024), 436 patients were randomly assigned (326 to MGT; 110 to chemotherapy). Median follow-up was 37.0 months (range, 0.0-67.8). Updated median PFS was 6.1 months (95% CI, 4.7 to 6.5) with MGT and 4.4 months (95% CI, 4.2 to 6.4) with chemotherapy (hazard ratio [HR], 0.75 [95% CI, 0.59 to 0.95]; P = .017); median OS was 15.2 months (95% CI, 13.9 to 18.4) and 12.8 months (95% CI, 9.8 to 15.4), respectively (HR, 0.79 [95% CI, 0.61 to 1.02]; P = .0689). No new safety signals were identified. These updated results aligned with the primary analysis, demonstrating the benefit of CGP with subsequent MGT and highlighting the importance of incorporating CGP at initial diagnosis to guide treatment decisions for patients with unfavorable CUP.

Supplementary Figure S2. Additional pharmacodynamic results.

Supplementary Figure S3. Pharmacodynamic changes and associated clinical outcomes.

Supplementary Methods. Includes Eligibility criteria for the clinical study, Study Treatment, DLT Criteria, Tumor Response Assessment, and Pharmacodynamic Methods.

Supplementary Table S3. Characterization of patients with partial response.

Supplementary Table S2. Overview of adverse events.

Supplementary Figure S1. Flow chart.

Supplementary Table S1. Representativeness of study participants.

BACKGROUND: International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients. METHODS: In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs). RESULTS: During 12-month follow-up, 237 (7.7%) developed VTE. The germline extended 297-single nucleotide polymorphism score was associated with VTE (HR per point increase, 2.11 [95% CI, 1.45–3.06]), as well as the total number of somatic structural variants (HR per 1000 increase, 1.21 [95% CI, 1.07–1.37]) and 129 somatic mutations (unadjusted P POLR2E (HR, 3.34 [95% CI, 1.68–6.97]), PALM (HR, 3.73 [95% CI, 1.74–7.99]), TBX22 (T-box Transcription Factor 22; HR, 2.47 [95% CI, 1.40–4.35]), and ELANE (HR, 3.22 [95% CI, 1.51–6.87]). To further explore the potential of tumor whole-genome sequencing, prediction models were constructed including selected clinical predictors only (model 1), clinical predictors and germline variants (model 2), and the combination of clinical predictors, germline variants, and 14 top discriminating somatic mutations (model 3). The optimism corrected concordance index was 0.66 (95% CI, 0.62–0.69) for model 1, 0.67 (95% CI, 0.62–0.72) for model 2, and 0.77 (95% CI, 0.72–0.81) for model 3. This was significantly higher than that of the currently endorsed clinical Khorana VTE risk score (concordance index, 0.55 [95% CI, 0.51–0.59]; P <0.005). CONCLUSIONS: These data indicate that tumor whole-genome sequencing may improve VTE prediction by clinical risk scores. Validation studies to confirm these findings are needed.