Fig. 4. Representative cases illustrating early molecular progression as indicated by elevated ΔVAF_mean and %Δt-MAD.

a Patient ALK_18 presented a case—during lorlatinib therapy—where both ΔVAF_mean and %Δt-MAD were informative of the lead time. Early molecular progression was apparent 129 days prior to clinical progression, as indicated by ΔVAF_mean of 0.13% and %Δt-MAD of 25%. Both values surpass the NGS metric thresholds identified in this study. b Patient ALK_04 depicts a case wherein ΔVAF_mean indicated early molecular progression during alectinib therapy. A ΔVAF_mean of 0.14% was calculated 41 days prior to clinical progression. c Patient ALK_37 emphasizes the relevance of untargeted NGS in ctDNA monitoring particularly in cases where genetic alterations remained undetected by tNGS. Here, %Δt-MAD of 46% was already apparent at a stable disease time point, 64 days prior to clinical progression. PD progressive disease, SD stable disease, BPD brain PD, TPD thoracic PD, R response, CBDP treatment continuation beyond disease progression, RT radiotherapy, CTx chemotherapy, ImmTx immunotherapy.