Circulating Tumor DNA Early Kinetics Predict Response of Metastatic Melanoma to Anti-PD1 Immunotherapy: Validation Study

Abstract

The ability of early (first weeks of treatment) ctDNA kinetics to identify primary resistance to anti-PD1 immunotherapies was evaluated with a validation cohort of 49 patients treated with anti-PD1 for metastatic BRAF or NRAS-mutated melanoma, alone and pooled with the 53 patients from a previously described derivation cohort. BRAF or NRAS mutations were quantified on plasma DNA by digital PCR at baseline and after two or four weeks of treatment. ctDNA kinetics were interpreted according to pre-established biological response criteria. A biological progression (bP, i.e., a significant increase in ctDNA levels) at week two or week four was associated with a lack of benefit from anti-PD1 (4-month PFS = 0%; 1-year OS = 13%; n = 12/102). Patients without initial bP had significantly better PFS and OS (4-month PFS = 78%; 1-year OS = 73%; n = 26/102), as did patients whose ctDNA kinetics were not evaluable, due to low/undetectable baseline ctDNA (4-month PFS = 80%; 1-year OS = 81%; n = 64/102). ctDNA detection at first-line anti-PD1 initiation was an independent prognostic factor for OS and PFS in multivariate analysis. Overall, early ctDNA quantitative monitoring may allow the detection of primary resistances of metastatic melanoma to anti-PD1 immunotherapies.

Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

“…PET/CT imaging has shown tumor responses with 4–6 weeks of treatment with ICIs in melanoma patients ( 118 ). Sample collection at 2 weeks following treatment found changes in ctDNA that correlated with outcome in ICI therapy of melanoma patients, but earlier time points were not collected ( 75 ). It possible that changes in ctDNA in response to treatment existed sooner, again, earlier, high-frequency sampling is needed to test such hypotheses.…”

“…The extent to which ctDNA levels might be directly affected by tumor cell targeting and/or clearance by immune cells is still an open question. Evidence for this phenomenon however, might be found in studies where ctDNA levels spike within 2 weeks of immune-therapy initiation in metastatic melanoma patients, if and only if, the tumors were responsive ( 75 ).…”

“…Furthermore, patients with ctDNA clearance after detectable pre-treatment levels had the best progression-free and overall survival. A recent study by Herbretreau et al ( 75 ) in patients with metastatic melanoma found that significant increases in ctDNA levels during the first 2–4 weeks of anti-PD1 (with or without anti-CTLA4) allowed early and highly-specific identification of treatment-resistant patients. Furthermore, ctDNA levels that rapidly decreased after starting PD-1 inhibitors were highly predictive of responses consistent with pseudoprogression ( 108 , 109 ).…”

Liquid Biopsy Biomarkers for Immunotherapy in Non-Small Cell Lung Carcinoma: Lessons Learned and the Road Ahead

“…These found that a significant drop in ctDNA levels was associated with clinical response to immunotherapy and prolonged survival [72,73]. These findings have also been validated in metastatic melanoma by digital droplet PCR (ddPCR), where quantitative monitoring of ctDNA revealed that an increase in ctDNA levels by weeks 2 or 4 of treatment was associated with no clinical benefit and eventual disease progression, while no increase in ctDNA was associated with better OS, PFS, and durable clinical benefit [74][75][76]. In NSCLC patients that have undergone primary tumour resection, ctDNA quantification showed that higher plasma ctDNA levels were associated with a worse OS, and increased ctDNA levels could be observed shortly before a patient experienced a relapse [77].…”

Liquid Biopsies in Sarcoma Clinical Practice: Where Do We Stand?

“…An increasing number of studies are using ctDNA mutation analysis to select patients who will benefit from targeted therapy. For various cancer types, circulating tumor DNA profiling has been assessed for select cases who will benefit from therapy and to detect primary resistance to these therapies [36][37][38]. The cobas ® EGFR Mutation Test v2 was the first PCR-based assay approved by the U.S. Food and Drug Administration (FDA) using circulating cfDNA for the detection of mutations in the epidermal growth factor receptor (EGFR) gene to identify patients with metastatic NSCLC eligible for treatment with the TKI erlotinib [2,39].…”