Longitudinal Monitoring of ctDNA in Patients with Melanoma and Brain Metastases Treated with Immune Checkpoint Inhibitors

Abstract

PurposeBrain involvement occurs in majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation. Experimental DesignThis study examined circulating BRAF, NRAS and c-KIT mutations in melanoma patients with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analysed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/ml plasma). ResultsOf a total of 72 patients; 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (p < 0.01).Undetectable ctDNA on-therapy was associated with extracranial response (p < 0.01) but not intracranial response. The median overall survival in patients with undetectable (n = 34) versus detectable (n = 38) ctDNA at baseline was 39.2 versus 10.6 months (HR 0.51 [95% CI 0.28 -0.94], p = 0.03) and on-therapy was 39.2 versus 9.2 months (HR 0.32 [95% CI 0.16 -0.63], p < 0.01). ConclusionctDNA remains a strong prognostic biomarker in melanoma patients with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.

Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy

“…This is the minimum ctDNA concentration that could be reliably detected given that ctDNA was isolated from 1-5 mL of plasma, eluted in 30-60 mL, an input of 5-8 mL in the ddPCR reaction and using different copies per mL of plasma (copies/mL) as threshold based on specific assays (Supplementary Table S2; refs. [16][17][18][19]. We confirmed the suitability of this cut-off value through ROC curve analysis using the discovery cohort data for prediction of 6-month PFS (Supplementary Fig.…”

“…We compared the predictive value of pretreatment ctDNA levels to inform survival outcomes in patients with metastatic melanoma receiving first-line or second-line systemic ICI. Our observations were validated using published datasets from two independent cohort studies (16)(17)(18)(19).…”

“…The brain is a common site of targeted therapy failure, often contributing to death (29). Given that brain metastases have been reported to shed less ctDNA into the circulation (18,30), the large proportion of disease progression within the brain, may contribute to the limited predictive value of ctDNA in this setting. In line with this, removal of patients with only intracranial metastases from the analysis improved the ctDNA predictive value in the validation cohort.…”

“…We pooled data from two independent cohorts of 128 unresectable stage III (n ¼ 3) and stage IV melanoma (n ¼ 125) patients recruited from the Melanoma Institute Australia (NSW) affiliated hospitals and Peter MacCallum Cancer Centre (Victoria, Australia), as described previously by Lee and colleagues (16)(17)(18) and Wong and colleagues (19). Additional details and patient characteristics are shown in Fig.…”

Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma

“…All 13 patients who contributed blood samples had undetectable ctDNA either during, at completion or after cessation of therapy. Unfortunately it appears that a limitation of ctDNA is in its detection of intracranial disease, likely accounting for the unmeasurable levels in both patients #6 and #7 who recurred intracranially 41 – 43 .…”