Abstract
Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy.
Highlights
Immunotherapies have changed the medical management of metastatic cutaneous melanoma fundamentally
We show that quantitative monitoring of circulating tumor DNA (ctDNA), using criteria accounting for digital PCR (dPCR) measurement imprecision, allows the early and specific detection of patients who do not respond to anti-Programmed-Death receptor 1 (PD1) therapy
Forty-nine patients were treated with nivolumab monotherapy and 4 patients were treated with a combination of nivolumab and ipilimumab
Summary
Immunotherapies have changed the medical management of metastatic cutaneous melanoma fundamentally. PD-L1 tumor expression cannot exclude a possible response to anti-PD1 with response rates of 43 to 58% in PD-L1 positive patients, and 13 to 41% in PD-L1 negative patients [1,2,3, 10, 11]. In this context, the identification of non-responders to anti-PD1 is, at the present time, solely based on radiological and clinical monitoring. Some www.oncotarget.com patients can experience pseudo progression which might be difficult to differentiate from true progression and delay the detection of primary resistance to anti-PD1 [12, 13]
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