Introduction • Anti-PD1 immunotherapies are drastically changing the current standard of care of metastatic cutaneous melanoma. however, about 60% of the treated patients do not respond to anti-PD1, and atypical radiological responses delays the detection of primary resistances. the objective of this study was to determine whether the quantitative monitoring of circulating tumor DNA (ctDNA) could early predict the tumor response to anti-PD1.

Material and Methods • Fifty-two patients treated with anti-PD1 at Nantes University hospital for metastatic cutaneous melanoma were selected on their BRAF and NRAS mutational status. Plasmas were collected at the initiation of the treatment, at 2 and 4 weeks of treatment, and then every 4 weeks until the progression. Circulating DNA was extracted from 2 ml of plasma. to evaluate specifically the concentration of tumor circulating DNA (ctDNA) fraction, the somatic alterations detected in tissue were quantified by digital PCR (dPCR). Results • ctDNA was detectable at initiation of treatment for 22/52 patients (42%). Absence of detectable ctDNA prior to the treatment was associated with a favorable prognosis in overall survival. During the follow-up, we defined a biological response (bR) as a significant decrease in the amount of ctDNA relative to the baseline level (considering the precision of dPCR measurement) and biological progression (bP) as a significant increase in the amount of ctDNA relative to its nadir. the absence of biological response after 2 weeks of treatment was associated with a lack of clinical benefit of anti-PD1, with a response rate of 0% and PFS all inferior to 120 days (n = 10). In contrast the detection of a bR at week 2 was associated with a response rate of 50% (n = 12). For these patients, detection of bP at 4, 8 or 16 weeks of treatment was 100% predictive of a subsequent progressive disease (n = 6), on average 75 days prior its radiological detection. All patients with a persistent bR beyond the 16th week (n = 6) did not experience any progressive disease and continued sustained responses, with PFS of at least 306 to 755 days (ongoing).

Conclusion • the quantitative monitoring of ctDNA, taking into account the measurement precision of dPCR, allows a specific, sensitive and early detection of non-responsive patients to anti-PD1. we propose a simple and non-invasive test to improve the management and follow-up of patients treated with anti-PD1, for whom predictive markers are still limited.

Keywords: metastatic melanoma; immunotherapy; tumor DNA

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