Circulating Tumor DNA and Pseudoprogression in Metastatic Melanoma Treated with Anti–PD-1 Antibodies
In a study reported in JAMA Oncology, Lee et al found that measurement of circulating tumor DNA (ctDNA) can help distinguish between pseudoprogression (radiologic progression prior to response) and true progression in patients with metastatic melanoma receiving anti–programmed cell death protein 1 (PD-1) antibody treatment.
Study Details
The study included 125 patients with established BRAF or NRAS mutations treated with pembrolizumab (Keytruda) or nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) between July 2014 and May 2016. Pseudoprogression was defined as radiologic progression not confirmed as progressive disease at the next radiologic assessment.
Plasma samples of ctDNA at baseline and during the first 12 weeks of treatment were assessed. Favorable ctDNA profiles, consisting of undetectable ctDNA at baseline or detectable ctDNA at baseline followed by > 10-fold decrease, and unfavorable ctDNA profiles, consisting of detectable ctDNA at baseline that remained stable or increased, were correlated with response and prognosis.
Pseudoprogression and ctDNA
According to Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 patients (23%). Of the 29 patients, 17 (59%) were aged ≤ 65 years, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the nine patients (7% of the total population) with confirmed pseudoprogression, all had a favorable ctDNA profile.
At a median follow-up of 110 weeks, 7 (78%) of these 9 patients were alive. All but two patients with true progression had an unfavorable ctDNA profile. Sensitivity and specificity of ctDNA for predicting pseudoprogression was 90% and 100%.
One-year overall survival for patients with RECIST-defined progression was 82% among those with a favorable ctDNA profile vs 39% among those with an unfavorable ctDNA profile (hazard ratio [HR] = 4.8, P = .02). In total, partial response was observed in 54 patients (43% of population), and 1-year overall survival was 100% in these patients. Overall survival was longer in patients with a partial response compared with the nine patients with progressive disease and a favorable ctDNA profile (HR = 0.09, P < .01).
The investigators concluded, “The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival.”
The study was supported by the National Health and Medical Research Council, SydneyWest Translational Cancer Research Centre, Sydney Vital–Translational Cancer Research Centre, and Cancer Institute New South Wales.
Matteo S. Carlino, PhD, of the Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, is the corresponding author for the JAMA Oncology article.
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