Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma

J. H. Lee, G. V. Long, S. Boyd, S. Lo, A. M. Menzies, V. Tembe, A. Guminski, V. Jakrot, R. A. Scolyer, G. J. Mann, R Kefford, M. S. Carlino, H. Rizos

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136 Citations (Scopus)

Abstract

Background: Programmed death 1 (PD1) inhibitors are now a foundation of medical management of metastatic melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information. Patients and methods: We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab. Results: ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [hazard ratio (HR) 0.09; P < 0.001 for group A versus C, and 0.16; P < 0.001 for group B versus C]. The median OS was not reached for groups A and B and was 9.2 months for group C (HR 0.02; P < 0.001 for group A versus C and 0.14; P < 0.001 for group B versus C). The poor outcome measures associated with group C remained significant in multivariate analysis adjusted for LDH, performance status, tumour stage and disease volume. The predictive value for ctDNA for response was confirmed in a separate validation cohort (n = 29, P < 0.01). Conclusion: Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.
Original languageEnglish
Pages (from-to)1130-1136
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • circulating tumour DNA
  • immunotherapy
  • PD1 antibodies
  • biomarkers
  • melanoma
  • biomarkers

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