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


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).


CONCLUSIONS
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.
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney.|Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney.|Translational Cancer Research Centre, The University of Sydney at The Westmead Institute, Sydney.
J H
JH
Lee
Melanoma Institute Australia, Sydney.|Sydney Medical School, The University of Sydney, Sydney.|Department of Medical Oncology, Northern Sydney Cancer Centre, Sydney.
G V
GV
Long
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney.
S
S
Boyd
Melanoma Institute Australia, Sydney.
S
S
Lo
Melanoma Institute Australia, Sydney.|Sydney Medical School, The University of Sydney, Sydney.|Department of Medical Oncology, Northern Sydney Cancer Centre, Sydney.
A M
AM
Menzies
Translational Cancer Research Centre, The University of Sydney at The Westmead Institute, Sydney.|Sydney Medical School, The University of Sydney, Sydney.
V
V
Tembe
Melanoma Institute Australia, Sydney.|Sydney Medical School, The University of Sydney, Sydney.|Department of Medical Oncology, Northern Sydney Cancer Centre, Sydney.
A
A
Guminski
Melanoma Institute Australia, Sydney.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
V
V
Jakrot
Sydney Medical School, The University of Sydney, Sydney.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
R A
RA
Scolyer
Translational Cancer Research Centre, The University of Sydney at The Westmead Institute, Sydney.|Melanoma Institute Australia, Sydney.|Sydney Medical School, The University of Sydney, Sydney.
G J
GJ
Mann
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney.|Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney.|Translational Cancer Research Centre, The University of Sydney at The Westmead Institute, Sydney.|Melanoma Institute Australia, Sydney.|Sydney Medical School, The University of Sydney, Sydney.
R F
RF
Kefford
Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney.|Translational Cancer Research Centre, The University of Sydney at The Westmead Institute, Sydney.|Melanoma Institute Australia, Sydney.|Sydney Medical School, The University of Sydney, Sydney.
M S
MS
Carlino
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney.|Melanoma Institute Australia, Sydney.
H
H
Rizos
D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000276:immunology; D014408:Biomarkers, Tumor / Q000097:blood*; D000074141:Circulating Tumor DNA / Q000097:blood*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000074324:Ipilimumab / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000097:blood / Q000188:drug therapy; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
PD1 antibodies; biomarkers; circulating tumour DNA; immunotherapy; melanoma