Detectable ctDNA at the time of treatment cessation of ipilimumab and nivolumab for toxicity predicts disease progression in advanced melanoma patients

Lydia Warburton; Anna Reid; Benhur Amanuel; Leslie Calapre; Michael Millward; Elin Gray

doi:10.3389/fonc.2023.1280730

Detectable ctDNA at the time of treatment cessation of ipilimumab and nivolumab for toxicity predicts disease progression in advanced melanoma patients

Front Oncol. 2023 Dec 19:13:1280730. doi: 10.3389/fonc.2023.1280730. eCollection 2023.

Authors

Lydia Warburton^{1

2}, Anna Reid^{1

3}, Benhur Amanuel^{4

5}, Leslie Calapre^{1

3}, Michael Millward⁶, Elin Gray^{1

3}

Affiliations

¹ Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia.
² Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, WA, Australia.
³ School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
⁴ Anatomical Pathology, PathWest, Queen Elizabeth II (QEII) Medical Centre, Nedlands, WA, Australia.
⁵ School of Biomedical Science, University of Western Australia, Crawley, WA, Australia.
⁶ School of Medicine, University of Western Australia, Crawley, WA, Australia.

Abstract

Background: Immune checkpoint inhibition (ICI) has led to unprecedented outcomes for melanoma patients but is associated with toxicity. ICI resumption after high grade irAEs poses a significant challenge in the clinical management of melanoma patients and there are no biomarkers that can help identify patients that might benefit from resuming treatment. This study aims to determine if circulating tumor DNA (ctDNA) levels at the time of treatment-limiting irAE could guide treatment decisions in this clinical context.

Methods: This is a retrospective exploratory biomarker study from 34 patients treated with combination ICI for stage IV melanoma. Patients had a treatment-limiting toxicity and a baseline plasma collection prior to commencing ICI and within 6 weeks of stopping therapy. Blood samples were tested for ctDNA at baseline and cessation therapy.

Results: Median progression free survival (PFS) and overall survival (OS) have not been reached (24-month PFS rate 54% and OS rate 72.3%). PD occurred in 47% (16/34) of patients. Median PFS with detectable ctDNA from plasma collected at the time of toxicity was 6.5 months while not reached (NR) with undetectable levels (HR: 4.0, 95% CI 0.95-17.5, p=0.0023). Median OS with detectable ctDNA at cessation for toxicity was 19.4 months and NR for undetectable ctDNA (HR: 3.9, 95%CI 20.8-18.6, p=0.024). Positive ctDNA at the time of cessation was highly specific (specificity 0.94, 95% CI 0.74-0.99, PPV 0.88, 95% CI 0.53-0.99). However, ctDNA negativity has low sensitivity as a predictor of ongoing disease control (sensitivity 0.437, 95% CI 0.23-0.67). Notably, 4/9 (44%) ctDNA negative patients who had disease progression had brain only disease progression.

Conclusions: Undetectable ctDNA and CR on imaging after stopping immunotherapy for toxicity results in high rates of long-term durable control. For patients with immunotherapy related toxicity, who have persistent ctDNA at 8 - 12 weeks, the risk of disease progression is significant.

Keywords: CtDNA; biomarkers; immunotherapy; melanoma; therapy cessation; toxicity.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. LW is a recipient of a Future Health Research and Innovation fund/Raine Clinician fellowship. LW is a recipient of an NHMRC postgraduate scholarship (1190643). EG is supported by a fellowship from Cancer Council WA. This research was funded by an NHMRC Grant (1117911) obtained by MM, BA, and EG, a Cancer Council Grant (1100249) awarded to EG, and MM; and grants from the Department of Health Western Australia, the Spinnaker Foundation and the Perpetual Foundation awarded to EG, MM, LW, and BA.