Serial plasma tumor-informed next generation sequencing as a new efficacy metric to guide immunotherapy treatment discontinuation

Background: Immune checkpoint inhibition (ICI) is a front-line standard-of-care treatment for patients with metastatic melanoma (MM). However, there are critical questions pertaining to optimal ICI management, particularly the ideal duration of therapy, for which biomarker guidance is lacking. Identifying patients who are safely able to receive a shorter course of ICI (<2 years), thereby limiting physical and financial toxicity, is an unmet need. In this non-randomized, prospective interventional trial (NCT06146920) we evaluated the use of the FDA-approved companion diagnostic test, FoundationOne®CDx (F1CDx), and the laboratory developed test FoundationOne®Tracker, a tissue-informed personalized ctDNA monitoring assay, as an efficacy metric to guide treatment discontinuation. Methods: Eligible patients had radiographic evidence of disease control (stable disease or response) on ICI (>12 months but ≤18 months) without the development of dose-limiting immune-related adverse event/s (irAEs). After successful sequencing with F1CDx, the FoundationOne Tracker assay was generated. Patients ctDNA positive were excluded. The ctDNA negative (neg) patients stopped ICI and continued with active surveillance, including standard of care imaging as well as serial ctDNA via FoundationOne Tracker at 1month, 2month, 3month and subsequently every 3months up to 1 year. Patients were followed for an additional year to monitor for recurrence. The primary endpoint was PFS 12-month post-ICI cessation. Results: From March 2024 through September 2024, 12 patients with MM were screened with two becoming ineligible due to development of an irAE prior to ICI cessation and one due to inadequate tissue for F1CDx. Of enrolled patients (n=9), six had cutaneous MM, one mucosal MM and two with MM from an unknown primary. ICI regimens included nivolumab-relatlimab (n=5), ipilimumab-nivolumab (n=2) and pembrolizumab (n=3) with a median duration on therapy of 13.9 mths. The best radiographic response prior to ICI cessation was Partial Response in 6, Complete Response in 3; in those who underwent PET imaging (n=6), 3 had a complete metabolic response (CMR), and 3 had a near-CMR. All patients remained ctDNA neg at 12months post-ICI cessation and after a median of 14.9 months (13.4-19.2) following enrollment, all patients remain ctDNA neg with no clinical or radiographic evidence of progression. Conclusion: ctDNA guided therapy decisions for advanced cancers is an active area under clinical investigation. To our knowledge, this is the first interventional study utilizing ctDNA to discontinue immunotherapy in patients with MM. Although this study was halted early due to programmatic decisions by the sponsor, the data from this small cohort highlights the potential benefit of ctDNA in guiding treatment discontinuation; further prospective study is needed.