A Pilot Study of ctDNA-Guided Immune Checkpoint Inhibitor Duration in Patients With Advanced Melanoma.

This is a study of patients with advanced melanoma who are potentially eligible to stop or shorten their duration of ICI. Patients with radiographic disease control and/or response with undetectable ctDNA levels will stop ICI therapy after 1 year. Patients who have responded to ICI but have experienced immune-related adverse events (irAE) requiring treatment interruption and immunosuppression are also eligible and will stop ICI therapy if ctDNA is undetectable. All patients with undetectable ctDNA who candidates are to stop treatment will undergo monitoring with standard of care imaging and ctDNA assessments every three months to assess for the primary outcome of the 12-month sustained ctDNA negativity rate. Undetectable ctDNA for the purposes of the treatment duration decision time point is defined as two consecutive negative ctDNA tests performed at least 4 weeks apart.

If ctDNA is detectable at the treatment duration decision time point, treatment will be continued as per an investigator's choice regimen. In patients whose ctDNA converts from undetectable to detectable during the monitoring period, the investigator may choose to restart ICI based upon imaging findings and/or other relevant clinical factors.

Inclusion criteria

• Age > 18 with any subtype of unresectable stage III or stage IV melanoma treated with anti-PD-1-based ICI which includes both anti-PD-1 monotherapy and dual checkpoint inhibitor regimens such as ipilimumab plus nivolumab and nivolumab plus relatlimab.

Disease control after at least 6-12 months of anti-PD-1-based ICI defined as a radiographic RECIST CR, PR, or SD and planned for at least 1 year of treatment

OR

Development of an irAE(s) on an anti-PD-1-based regimen requiring treatment interruption and immunosuppression where the investigator is considering treatment discontinuation. Patients must have a radiographic RECIST PR or CR at the treatment duration decision time point.

• Any line of therapy, with the exception of adjuvant therapy.
• Ability to understand and the willingness to sign a written informed consent document.
• Patients with brain metastasis may be included only if there was also presence of extracranial disease.
• ECOG performance status 0-2.

Exclusion criteria

• Participants who are receiving investigational therapies.
• Inadequate tumor quantity or quality to conduct initial Signatera ctDNA testing.
• Intracranial-only metastatic melanoma.
• Patients with best response of progressive disease at time of screening.
• Patients who have had their melanoma completely surgically resected such that response to immunotherapy is no longer evaluable.
• Patients who are unwilling to continue or stop ICI therapy using ctDNA guidance in combination with imaging response.
• History of a life-threatening or severe irAE that would make ICI rechallenge unsafe. These cases will be discussed with the Principal Investigator.
• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.