Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma

Abstract

BackgroundRandomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.MethodsData of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (>6 months and <18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy, had prior exposure to PD-1 therapy, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation, progression-free survival (PFS), and retreatment characteristics was analyzed.ResultsOf 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3–49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7–30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.ConclusionIn this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.

Prognoses of patients with melanoma who continue/discontinue anti-programmed death-1 therapy after achieving a complete response in a real-world setting: a multicentre retrospective study

“…Pokorny et al . also reported two (15%) relapses among 13 patients who achieved a CR, 4 and Valentin et al . observed three (12%) patients among 25 who achieved a CR after a median time after anti‐PD‐1 discontinuation of 22·3 months 5 .…”

“…Dear Editor , It is not known how long anti‐programmed death‐1 (anti‐PD‐1) therapy should be continued for patients with melanoma who have achieved a good response. Only a few studies have investigated this topic, and most did not include acral or mucosal melanomas 1–6 . We retrospectively analysed 57 patients with advanced melanoma (including 12 patients with unresectable lymph node involvement) treated with anti‐PD‐1 monotherapy who achieved a complete response (CR) from 16 collaborating institutions treated during the period from 1 September 2014 to 31 July 2019.…”

Factors Determining Long-Term Antitumor Responses to Immune Checkpoint Blockade Therapy in Melanoma

“…Here, the majority of patients with metastatic melanoma following 1 year of anti-PD-1 treatment remained without progression in the long-term follow-up evaluation, with a low risk of disease progression even in patients with residual disease on imaging. Median follow-up in this cohort study was 20.5 months from anti-PD-1 treatment discontinuation with 75% of patients remaining without disease progression, while 25% had disease progression, with a median PFS of 3.9 months (range 0.7–30.9 months) ( 47 ). Given this, elective discontinuation of anti-PD-1 therapy may still achieve favorable long-term outcomes while also reducing the immunotherapy-related toxicities and financial burdens associated with prolonged anti-PD-1 treatment.…”

Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course

“…The 2-year PFS and OS were 64% and 88%, 53% and 82%, 31% and 64% for CR, PR, and SD patients, respectively ( 115 ). Pokorny reviewed 52 metastatic melanoma who responded well to 1-year treatment and selectively discontinue therapy, with a median follow-up of 20.5 months after discontinuation 39 (75%) patients had no disease progression ( 116 ). A study from Memorial Sloan Kettering Hospital showed that CR patients discontinued therapy after a median treatment duration of 9.4 months, with a 3-year PFS of 72.1% and a 3-year OS rate of 82.7% ( 117 ).…”