The introduction of immune checkpoint inhibitors such as anti-PD-1 monoclonal antibodies radically altered the treatment paradigm for advanced melanoma, from a disease with limited treatment options and short survival to one in which durable responses and long-term survival can be achieved. While PD-1 inhibitors have become an essential component of melanoma treatment, little is known regarding the optimal duration of treatment for these agents and if patients with long-term responses can safely discontinue therapy. In a real-world cohort analysis recently published in Annals of Oncology, outcomes were evaluated for 185 patients with advanced melanoma who discontinued treatment with a PD-1 inhibitor in the absence of progressive disease or treatment-limiting toxicity.
Compared to patients that did not discontinue anti-PD-1, patients that electively stopped therapy had lower frequency of BRAF mutation, better performance status, lower tumor stage, lower incidence of brain metastases, and were less likely to have increased CRP or LDH levels.
Prior to treatment discontinuation, patients had received treatment with either pembrolizumab (n = 167) or nivolumab (n = 18) for a median duration of 12 months, either as first-line therapy (43% of patients) or a second-line immunotherapy (49%) or after progression on a BRAF inhibitor (15%). Median duration of anti-PD-1 therapy before elected discontinuation was 12 months for most of the patients, except 26 (14%) who were treated for less than 6 months. At time of anti-PD-1 discontinuation, 63% of patients had achieved complete response (CR), while 24% had a partial response (PR), and 9% maintained stable disease (SD). At a median follow-up of 18 months postdiscontinuation, 22% of patients had progressed. The estimated 1-year and 2-year progression-free survival (PFS) was 90% and 71%, respectively. Progression was significantly less common in patients who achieved a CR prior to discontinuation than in those whose best response was a PR (P = .002) or SD (P<.001). Of note, only 14% of patients who achieved a CR progressed. Treatment discontinuation prior to 12 months was associated with an increased risk of progression, while duration of therapy beyond 12 months did not impact outcomes. Interestingly, prior treatment with ipilimumab and targeted therapy did not impact the risk of disease progression. The median PFS had not yet been reached, and the median time to progression was 12 months. Among 19 patients who were retreated with a PD-1 inhibitor following progression, 6 (32%) obtained a new antitumor response.
In their conclusions, the investigators stated that these data indicate that treatment discontinuation after a year of therapy may be appropriate in patients with advanced melanoma who have achieved a CR on PD-1 inhibitor therapy. However, when recognizing the limitations of a real-world, retrospective analysis; results from prospective, randomized clinical trials will be needed to validate these findings. Currently, three ongoing trials are evaluating treatment discontinuation and immunotherapy duration strategies: STOP-GAP, SAFE-STOP, and DANTE.
Ann Oncol. 2019 March 28. [Epub ahead of print.]