Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma

Abstract

Background: Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods: This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N ¼ 167) or nivolumab (N ¼ 18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results: Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions: In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients.

Site‐specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti–PD‐1 therapy

“…In our cohort, one‐half of the patients who developed acquired resistance were off treatment at the time of progression because of toxicity. The mechanisms responsible for resistance in this setting may be different from those in patients who develop acquired resistance while on treatment; however, response rates in those retreated with PD‐1 immunotherapy who progress while off treatment are low . All patients but 1 received further systemic and/or local therapy, with a 1‐year (from progression) OS rate of 83%.…”

Metastatic melanoma: can FDG-PET predict success of anti-PD-1 therapy and help determine when it can be discontinued?

“…After a median follow-up of 18 months from treatment discontinuation, the risk of progression among patients with CR (n = 117) was 14% (with higher relative risk in patients treated for < 6 months), while its was 32% among patients (n = 44) with PR [42]. The probability of response to retreatment with an anti-PD-1 was low (32%) [42].…”

“…The outcomes after discontinuation of anti-PD-1 treatment has also been studied in patients with partial response (PR) [2,42]. In KEYNOTE-006, among patients who completed 2 years of pembrolizumab, there were 69 patients who achieved PR, while 13 had stable disease (SD).…”

“…Estimated 24-month PFS was 82.3% for patients with PR as compared with 39.9% for patients with SD [2]. A large retrospective multicentric study investigated the outcome of patients who electively discontinued anti-PD-1 therapy w ith pembrolizumab or nivolumab outside clinical trials [42]. After a median follow-up of 18 months from treatment discontinuation, the risk of progression among patients with CR (n = 117) was 14% (with higher relative risk in patients treated for < 6 months), while its was 32% among patients (n = 44) with PR [42].…”

Possibilities of Improving the Clinical Value of Immune Checkpoint Inhibitor Therapies in Cancer Care by Optimizing Patient Selection

“…The results of the study showed that PFS was inferior for patients whose therapy was discontinued but OS was similar [150]. In addition, data from retrospective studies have shown that discontinuing anti-PD-1 therapy in response does not lead to rapid disease progression [151][152][153]. However, there is a strong need for high-quality evidence to define early stopping rules.…”