An FDA Pooled Analysis of Patients with Melanoma Treated with an Anti-PD1 Antibody Beyond RECIST Progression

BACKGROUND: Patients who receive immunotherapeutics may develop an atypical response pattern, which warrants further investigation into the potential benefits and risks for patients who continue immunotherapy beyond RECIST-defined disease progression. METHODS: A pooled analysis including all submissions to U.S. Food and Drug Administration (FDA) in support of marketing applications for anti-PD-1 antibodies and approved by FDA for treatment of patients with unresectable or metastatic melanoma (MM) was conducted to evaluate the potential benefits and safety of treatment beyond progression (TBP). Trials had to allow for continuation of the antibody beyond RECIST-defined progression (RECISTPD) in the anti-PD-1 arm. Any patient receiving the anti-PD-1 antibody after their RECISTPD date were included in the TBP cohort and analyzed descriptively at baseline and at time of progression with the cohort not receiving treatment beyond progression (noTBP). Patients in the TBP cohort had target lesion (TL) response after progression analyzed relative to PD and baseline TL burden. FINDINGS: Of 2624 pooled patients receiving immunotherapy, 52% (1361/2624) had progressive disease (PD); of these, 51% (692/1361) received continued anti-PD-1 antibody beyond RECIST-defined progression. Nineteen percent (95/500) of patients in TBP cohort with evaluable assessments experienced a ≥ 30% decrease in tumor burden, when considering burden at RECISTPD as the reference, representing 14% (95/692) of those TBP and 3·6% (95/2624) of all immunotherapy treated patients. Overall survival (OS) was greater in the TBP cohort compared with the noTBP cohort. One of the pooled trials was a double-blind, randomized, active-controlled trial evaluating an anti-PD-1 antibody vs. chemotherapy in which OS appeared similar in both arms for patients treated beyond progression and longer than the noTBP cohorts. Immune-related adverse events (irAE) up to 90-days from discontinuation were similar between the TBP cohort and the noTBP cohort. INTERPRETATION: Continuation of TBP in the product labeling of these immunotherapies has not been recommended as the clinical benefit remains to be proven. TBP with anti-PD-1 antibody therapy may be appropriate for select patients with MM, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile. FUNDING: none