Julia A. Beaver, MD

A POOLED analysis by the U.S. Food and Drug Administration (FDA) has shown a benefit of treatment beyond disease progression on Response Evaluation Criteria in Solid Tumors (RECIST) in some patients receiving anti–programmed cell death protein 1 (anti–PD-1) antibodies for unresectable or metastatic melanoma. The analysis was reported in The Lancet Oncology by Julia A. Beaver, MD, of the Center for Drug Evaluation and Research, FDA, and colleagues.¹ 

Study Details 

THE STUDY included data from all submissions of trial reports and data to the FDA in support of marketing applications for anti–PD-1 antibodies used alone or in combination in the treatment of unresectable or metastatic melanoma that allowed for continuation of antibody treatment beyond RECIST-defined (version 1.1) disease progression in the anti–PD-1 antibody group and that were approved by the FDA before January 1, 2017. Individual patient data were pooled for patients who received at least one dose of an anti–PD-1 antibody in the included trials. Any patient receiving an anti-PD–1 antibody after the RECIST-defined disease progression date was included in the treatment beyond disease progression cohort. Treatment beyond disease progression response was defined as a decrease in target lesion tumor burden (sum of reference diameters) of at least 30% from the time of RECIST-defined disease progression that did not require confirmation at a subsequent assessment. 

“Treatment beyond progression with anti–PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma….”

— Julia A. Beaver, MD

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Outcomes With Continued Treatment 

A TOTAL 2,624 patients from 8 multicenter trials of pembrolizumab (Keytruda) or nivolumab (Opdivo), including 2 with combined nivolumab plus ipilimumab (Yervoy) treatment, were included in the analysis. A total of 1,361 (52%) had progressive disease on RECIST criteria; of them, 692 (51%) continued anti– PD-1 antibody treatment beyond disease progression and 669 (49%) did not. 

Among 500 patients in the treatment beyond disease progression cohort who were evaluable for response, 95 (19%) exhibited at least a 30% decrease in tumor burden from the time of RECIST-defined disease progression; the 95 patients with such a response represent 14% of the total of 692 patients treated beyond disease progression and 4% of all 2,624 patients receiving anti–PD-1 antibodies. Among the 500 patients, increases in the target lesion tumor burden meeting the threshold of at least 20% occurred in 64 (13%). The median time from RECIST-defined disease progression to a treatment beyond disease progression response was 2.8 months. Treatment beyond disease progression responders received treatment beyond disease progression for a median of 9.4 months, compared with 1.3 months for treatment beyond disease progression nonresponders. 

Analysis of response after RECIST-defined disease progression in the no treatment beyond disease progression cohort was limited to 64 patients who had both target-lesion tumor burden levels recorded at the time of initial RECIST-defined disease progression and additional target lesion tumor assessments during observation before starting any subsequent therapy; of them, 10 (16%) had post–disease progression response. In the entire no treatment beyond disease progression cohort, the median time from RECIST-defined disease progression to the start of subsequent therapy was 0.5 months. 

Overall Survival 

AMONG PATIENTS with RECIST-defined disease progression, the median overall survival was 24.4 months in the treatment beyond disease progression cohort, vs 11.2 months in the no treatment beyond disease progression cohort, and 32.5 months among patients without RECIST-defined disease progression. At the time of data cutoff in the individual trials, death from any cause had occurred in 235 of 652 patients (36%) in the treatment beyond disease progression cohort, 361 of 636 patients (57%) who did not receive treatment beyond disease progression, and 302 of 1,229 patients (25%) who had no disease progression. Immunotherapy as part of subsequent therapy was given to 15% of patients not treated beyond disease progression and 20% of those treated beyond disease progression. 

Adverse Event Profile 

SERIOUS ADVERSE events within 90 days after treatment discontinuation occurred in 295 of the treatment beyond disease progression cohort (43%) vs 362 of the no treatment beyond disease progression cohort (54%). Immune-related adverse events within 90 days after treatment discontinuation occurred in 78 patients (11%) vs 106 patients (16%). In the treatment beyond disease progression cohort, 121 of 692 patients (17%) had a serious adverse event in the period before disease progression, and 163 patients (24%) had a serious adverse event in the period after disease progression up to 30 days after treatment discontinuation. In the treatment beyond disease progression cohort, 4% of patients had an immune-related adverse event before RECIST-defined disease progression, and 4% had an immune-related adverse event in the time after disease progression up to 30 days after treatment discontinuation. 

The investigators concluded: “Continuation of treatment beyond progression in the product labelling of these immunotherapies has not been recommended because the clinical benefit remains to be proven. Treatment beyond progression with anti–PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile.” ■

DISCLOSURE: Dr. Beaver reported no conflicts of interest. 

REFERENCE 

1. Beaver JA, Hazarika M, Mulkey F, et al: Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: A US Food and Drug Administration pooled analysis. Lancet Oncol 19:229-239, 2018.