Patients with melanoma who continued treatment with anti-PD-1 therapy following disease progression demonstrated decreased tumor burden and prolonged survival compared with patients who stopped treatment, according to results of a pooled analysis.
Typically, researchers of clinical trials use RECIST v.1.1 criteria to characterize clinical activity of immunotherapy agents and to inform decisions about continuing treatment beyond progression.
However, patients treated with immunotherapy might develop an atypical response pattern, meaning they initially show disease progression per RECIST, but later demonstrate decreased tumor burden.
“In view of the uncertainty regarding whether treatment discontinuation based on disease progression per RECIST could be premature in the context of immunotherapies, clinical trials of immunotherapies often allow for treatment beyond RECIST-defined progression,” Julia A. Beaver, MD, director of the division of oncology products at the FDA, and colleagues wrote.
“However, the clinical benefit of treatment beyond progression remains difficult to assess because these trials rarely allowed for continuation of treatment in the control group beyond progression, the studies of treatment beyond progression reported before our analysis generally had small numbers of patients who developed significant tumor responses after progression, and the studies permitting treatment beyond progression that previously reported associations between this treatment and OS in patients with metastatic melanoma did not include similar analyses of the control group in which treatment beyond progression was also allowed.”
To evaluate the effect of treatment beyond progression as assessed by RECIST v.1.1 and to characterize which patients may benefit from extended treatment, Beaver and colleagues assessed all trial reports and data submitted to the FDA for anti-PD-1 antibodies alone or in combination for the treatment of patients with unresectable or metastatic melanoma.
Researchers compared patients who received anti-PD-1 antibody after RECIST-defined progression with those who did not receive continued treatment after disease progression.
Target lesion response and OS served as the primary modes of comparison.
The analysis included data from 2,624 patients across eight trials who received anti-PD-1 antibody treatment for metastatic melanoma.
Overall, 52% had progressive disease, 51% of whom (n = 692) continued anti-PD-1 antibody treatment after RECIST-defined progression.
Five hundred patients treated beyond progression were eligible for assessment. Only 11% (n = 76 of 669) of patients who did not receive anti-PD-1 antibody treatment after disease progression were evaluable.
Researchers observed a 30% or greater decrease in target lesion tumor burden from the time of RECIST-defined progression among 19% (n = 95) of patients who continued anti-PD-1 antibody treatment after progression, compared with 16% (n = 10) of those who did not continue to receive treatment.
Median OS was 24.4 months (95% CI, 21.2-26.3) among patients treated after disease progression compared with 11.2 months (95% CI, 10.1-12.9) among patients not treated with an anti-PD-1 antibody after progression.
More patients who did not receive anti-PD-1 antibody treatment after progression had a serious adverse event within 90 days of treatment discontinuation than those who continued treatment (54% vs. 43%). However, incidence of immune-related adverse events appeared similar between the two groups (16% vs. 11%).
The limitations of the study included differences in the pooled populations and the inability to assess associations between survival and tumor measurement-based criteria aside from RECIST v.1.1.
The study findings raise questions regarding whether RECIST criteria are still applicable for immunotherapy trials, Adil I. Daud, MD, clinical professor of medicine at University of California, San Francisco, and director of melanoma clinical research at the Helen Diller Family Comprehensive Cancer Center, wrote in an accompanying editorial.
“Although the concept of so-called pseudoprogression is widely accepted in the immunotherapy scientific literature, as Beaver and colleagues make clear, the core issue might be discordance between RECIST-defined progression and the point where the utility of treatment is exhausted,” he wrote. “Although RECIST and the previous bidimensional WHO classifications have always carried within them an element of arbitrariness, I believe it is time to reexamine these criteria and base them on a sounder biological footing, perhaps by incorporating global tumor control indices rather than basing them on the development of new lesions.” – by Cassie Homer
Disclosures: Beaver reports no relevant financial disclosures. One study author reports employment with the FDA during her work with this study but current employment with AstraZeneca. Daud reports research funding from Bristol-Myers Squibb, Genentech/Roche, Incyte, Merck, OncoSec and Pfizer, as well as stock ownership in OncoSec.