Investigators with the FDA’s Center for Drug Evaluation and Research and Oncology Center of Excellence conducted a pooled analysis of all trial reports and data marketing applications for the use of anti–PD-1 antibodies alone or in combination to treat patients with unresectable or metastatic melanoma.
Julia A. Beaver, MD
Continuing treatment with PD-1 inhibitors after progression is not currently indicated for patients with melanoma, but researchers affiliated with the FDA have suggested there might be value in such a strategy.
Investigators with the FDA’s Center for Drug Evaluation and Research and Oncology Center of Excellence conducted a pooled analysis of all trial reports and data marketing applications for the use of anti—PD-1 antibodies alone or in combination to treat patients with unresectable or metastatic melanoma that allowed for continuation of the antibody beyond RECIST-defined progression in the anti–PD-1 group submitted to the FDA approved before January 1, 2017.
Eight multicenter clinical trials evaluating 2624 patients were included in the analysis. Roughly half of patients had progressive disease, 51% of whom continued anti—PD-1 treatment beyond RECIST-defined progression. Ninety-five (19%) of 500 patients in the treatment beyond progression cohort with evaluable assessments had a ≥30% decrease in tumor burden, when considering burden at RECIST-defined progression as the reference point, representing 14% of the 692 patients treated beyond progression.
The median duration of treatment beyond progression was 1.41 months (IQR, 0.69-4.86). Patients in the treatment beyond progression cohort were followed for a median of 15.7 months (IQR, 11.7-23.6) and patients in the no treatment beyond progression cohort had 14.1 months (IQR, 11.2-22.2) of follow-up.
Patient characteristics at baseline were similar between the 2 groups, except that patients who received treatment after progression were more likely to have ECOG performance status of 0 (77% vs 65%) and normal lactate dehydrogenase concentrations. Researchers found that these differences became more pronounced at the time of RECIST-defined progression.
The median overall survival (OS) was 24.4 months (95% CI, 21.2-26.3) in patients treated beyond progression, 11.2 months (95% CI, 10.1-12.9) in the no treatment beyond progression cohort, and 32.5 months (95% CI, 31.0-not reached) in the no disease progression group.
At the time of data cutoff for each trial, 36% of patients in the treatment beyond progression cohort had died from any cause compared with 57% who did not receive treatment beyond progression and 25% of those who had no disease progression.
“The FDA has not recommended continuation of treatment beyond progression in the product labelling of anti—PD-1 antibody therapies,” Julia A. Beaver, MD, Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, FDA, and colleagues wrote. “However, we believe that the strategy to continue an immunotherapeutic treatment in clinical practice to maximize the potential for a patient to have a late response should be informed by a risk-benefit analysis that takes into account clinical criteria, such as those used in clinical trials based on extent of progression of disease and subjective assessment of patient status.”
Overall, 54% of patients who were not treated after progression had a serious adverse event (AE) up to 90 days after treatment discontinuation compared with 43% of patients who received treatment. In the treatment beyond progression cohort, 17% had a serious AE in the period before progression and 24% had a serious AE in the period after disease progression up to 30 days after treatment discontinuation. The only AE of any grade with a more than 2% increase occurring in the period after progression compared with the treatment in the period before progression was vitiligo (8% vs 5%).
Eleven percent of patients treated beyond progression and 16% of those who were not treated had an immune-related AE within 90 days of receiving an anti—PD-1 antibody. In the treatment beyond progression cohort, 4% had an immune-related AE before RECIST-defined progression, and 4% had an immune-related AE in the time after progression up to 30 days after treatment discontinuation.
The CheckMate-066 trial provided researchers with a unique opportunity to assess treatment beyond progression in a double-blind, randomized, active-controlled clinical study. Patients with disease progression (n = 250) could continue their assigned treatment with nivolumab (Opdivo) or chemotherapy with dacarbazine. Of the progressive disease population, 24% received treatment beyond progression in the nivolumab group and 22% received treatment beyond progression in the dacarbazine group.
Estimated 1-year OS within the nivolumab group who did not receive treatment beyond progression was 62% (95%, CI 42-77) compared with 61% (95% CI, 45-74) in patients who were treated beyond progression. In the dacarbazine group, 1-year OS was 53% (32-70) in the treatment beyond progression cohort and 37% (95% CI, 25-49) in the cohort who did not receive treatment beyond progression.
Patient mortality rates were similar across both groups treated after progression, (nivolumab, 32%, vs dacarbazine, 31%) and in the patients who received nivolumab but did not receive treatment beyond progression (29%). Researchers found that the mortality rate was higher in patients who received dacarbazine without treatment beyond progression (54%).
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 [published online January 17, 2018. Lancet Oncol. 2018; 19:229-239. doi: 10.1016/S1470-2045(17)30846-X.