Immunotherapy Beyond Progression May Be Feasible For Select Advanced Melanoma Patients

Some patients with inoperable or metastatic melanoma might continue to benefit from anti-programmed cell death protein 1 antibody therapy after disease progression

medwireNews: Pooled analysis from eight clinical trials of anti-programmed cell death protein 1 (PD-1) therapy might point to a possible role for treatment beyond RECIST-defined progression in selected patients with unresectable or metastatic melanoma.

Acknowledging reports of immunotherapy-treated patients showing an atypical response pattern, with a reduction in tumour burden after disease progression, researchers collated data from 2624 patients who received at least one dose of pembrolizumab or nivolumab in a KEYNOTE or CheckMate trial.

Among patients who developed new lesions, those who continued with therapy were more likely to have new lesions outside of the visceral tissue than those who did not continue treatment (50 vs 64%), but less likely to have lesions involving the central nervous system (8 vs 21%).

Patients who continued treatment also had a more favourable ECOG performance status and a normal lactate dehydrogenase level, observe Julia Beaver, from the Food and Drug Administration in Silver Spring, Maryland, USA, and co-workers.

“This finding seems consistent with protocol patient selection criteria intended to limit risks to patients who continue anti-PD-1 antibody therapy after initial documentation of RECIST-defined progression”, they write.

Approximately half (51%) of the 1361 patients with RECIST-defined progressive disease continued to receive anti-PD-1 therapy, 500 of whom were assessed for tumour burden after disease progression. Nineteen percent of these patients showed a 30% or greater decrease in tumour burden after progression. Overall, this represents 14% of the patients treated beyond progression and 4% of the total immunotherapy cohort, the researchers comment in The Lancet Oncology.

Median overall survival (OS) was 24.4 months for the patients who continued with anti-PD-1 therapy after progression versus 11.2 months for those who did not, whilst the median value was 32.5 months for patients without disease progression.

Serious adverse events up to 90 days after treatment discontinuation were reported for 43% of patients who continued immunotherapy and 54% of those who did not, and the groups had a similar rate of immune-related adverse events in the first 90 days of treatment (11 vs 16%).

“Overall, in our pooled analyses, the safety profile of anti-PD-1 antibody treatment in the treatment beyond progression period seems consistent with the safety profile seen in the period before disease progression”, the researchers summarise.

Julia Beaver et al took a closer look at data from the CheckMate 066 trial used in the pooled analysis, where 250 patients with RECIST-defined progression were randomly assigned to receive nivolumab (n=59) or control chemotherapy with dacarbazine (n=54) and were permitted to continue treatment beyond progression.

Nivolumab- and dacarbazine-treated patients continued therapy for a median of 1.3 and 0.4 months, respectively. Median OS was unreached in both these groups whereas median OS was 9.6 months for dacarbazine-treated patients who received no further treatment. One-year OS was estimated to be 61%, 53% and 37%, respectively.

“[T]he overall survival analysis from the [CheckMate 066] trial suggests that patients receiving treatment beyond progression in the nivolumab and dacarbazine groups had similar outcomes despite a clear improvement in efficacy with nivolumab versus dacarbazine in the overall trial population”, the study authors observe.

They believe their findings “support the hypothesis that patients being selected for treatment beyond progression might have a different natural history of disease compared with patients not selected, rather than that they are receiving a delayed immunotherapeutic benefit.”

The team therefore concludes that “[c]ontinuation of treatment beyond progression in the product labelling of these immunotherapies has not been recommended because the clinical benefit remains to be proven.”

Nevertheless, the authors add: “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.”


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; Advance online publication 17 January 2018 . DOI:

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