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Patients with melanoma that progressed on Ipilimumab: survival, biomarker, and toxicity analysis of Nivolumab


PD-1 antibody, Nivolumab ( Opdivo ), was administered with/without a multi-peptide vaccine to 126 patients ( pts ) with unresectable melanoma that failed at least one regimen and were Ipilimumab ( Yervoy ) naïve ( n=34 ), or progressed after IPI ( n=92 ).

Researchers assess its toxicity especially in those with prior dose limiting immune related adverse events ( irAEs ) to Ipilimumab, update survival and response duration data, and characterize myeloid derived suppressor cell ( MDSC ) and T cell subsets in Ipilimumab-refractory patients.

Patients refractory to Ipilimumab received Nivolumab at 3 mg/kg: two cohorts of pts were A*0201 positive and had either grade 2 or less IPI-related irAE ( n=10 ), or grade 3-4 dose limiting immune related adverse events ( n=21 ); 61 patients had grade 2 or less immune related adverse events, were not HLA restricted and received Nivolumab alone.

Pre- and 12 week post-treatment peripheral blood was analyzed.

Median follow-up for Ipilimumab-refractory patients was 18.7 months; the response ratewas 29% by mWHO; 44% had clinical benefit with confirmed partial and complete response or stable disease at 24 weeks ( CR [ complete response ] + PR [ partial response ] + SD [ stable disease ] ).

Median duration of response was 14.3 months.

Median progression-free survival ( PFS ) was 5.4 months, and estimated median overall survival ( OS ) was 20.1 months ( 95% CI: 17.0, not reached ) with 1 and 2 year overall survival of 69.2% ( 95% CI: 57.9-78.0% ) and 39.1% ( 95% CI 26.0-52.0% ).

Of 14 patients that have completed all therapy or stopped due to toxicity while stable or in response, all remain in remission.

Of 21 patients with prior Ipilimumab-induced grades 3-4 immune related adverse events, only 2 had a subsequent dose limiting ( and different ) immune related adverse events with Nivolumab, with 8 PR and 5 SD seen; all 8 PR and 3 SD are without progression.

Biomarker studies showed that circulating pre-treatment HLA-DR lo/CD14+/CD11b+ myeloid-derived suppressor cells ( MDSC ) were associated with progression and worse overall survival ( p = 0.0001 and 0.0009 ).
Pre-treatment, MDSC suppressed T cell reactivity ( p = 0.006 ) which was overcome by PD-1 blockade ex vivo, and had high levels of VISTA, CD244 and BTLA.
Low PD-L1 and Tim3 expression on MDSC was associated with response.

In conclusion, this is the first survival assessment in patients with melanoma, refractory to Ipilimumab, treated with Nivolumab, with median overall survival of 20.1 months and progression-free survival of 5.4 months.
Prior immune related adverse events to Ipilimumab were not replicated with Nivolumab.
Novel biomarkers of outcome were found on circulating MDSC. ( Xagena )

Weber JS et al, J Clin Oncol 33, 2015 (suppl; abstr 9055)

XagenaMedicine_2015



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