Lesion-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma (MM)

Background: Anti-PD-1 therapy has demonstrated activity in MM but current data may not fully reflect patterns of response and relapse as discerned by comprehensive lesion-specific analysis. Methods: Bidimensional measurements of every metastasis (met) ≥5mm (≥15mm short axis for lymph nodes [LN]) in MM pts enrolled in the MK3475-001 phase 1 trial at a single center were obtained on CT scan at baseline, 12 wks and thereafter. Response of each individual met was determined by change in product of longest perpendicular diameters (POD) and classified as complete (CR, disappearance or <10mm short axis for LN), partial (PR, ≥50% reduction in POD), stable (SD, neither CR/PR/PD) or progressive (PD, ≥25% increase in POD and ≥5mm in 1 axis). Overall pt response was investigator determined using standard immune related response criteria (irRC). Results: 27 evaluable pts with med. follow up of 54 wks had a total of 442 discrete mets at baseline (med. 10/pt; range 2-68/pt; med. POD 129mm2). 13/27 (48%) pts had an irRC objective response (OR), 11 (85%) by first scan. Med. time to best response in pts with OR was 24 wks. Although only 1/27 pts had CR (3.7%), 228/442 (52%) individual mets underwent CR and 81% of pts (22/27) had ≥1 CR met at first scan. CR mets were smaller than non-CR [med. POD 80 vs 246mm2(p<0.05)] but 92/244 mets (38%) ≥100mm2 reached CR. CR rate was highest in lung vs other sites combined (p<0.05) (Table). Only 1 CR met subsequently progressed. Of 12 (44%) pts who progressed only 1 had prior OR. 10 (83%) of these pts PD in new and existing mets simultaneously. No site of PD predominated; only 1 pt (8%) PD in brain. 98/442 baseline mets (22%) progressed and most (74%) had PD as best response. Of 80 new or growing mets at first scan, only 4 (5%) subsequently had OR. Conclusions: Response to anti-PD1 therapy is rare in mets that are new or growing at first scan. CR in individual mets is common, sustained, and influenced by site and size. These results have implications for the biology of PD-1 inhibition, resistance, biomarker development and patient selection.Site of met CR PR/SD/PDLung 141(64%) 79 (36%)Liver 20 (54%) 17 (46%)Subcut 26 (42%) 36 (58%)LN 14 (41%) 20 (59%)Soft tissue 18 (32%) 39 (68%)Other 9 (28%) 23 (72%)Total 228 (52%) 214 (48%)