Lesion-level heterogeneity of radiologic progression in patients treated with pembrolizumab

Disease progression is often considered a binary state reflecting presence or absence of response. Meaningful heterogeneity between metastatic sites of a given patient may exist, however, and may impact therapeutic outcomes. To characterize the heterogeneity of progression with immunotherapy, we evaluated lesion-level dynamics of pembrolizumab-treated patients across three tumor types.Individual metastatic lesion dynamics were analyzed retrospectively in patients with advanced melanoma, non-small-cell lung cancer (NSCLC), and gastric or gastroesophageal junction (G/GEJ) cancer who received pembrolizumab in KEYNOTE-001 or KEYNOTE-059. Primary progression was defined as radiologic progression as per RECIST v1.1 occurring at the first on-treatment study scan (∼9-12 weeks, +2-week window) and secondary progression as progression occurring beyond the first scan (∼14 weeks and beyond). The change in sum of target lesions and of individual lesions was examined, as were patterns and timing of progression.9239 individual lesions from 1194 patients were analyzed. Among patients with primary progression [39% (200/511) of patients with melanoma, 41% (179/432) with NSCLC, 61% (154/251) with G/GEJ cancer], most patients (51%-63%) had a mixture of growing, stable, and shrinking lesions. Despite overall primary progression, a minority of patients (19%-25%) had tumor growth at every metastatic site and 17%-32% had ≥1 shrinking lesion. Among patients with secondary progression [22% (113/511) of patients with melanoma, 27% (117/432) with NSCLC, 18% (44/251) with G/GEJ cancer], few patients had rebound growth (>20% increase in diameter from nadir) in all lesions whereas the majority (74%-84%) had sustained regression in ≥1 lesion.Lesion-level heterogeneity at the time of disease progression was common in pembrolizumab-treated patients, with many patients demonstrating ongoing disease control in a subset of tumor sites. These results may inform clinical decision-making, trial design, and tumor sampling in the future.