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. 2021 Dec;32(12):1618-1625.
doi: 10.1016/j.annonc.2021.09.006. Epub 2021 Sep 17.

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

B G Topp  1 , K Thiagarajan  2 , D P De Alwis  3 , A Snyder  4 , M D Hellmann  5
Affiliations
Free article

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

B G Topp et al. Ann Oncol. 2021 Dec.
Free article

Abstract

Background: 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.

Patients and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: gastric cancer; gastroesophageal junction cancer; intertumoral heterogeneity; melanoma; non-small-cell lung cancer; progression.

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Conflict of interest statement

Disclosure BGT reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. KT has declared no conflicts of interest. DPDA reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. AS reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a shareholder in Merck & Co., Inc., Kenilworth, NJ, USA. MDH reports grants from Bristol Myers Squibb; nonfinancial support from AstraZeneca and Bristol Myers Squibb; and personal fees from Achilles; Arcus AstraZeneca; Blueprint Medicines; Bristol Myers Squibb; Genentech/Roche; Immunai; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Mirati; Nektar; Pact Pharma; Shattuck Labs; Syndax; Janssen; and Regeneron; as well as equity options from Immunai, Shattuck Labs, and Arcus. A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx.

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