4.7 Article

Soluble PD-L1 as an early marker of progressive disease on nivolumab

Journal

JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 10, Issue 2, Pages -

Publisher

BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-003527

Keywords

melanoma; biomarkers; tumor; immunoassay; immunotherapy; kidney neoplasms

Funding

  1. Bristol Myers Squibb
  2. NIH [P50 CA101942, P50CA206963, AI056299]
  3. Dana-Farber/Harvard Cancer Center Kidney SPORE [2P50CA101942-16, 5P30CA006516-56]
  4. Kohlberg Chair at Harvard Medical School
  5. Trust Family

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This study investigated the levels of soluble PD-L1 (sPD-L1) before and during nivolumab treatment in metastatic clear cell renal cell carcinoma (RCC) and melanoma patients. The results showed that sPD-L1 levels were associated with worse prognosis and clinical factors. Additionally, changes in sPD-L1 levels during treatment were linked to treatment outcomes.
Background Soluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear cell renal cell carcinoma (RCC) and melanoma patients, and investigated its relationship to clinical factors, biomarkers, and outcome. Methods Using a new Single Molecule Array assay, serum sPD-L1 level were determined in RCC (CheckMate 009, n=91) and melanoma (CheckMate 038-Part 1, n=78) prior to, and at two time points on treatment. Gene expression data was obtained from biopsies taken prior to, and at day 28 on treatment. Results were integrated with clinical variables, tumor PD-L1 status from immuno-histochemistry, and genomic mutation status. Results In RCC patients, sPD-L1 levels were higher in patients with progressive disease as their best response. For both RCC and melanoma patients, progressive or stable disease was associated with an increase in sPD-L1 on nivolumab therapy, whereas mean sPD-L1 levels did not change or declined in patients with objective responses. By categorizing RCC patients into transcriptomic molecular subtypes, we identified a subgroup where the associations between sPD-L1 and progressive disease were particularly evident. In baseline biopsies, we identified six biological processes that were associated with sPD-L1 level in both RCC and melanoma: higher sPD-L1 is associated with lower tumor expression of the Hallmark gene sets 'hypoxia', 'fatty acid metabolism', 'glycolysis', 'MTORC1 signaling' and 'androgen response', and with higher expression of 'KRAS signaling_Down'. Conclusion Baseline and on-therapy sPD-L1 levels in RCC have the potential to predict progressive disease on PD-1 inhibitor nivolumab. In a hypothesis-generating analysis of tumor gene expression, high baseline sPD-L1 is associated with a tumor metabolic state reflecting potentially targetable processes in both melanoma and RCC. In both trials, we observed associations between change in sPD-L1 on treatment and outcome metrics. sPD-L1 levels may further refine a nivolumab-refractory subtype of RCC within transcriptionally based subtypes of RCC.

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