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Serum Protein Signature Predicts Survival in Patients With Melanoma Receiving Anti–PD-1 Therapy

Jaime Rosenberg
A pre-treatment signature of proteins used to predict survival in patients with metastatic melanoma receiving PD-1 inhibitors found that patients deemed sensitive by the test demonstrated significantly better overall survival.
A pre-treatment signature of proteins predicted survival in patients with metastatic melanoma receiving programmed cell death protein-1 (PD-1) blocking antibodies, according to a new study published in Cancer Immunology Research.

Prior clinical results in patients with metastatic melanoma being treated with PD-1 inhibitors, nivolumab and pembrolizumab, have led to substantial improvements in progression-free survival (PFS) and overall survival (OS). According to the authors of the study, there have also been efforts made toward determining the utility of programmed cell death ligand-1 (PD-L1) expression on tumor and/or immune infiltrating cells, as measured by immunohistochemistry (IHC).

“Correlations between PD-L1 expression and outcome with PD-1/PD-L1 antibodies have been observed in many studies, but melanoma patients with negatively stained tumors may still benefit from anti-PD-1 therapy,” wrote the authors. They continued: “A serum-based pre-treatment test of circulating proteins would not require tissue, and if found to be associated with a favorable response to PD-1 blocking antibodies, would be clinically useful.”

The authors conducted the test by collecting sera from 6 sample sets for test development and validation:
  • A development set of 119 patients with stage IV melanoma prior to treatment in which the efficacy of nivolumab monotherapy at 1, 3, and 10 mg/kg with or without a multi-peptide vaccine was evaluated
  • 3 validation sets of 101 patients receiving nivolumab or pembrolizumab
  • A validation set of 48 patients receiving ipilimumab
  • A validation set of 21 patients receiving ipilimumab and nivolumab
The sera were obtained with a matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry. These data, along with clinical data, were used to identify patients with better or worse outcomes. The test, developed with the Diagnostic CortexTM platform, was based on mass spectrometry analysis of patient serum samples.

A signature consisting of 209 proteins or peptides was associated with OS and PFS in a multivariate analysis.

For the development set, the test classified 34 (29%) patients as sensitive and 85 (71%) as resistant. Both OS and PFS showed significant separation (= .002 and 0.016, respectively) by test classification with substantial effect sizes for each (hazard ratios [HRs] of 0.37 and 0.55, respectively). Patients deemed sensitive had a 2-year survival rate of 67%.

The authors found that the test performance across validation cohorts was consistent with the development set results. Results of the pooled analysis showed significantly better OS for patients classified as sensitive compared with patients classified as resistant (HR, 0.15; 95% Cl, .06-.40; P<.001). The ipilimumab-treated validation set demonstrated a significant difference in OS between sensitive and resistant groups (HR, .40, P = .004).

“The serum test described herein might identify patients expressing the ‘sensitive’ serum classification that have long overall survival with PD-1 blockade alone or with the addition of ipilimumab to nivolumab,” concluded the authors.

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