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Effect of concomitant medications with immune-modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: development and validation of a novel prognostic index

Published:November 16, 2020DOI:https://doi.org/10.1016/j.ejca.2020.09.033

      Highlights

      • The impact of concomitant drugs was investigated in patients with advanced cancer treated with immune checkpoint inhibitors.
      • We firstly tested a single-institution cohort of 217 patients with advanced cancer.
      • Corticosteroids, antibiotics and proton-pump inhibitors were related to shorter overall survival (OS).
      • We created a drug-based prognostic score predicting OS, progression-free survival and objective response rate.
      • The score was externally validated in a multicenter cohort of 1012 patients.

      Abstract

      Background

      Concomitant medications are known to impact on clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs). We aimed weighing the role of different concomitant baseline medications to create a drug-based prognostic score.

      Methods

      We evaluated concomitant baseline medications at immunotherapy initiation for their impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in a single-institution cohort of patients with advanced cancer treated with ICIs (training cohort, N = 217), and a drug-based prognostic score with the drugs resulting significantly impacting the OS was computed. Secondly, we externally validated the score in a large multicenter external cohort (n = 1012).

      Results

      In the training cohort (n = 217), the median age was 69 years (range: 32–89), and the primary tumours were non–small-cell lung cancer (70%), melanoma (14.7%), renal cell carcinoma (9.2%) and others (6%). Among baseline medications, corticosteroids (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.60–3.30), systemic antibiotics (HR = 2.07; 95% CI: 1.31–3.25) and proton-pump inhibitors (PPIs) (HR = 1.57; 95% CI: 1.13–2.18) were significantly associated with OS. The prognostic score was calculated using these three drug classes, defining good, intermediate and poor prognosis patients. Within the training cohort, OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0297) were significantly distinguished by the score stratification. The prognostic value of the score was also demonstrated in terms of OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0006) within the external cohort.

      Conclusion

      Cumulative exposure to corticosteroids, antibiotics and PPIs (three likely microbiota-modulating drugs) leads to progressively worse outcomes after ICI therapy. We propose a simple score that can help stratifying patients in routine practice and clinical trials of ICIs.

      Keywords

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