Journal for ImmunoTherapy of Cancer (Oct 2020)

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice

  • Alessandro Russo,
  • Paolo Antonio Ascierto,
  • Alessio Cortellini,
  • Daniele Santini,
  • Raffaele Giusti,
  • Federica Zoratto,
  • Enzo Veltri,
  • Riccardo Marconcini,
  • Marco Russano,
  • Cecilia Anesi,
  • Marco Filetti,
  • Paolo Marchetti,
  • Andrea Botticelli,
  • Maria Giuseppa Vitale,
  • Francesca Rastelli,
  • Rita Chiari,
  • Alain Gelibter,
  • Giampiero Porzio,
  • Corrado Ficorella,
  • Domenico Mallardo,
  • Sergio Bracarda,
  • Claudia Bareggi,
  • Maria Grazia Vitale,
  • Alessandro Inno,
  • Olga Nigro,
  • Vincenzo Adamo,
  • Laura Pala,
  • Alessandro Tuzi,
  • Enrica Teresa Tanda,
  • Marco Tucci,
  • Luigia Stefania Stucci,
  • Francesco Spagnolo,
  • Renato Bisonni,
  • Linda Nicolardi,
  • Nicola Petragnani,
  • Serena Macrini,
  • Barbara Di Cocco,
  • David James Pinato

DOI
https://doi.org/10.1136/jitc-2020-001361
Journal volume & issue
Vol. 8, no. 2

Abstract

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Background Concomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.Methods We conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids.Results From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death.Conclusion We confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.