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

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

doi:10.1136/jitc-2020-001361

Cited by 173 publications

(198 citation statements)

References 56 publications

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“…7 10 ► Baseline PPIs. [8][9][10] ► Baseline statins (yes vs no). 10 18 ► Baseline aspirin (considered as low-dose daily intake for cardiovascular prevention) (yes vs no).…”

Section: Concomitant Baseline Medicationsmentioning

confidence: 99%

“…10 18 ► Baseline aspirin (considered as low-dose daily intake for cardiovascular prevention) (yes vs no). 10 19 ► Baseline β-blockers (yes vs no). 10 20 21 ► Baseline metformin (yes vs no) and other oral antidiabetics (yes vs no).…”

Section: Concomitant Baseline Medicationsmentioning

confidence: 99%

“…In a recent observational study of over 1000 ICI recipients, ATB emerged as strong predictor of outcome, irrespective of the indication for their administration (prophylaxis vs treatment of active infections), whereas corticosteroids were only associated with worse outcomes if administered for palliative indications. 10 Moreover, in the same study population, both corticosteroids and PPIs were significantly associated with a higher baseline burden of disease, 10 suggesting that the indication for prescription of concomitant medications and their association with negative prognostic features could be important confounding factors assessing their supposed immunemodulatory profile. ATB are usually indicated to treat infections rather than cancer-related symptoms, therefore the ATB-ICI paradigm might represent the proper model to verify whether the effect on clinical outcomes truly depends on an immune-modulatory effect.…”

Section: Introductionmentioning

confidence: 98%

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Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

Cortellini

Maïo

Nigro³

et al. 2021

J Immunother Cancer

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BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

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“…7 10 ► Baseline PPIs. [8][9][10] ► Baseline statins (yes vs no). 10 18 ► Baseline aspirin (considered as low-dose daily intake for cardiovascular prevention) (yes vs no).…”

Section: Concomitant Baseline Medicationsmentioning

confidence: 99%

Section: Concomitant Baseline Medicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

Cortellini

Maïo

Nigro³

et al. 2021

J Immunother Cancer

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“…Indeed, it has been shown, on mice spleen models, the presence of μ receptors on lymphocytes surface and in vitro experiments that the administration of morphine affected directly the lymphocytes proliferation and antibody formation, by binding to μ receptors [ 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

The role of opioids in cancer response to immunotherapy

et al. 2021

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Background The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. Methods This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p < 0.0001; median OS, 4 months vs. 35 months, HR 1.60, 95% CI 1.26–2.02, p < 0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥ 1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden. Discussion Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. Conclusions A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.

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“…Indeed, corticosteroids are able to activate the glucocorticoids responsive elements (GRE) resulting in a inhibition in IL-1 and IL-6 transcription and in a reduction in T cell function [39].…”

Section: Discussionmentioning

confidence: 99%

The Role of Opioids in Cancer Response to Immunotherapy

Botticelli

Cirillo

Pomati

et al. 2021

Preprint

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Background: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.Methods: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p<0.0001; median OS, 4 months vs. 35months, HR 1.60, 95 % CI 1.26-2.02, p <0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.Discussion: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. Conclusions: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.

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

Cited by 173 publications

References 56 publications

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

The role of opioids in cancer response to immunotherapy

The Role of Opioids in Cancer Response to Immunotherapy

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