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

被引：90

作者：

Buti, Sebastiano ^{[1
]}

Bersanelli, Melissa ^{[1
,2
]}

Perrone, Fabiana ^{[1
]}

Tiseo, Marcello ^{[1
,2
]}

Tucci, Marco ^{[3
,4
]}

Adamo, Vincenzo ^{[5
,6
]}

Stucci, Luigia S. ^{[3
]}

Russo, Alessandro ^{[5
,6
]}

Tanda, Enrica T. ^{[7
]}

Spagnolo, Francesco ^{[7
]}

Rastelli, Francesca ^{[9
]}

Pergolesi, Federica ^{[8
]}

Santini, Daniele ^{[9
]}

Russano, Marco ^{[9
]}

Anesi, Cecilia ^{[9
]}

Giusti, Raffaele ^{[10
]}

Filetti, Marco ^{[10
]}

Marchetti, Paolo ^{[10
,11
,12
]}

Botticelli, Andrea ^{[11
,12
]}

Gelibter, Alain ^{[12
]}

Occhipinti, Mario Alberto ^{[13
]}

Ferrari, Marco ^{[13
]}

Vitale, Maria Giuseppa ^{[14
]}

Nicolardi, Linda ^{[15
]}

Chiari, Rita ^{[15
]}

Rijavec, Erika ^{[16
]}

Nigro, Olga ^{[17
]}

Tuzi, Alessandro ^{[17
]}

De Tursi, Michele ^{[18
]}

Di Marino, Pietro ^{[19
]}

Conforti, Fabio ^{[20
]}

Queirolo, Paola ^{[20
]}

Bracarda, Sergio ^{[21
]}

Macrini, Serena ^{[21
]}

Gori, Stefania ^{[22
]}

Zoratto, Federica ^{[23
]}

Veltri, Enzo ^{[23
]}

Di Cocco, Barbara ^{[23
]}

Mallardo, Domenico ^{[24
]}

Vitale, Maria Grazia ^{[24
]}

Santoni, Matteo ^{[25
]}

Patruno, Leonardo ^{[26
,27
]}

Porzio, Giampiero ^{[26
]}

Ficorella, Corrado ^{[26
,27
]}

Pinato, David J. ^{[28
]}

Ascierto, Paolo A. ^{[24
]}

Cortellini, Alessio ^{[26
,27
]}

机构：

[1] Univ Hosp Parma, Med Oncol Unit, Parma, Italy

[2] Univ Parma, Dept Med & Surg, Parma, Italy

[3] Univ Bari, Dept Biomed Sci & Human Oncol, Med Oncol Unit, Bari, Italy

[4] Tumori Inst IRCCS Giovanni Paolo II, Natl Canc Res Ctr, Bari, Italy

[5] Univ Messina, AO Papardo, Med Oncol, Messina, Italy

[6] Univ Messina, Dept Human Pathol, Messina, Italy

[7] IRCCS Osped Policlin San Martino, Genoa, Italy

[8] Fermo Area Vasta 4, Med Oncol, Fermo, Italy

[9] Campus Biomed Univ, Med Oncol, Rome, Italy

[10] St Andrea Hosp Rome, Med Oncol Unit, Rome, Italy

[11] Sapienza Univ Rome, Dept Clin & Mol Med, Rome, Italy

[12] Sapienza Univ Rome, Policlin Umberto I, Med Oncol B, Rome, Italy

[13] Azienda Osped Univ Pisana, Med Oncol, Pisa, Italy

[14] Univ Hosp Modena, Med Oncol, Modena, Italy

[15] UOC Oncol Padova Sud AULSS6 Euganea, Padua, Italy

[16] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Med Oncol Unit, Milan, Italy

[17] Osped Circolo & Fdn Macchi, ASST Sette Laghi, Med Oncol, Varese, Italy

[18] Univ G DAnnunzio, Dept Med Oral & Biotechnol Sci, Chieti, Italy

[19] SS Annuniata Hosp, Clin Oncol Unit, Chieti, Italy

[20] European Inst Oncol IRCCS, Div Med Oncol Melanoma Sarcoma & Rare Tumors, IEO, Milan, Italy

[21] Azienda Osped S Maria, SC Med Oncol, Terni, Italy

[22] IRCCS Osped Sacro Cuore Don Calabria, Oncol Unit, Negrar, VR, Italy

[23] Santa Maria Goretti Hosp, Med Oncol, Latina, Italy

[24] Ist Nazl Tumori IRCCS Fdn G Pascale, Melanoma Canc Immunotherapy & Dev Therapeut Unit, Naples, Italy

[25] Macerata Hosp, Dept Oncol, Macerata, Italy

[26] St Salvatore Hosp, Med Oncol Unit, Laquila, Italy

[27] Univ Aquila, Dept Biotechnol & Appl Clin Sci, Laquila, Italy

[28] Imperial Coll London, Hammersmith Hosp, Fac Med, Dept Surg & Canc, London, England

来源：

EUROPEAN JOURNAL OF CANCER | 2021年 / 142卷

关键词：

Concomitant medications; Drugs; Immunotherapy; Corticosteroids; Proton-pump inhibitors; Antibiotics; Immune checkpoint inhibitors; Cancer patients; Score; Index; Prognostic; PROTON PUMP INHIBITORS; GUT MICROBIOME; ANTIBIOTICS; EFFICACY; IMPACT; PD-1;

D O I：

10.1016/j.ejca.2020.09.033

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 nonesmall-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. (C) 2020 Elsevier Ltd. All rights reserved.

引用

页码：18 / 28

页数：11

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