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

被引：120

作者：

Cortellini, Alessio ^{[1
,2
]}

Di Maio, Massimo ^{[3
]}

Nigro, Olga ^{[4
]}

Leonetti, Alessandro ^{[5
]}

Cortinovis, Diego L. ^{[6
]}

Aerts, Joachim G. J., V ^{[7
]}

Guaitoli, Giorgia ^{[8
]}

Barbieri, Fausto ^{[8
]}

Giusti, Raffaele ^{[9
]}

Ferrara, Miriam G. ^{[10
,11
]}

Bria, Emilio ^{[10
,11
]}

D'Argento, Ettore ^{[10
]}

Grossi, Francesco ^{[12
]}

Rijavec, Erika ^{[13
]}

Guida, Annalisa ^{[14
]}

Berardi, Rossana ^{[15
]}

Torniai, Mariangela ^{[15
]}

Sforza, Vincenzo ^{[16
]}

Genova, Carlo ^{[17
]}

Mazzoni, Francesca ^{[18
]}

Garassino, Marina Chiara ^{[19
]}

De Toma, Alessandro ^{[19
]}

Signorelli, Diego ^{[19
,20
]}

Gelibter, Alain ^{[21
]}

Siringo, Marco ^{[21
]}

Marchetti, Paolo ^{[22
]}

Macerelli, Marianna ^{[23
]}

Rastelli, Francesca ^{[24
]}

Chiari, Rita ^{[25
]}

Rocco, Danilo ^{[26
]}

Della Gravara, Luigi ^{[26
]}

Inno, Alessandro ^{[27
]}

Michele, De Tursi ^{[28
]}

Grassadonia, Antonino ^{[28
]}

Di Marino, Pietro ^{[29
]}

Mansueto, Giovanni ^{[30
]}

Zoratto, Federica ^{[31
]}

Filetti, Marco ^{[9
]}

Santini, Daniele ^{[32
]}

Citarella, Fabrizio ^{[32
]}

Russano, Marco ^{[32
]}

Cantini, Luca ^{[7
,15
]}

Tuzi, Alessandro ^{[4
]}

Bordi, Paola ^{[5
]}

Minuti, Gabriele ^{[33
]}

Landi, Lorenza ^{[33
]}

Ricciardi, Serena ^{[34
]}

Migliorino, Maria R. ^{[34
]}

Passiglia, Francesco ^{[35
]}

Bironzo, Paolo ^{[36
]}

机构：

[1] Imperial Coll London, Dept Surg & Canc, Div Canc, London, England

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

[3] Univ Turin & Ordine Mauriziano, Dept Oncol & Med Oncol, Turin, Italy

[4] ASST Sette Laghi, Med Oncol, Varese, Italy

[5] Univ Hosp Parma, Med Oncol, Parma, Italy

[6] Azienda Osped San Gerardo, Med Oncol, Monza, Italy

[7] Erasmus MC, Dept Pulm Dis, Rotterdam, Netherlands

[8] AOU Policlin Modena, Dipartimento Oncol Ematol, Modena, Italy

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

[10] Fdn Policlin Univ Agostino Gemelli, Comprehens Canc Ctr, Rome, Italy

[11] Univ Cattolica Sacro Cuore, Dept Translat Med & Surg, Rome, Italy

[12] Univ Insubria, Div Med Oncol, Varese, Italy

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

[14] Azienda Osped Santa Maria Terni, Struttura Complessa Oncol Med & Traslaz, Terni, Italy

[15] Univ Politecn Marche, Oncol Clin, Osped Riuniti Ancona, Ancona, Italy

[16] Natl Canc Inst IRCCS Pascale Fdn, Thorac Med Oncol, Naples, Italy

[17] IRCCS Osped Policlin San Martino, Lung Canc Unit, Genoa, Italy

[18] Careggi Univ Hosp, Dept Med Oncol, Florence, Italy

[19] Fdn IRCCS Ist Nazl Tumori, Med Oncol, Milan, Italy

[20] Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy

[21] Sapienza Univ Rome, Med Oncol Unit B, Policlin Umberto 1, Rome, Italy

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

[23] Univ Hosp Santa Maria Misericordia, Med Oncol, Udine, Italy

[24] ASUR Area Vasta 4, Med Dept, Fermo, Italy

[25] Osped Riuniti Padova Sud Madre Teresa Calcutta, Med Oncol, Padua, Italy

[26] Osped Colli Monaldi Cotugno CTO, Oncol Unit, Naples, Italy

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

[28] Univ G DAnnunzio, Dipartimento Terapie Innovat Med & Odontoiatria, Chieti, Italy

[29] SS Annunziata Hosp, Clin Oncol Unit, Chieti, Italy

[30] Azienda Sanitaria Locale Frosinone, Med Oncol, Frosinone, Italy

[31] Osped Santa Maria Goretti, Med Oncol, Latina, Italy

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

[33] AUSL Romagna, Dept Oncol & Hematol, Ravenna, Italy

[34] San Camillo Forlanini Hosp, Oncol Unit, Rome, Italy

[35] San Luigi Gonzaga Univ Hosp, Dept Oncol, Orbassano, Italy

[36] San Luigi Hosp, Dept Oncol, Orbassano, Italy

[37] Santa Maria Misericordia Hosp, Dept Med Oncol, Perugia, Italy

[38] Azienda Osped Papardo, Med Oncol, Messina, Italy

[39] Azienda Osped Papardo, Dept Human Pathol, Messina, Italy

[40] Univ Studi Messina, Messina, Italy

[41] Sapienza Univ Rome, UOC Terr Oncol Aprilia, AUSL Latina, Aprilia, Italy

[42] Portsmouth Univ Hosp NHS Trust, Med Oncol, Portsmouth, Hants, England

[43] Univ Hosp Geneva, Oncol Dept, Geneva, Switzerland

[44] San Salvatore Hosp, Med Oncol, Laquila, Italy

[45] Univ Piemonte Orientale, Dept Translat Med, Novara, Italy

来源：

JOURNAL FOR IMMUNOTHERAPY OF CANCER | 2021年 / 9卷 / 04期

基金：

英国惠康基金;

关键词：

immunotherapy; lung neoplasms;

D O I：

10.1136/jitc-2021-002421

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Some 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. Methods We 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. Results 950 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, beta-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. Conclusion In 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.

引用

页数：10

共 29 条

[21] Proton pump inhibitors alter the composition of the gut microbiota [J].

Jackson, Matthew A. ;

Goodrich, Julia K. ;

Maxan, Maria-Emanuela ;

Freedberg, Daniel E. ;

Abrams, Julian A. ;

Poole, Angela C. ;

Sutter, Jessica L. ;

Welter, Daphne ;

Ley, Ruth E. ;

Bell, Jordana T. ;

Spector, Tim D. ;

Steves, Claire J. .

GUT, 2016, 65 (05) :749-756

[22] Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice [J].

Kokolus, Kathleen M. ;

Zhang, Ying ;

Sivik, Jeffrey M. ;

Schmeck, Carla ;

Zhu, Junjia ;

Repasky, Elizabeth A. ;

Drabick, Joseph J. ;

Schell, Todd. D. .

ONCOIMMUNOLOGY, 2018, 7 (03)

[23] Effective immunotherapy against cancer - A question of overcoming immune suppression and immune escape? [J].

Malmberg, KJ .

CANCER IMMUNOLOGY IMMUNOTHERAPY, 2004, 53 (10) :879-892

[24] Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis [J].

Petrelli, Fausto ;

Signorelli, Diego ;

Ghidini, Michele ;

Ghidini, Antonio ;

Pizzutilo, Elio Gregory ;

Ruggieri, Lorenzo ;

Cabiddu, Mary ;

Borgonovo, Karen ;

Dognini, Giuseppina ;

Brighenti, Matteo ;

De Toma, Alessandro ;

Rijavec, Erika ;

Garassino, Marina Chiara ;

Grossi, Francesco ;

Tomasello, Gianluca .

CANCERS, 2020, 12 (03)

[25] Impact of corticosteroid therapy on the outcomes of hepatocellular carcinoma treated with immune checkpoint inhibitor therapy [J].

Pinato, David J. ;

Kaseb, Ahmed ;

Wang, Yinghong ;

Saeed, Anwaar ;

Szafron, David ;

Jun, Tomi ;

Dharmapuri, Sirish ;

Naqash, Abdul Rafeh ;

Muzaffar, Mahvish ;

Navaid, Musharraf ;

Khan, Uqba ;

Lee, ChiehJu ;

Bulumulle, Anushi ;

Yu, Bo ;

Paul, Sonal ;

Fessas, Petros ;

Nimkar, Neil ;

Bettinger, Dominik ;

Hildebrand, Hannah ;

Pressiani, Tiziana ;

Abugabal, Yehia, I ;

Personeni, Nicola ;

Huang, Yi-Hsiang ;

Lozano-Kuehne, Jingky ;

Rimassa, Lorenza ;

Ang, Celina ;

Marron, Thomas U. .

JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2020, 8 (02)

[26] Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer [J].

Pinato, David J. ;

Howlett, Sarah ;

Ottaviani, Diego ;

Urus, Heather ;

Patel, Aisha ;

Mineo, Takashi ;

Brock, Cathryn ;

Power, Danielle ;

Hatcher, Olivia ;

Falconer, Alison ;

Ingle, Manasi ;

Brown, Anna ;

Gujral, Dorothy ;

Partridge, Sarah ;

Sarwar, Naveed ;

Gonzalez, Michael ;

Bendle, Maggie ;

Lewanski, Conrad ;

Newsom-Davis, Thomas ;

Allara, Elias ;

Bower, Mark .

JAMA ONCOLOGY, 2019, 5 (12) :1774-1778

[27] Immune Checkpoint Inhibitor Outcomes for Patients With Non-Small-Cell Lung Cancer Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative Indications [J].

Ricciuti, Biagio ;

Dahlberg, Suzanne E. ;

Adeni, Anika ;

Sholl, Lynette M. ;

Nishino, Mizuki ;

Awad, Mark M. .

JOURNAL OF CLINICAL ONCOLOGY, 2019, 37 (22) :1927-+

[28] Understanding the impact of antibiotic perturbation on the human microbiome [J].

Schwartz, D. J. ;

Langdon, A. E. ;

Dantas, G. .

GENOME MEDICINE, 2020, 12 (01)

[29]

Yasir M., 2021, STATPEARLS

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