The Association Between Antibiotic Use and Outcome Among Metastatic Melanoma Patients Receiving Immunotherapy

Florence Poizeau, MD, MSc; Sandrine Kerbrat, MSc; Frédéric Balusson, MSc; Pierre Tattevin, MD, PhD; Matthieu Revest, MD, PhD; Vincent Cattoir, PharmD, PhD; David Luque-Paz, MD, MSc; Thierry Lesimple, MD; Marc Pracht, MD; Monica Dinulescu, MD; David Russo, MD; Emmanuel Oger, MD, PhD; Alain Dupuy, MD, PhD

Disclosures

J Natl Cancer Inst. 2022;114(5):686-694.

Results

Patient Characteristics

In the anti-PD-1 antibody cohort (n = 2605), 749 (28.6%) patients received antibiotics in the 3 months prior to anti-PD-1 initiation. In the targeted therapy cohort (n = 1527), 460 (30.1%) patients received antibiotics in the 3 months prior to targeted therapy initiation. Age, sex, metastatic sites, previous surgery or radiotherapy, and comorbidities were reported for the ICI and targeted therapy cohorts. After overlap weighting, standardized mean differences between patients receiving or not receiving antibiotics were close to zero for all covariates (Table 1; Supplementary Table 2, available online). All the characteristics measured were thus well balanced across groups within the pseudo-populations.^[32]

Antibiotic Exposure Before First-line Antimelanoma Treatment

In the anti-PD-1 antibody cohort, 749 patients received 954 antibiotic prescriptions in the 3 months prior to their first-line treatment. In the targeted therapy cohort, there were 583 antibiotic prescriptions for 460 patients. The main antibiotics prescribed were amoxicillin and clavulanate (28.9%), amoxicillin (19.8%), pristinamycin (10.3%), and ofloxacin (4.5%). Primary infections requiring hospitalization were urinary tract (26.3%), respiratory tract (22.6%), skin and skin-associated structures infections (22.9%), and fever of undetermined cause (16.7%). The proportion of patients receiving an antibiotic prescription each day was estimated in the 2 years before the initiation of the first-line antimelanoma treatment. The incidence of antibiotic prescriptions rose steadily from 12 months before the first-line treatment in both cohorts (Figure 1).

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Figure 1.

Evolution of antibiotic use according to the progression of melanoma disease over time. The proportion of patients initiating an antibiotic course in the 2 years before the initiation of the first anticancer treatment line is shown for the anti-PD-1 cohort and the targeted therapy cohort. The 95% confidence band for the proportion of antibiotic prescriptions is shown in gray. The time frame for antibiotics exposure in the main analysis is circled.

Association Between Antibiotic use in the 3 Months Prior to Antimelanoma Treatment and Outcome

In the anti-PD-1 antibody cohort, 956 (36.7%) patients had died, and 1602 (61.5%) had discontinued their first treatment line by December 31, 2017. Antibiotic exposure was not associated with shorter OS (wHR = 1.01, 95% CI = 0.88 to 1.17) or TTD (wHR = 1.00, 95% CI = 0.89 to 1.11). Kaplan-Meier curves were superimposed according to antibiotic receipt in the pseudo-populations (Figure 2, A and B).

(Enlarge Image)

Figure 2.

Kaplan-Meier curves for overall survival and time-to-treatment discontinuation according to antibiotic treatment in pseudo-populations of patients receiving anti-PD-1 antibody or targeted therapy as a first-line treatment for metastatic melanoma. Pseudo-populations are obtained using overlap weighting from the initial anti-PD-1 antibody cohort (A and B) and targeted therapy cohort (C and D). Patients receiving antibiotics in the 3 months prior to anti-PD-1 antibody or targeted therapy are compared to nonexposed patients. Overall survival is shown in panels A and C and time-to-treatment discontinuation in panels B and D. Weighted log-rank tests are provided. The numbers of at-risk individuals correspond to fictive weighted individuals. All the study participants from the anti-PD-1 antibody cohort (n = 2605) and the targeted therapy cohort (n = 1527) were included. All statistical tests were 2-sided.

In the targeted therapy cohort, 701 (45.9%) patients had died, and 1074 (70.3%) had discontinued their first treatment line by December 31, 2017. Antibiotic exposure was not associated with OS (wHR = 1.08, 95% CI = 0.92 to 1.27) or TTD (wHR = 1.04, 95% CI = 0.91 to 1.18) (Figure 2, C and D).

Sensitivity Analyses

As the impact of antibiotic treatment was suspected to be more detrimental in the month prior to ICI initiation, a first sensitivity analysis was performed, narrowing the antibiotic time frame to 1 month. No statistically significant association between antibiotic treatment and OS or TTD was evidenced in either cohort (Figure 3).

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Figure 3.

Forest plot summarizing the analyses performed in both cohorts of patients receiving anti-PD-1 antibody or targeted therapy as a first-line treatment for metastatic melanoma. Main analysis investigated the impact of antibiotics in the 3 months prior to antimelanoma treatment on overall survival and time-to-treatment discontinuation. In the first sensitivity analysis, the antibiotic time frame was narrowed to 1 month prior to antimelanoma treatment initiation. In the second sensitivity analysis, antibiotic exposure was restricted to antibiotics having a high impact on the gut microbiota (fluoroquinolones, second- and third-generation cephalosporins, and penicillin associated with β-lactamase inhibitors). In the third sensitivity analysis, patients with infections requiring hospitalization were excluded. The error bars represent the 95% confidence intervals (CIs). ATB = antibiotics; HR = hazard ratio.

As high-impact antibiotics (fluoroquinolones, penicillin associated with β-lactamase inhibitors, and second- and third-generation cephalosporins) induce more profound gut dysbiosis (21–24), a second sensitivity analysis restricted the analysis to these antibiotics. In both the anti-PD-1 antibody and targeted therapy cohorts, no statistically significant association between high-impact antibiotics and OS or TTD was evidenced (Figure 3).

In a third sensitivity analysis, patients hospitalized with a diagnosis of infection were excluded, as antibiotics administered during hospital stays are not recorded in the SNDS database. OS and TTD were not associated with antibiotic treatment after exclusion of these patients in either the anti-PD-1 antibody or the targeted therapy cohort (Figure 3).

Crude hazard ratios (resulting from analyses in the initial nonweighted populations) and weighted hazard ratios (obtained from pseudo-populations) for the main and sensitivity analyses are provided in Supplementary Table 3 (available online).

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Table 1. Characteristics of patients receiving anti-PD-1 antibody as a first-line treatment for metastatic melanoma and standardized mean differences according to antibiotic exposure
Characteristic	No. (%)	Standardized mean difference, %
Characteristic	No. (%)	In the initial population^a	In the pseudo-population^b
Antibiotics
Antibiotics in the 3 months before initiation of the first-line treatment	749 (28.8)	—	—
Antibiotics in the month before initiation of the first-line treatment	336 (12.9)	—	—
High-impact antibiotics in the 3 months before initiation of the first-line treatment	409 (15.7)	—	—
Age, y
Mean (SD)	69 (14)	4.5	6.3 × 10⁻¹²
Range	6–98
Sex
Male	1508 (57.9)	−3.6	−6.9 × 10⁻¹²
Female	1097 (42.1)	−3.6	−6.9 × 10⁻¹²
Location of metastatic sites
Brain	422 (16.2)	−11.6	4.9 × 10⁻¹²
Lung	802 (30.8)	3.4	1.1 × 10⁻¹¹
Bone	273 (10.5)	9.8	2.1 × 10⁻¹¹
Liver	434 (16.7)	1.1	5.4 × 10⁻¹²
Digestive system	242 (9.3)	−5.0	2.6 × 10⁻¹²
Lymph node	1208 (46.4)	8.9	2.0 × 10⁻¹¹
Skin	504 (19.3)	−7.2	−7.2 × 10⁻¹²
Mediastinum	24 (0.9)	0.2	3.4 × 10⁻¹²
Urinary tract	133 (5.1)	−0.2	7.9 × 10⁻¹²
Others	217 (8.3)	−5.1	−1.3 × 10⁻¹²
Number of metastatic sites
Mean (SD)	1.6 (1.4)	−0.2	1.8 × 10⁻¹¹
Previous therapies
Stereotactic radiotherapy	129 (5.0)	−0.7	4.0 × 10⁻¹²
External beam radiotherapy	134 (5.1)	0.6	5.0 × 10⁻¹³
Lymphadenectomy	834 (32.0)	1.1	−4.2 × 10⁻¹²
Surgical resection of distant metastases	309 (11.9)	−3.3	−4.6 × 10⁻¹²
Comorbidities
Cardiovascular and cerebrovascular disease
Recent acute ischemic heart disease	29 (1.1)	1.2	3.7 × 10⁻¹²
Chronic ischemic heart disease	235 (9.0)	2.9	7.2 × 10⁻¹²
Recent acute ischemic cerebrovascular disease	28 (1.1)	6.7	9.0 × 10⁻¹²
Recent hemorrhagic stroke	44 (1.7)	−4.0	4.7 × 10⁻¹²
Sequelae or history of cerebrovascular disease	88 (3.4)	3.8	5.1 × 10⁻¹²
Recent acute heart failure	81 (3.1)	3.9	5.1 × 10⁻¹²
Chronic heart failure	113 (4.3)	5.8	1.2 × 10⁻¹¹
Cardiac arrhythmia	284 (10.9)	3.2	4.7 × 10⁻¹²
Cardiac valve disease	91 (3.5)	−0.2	1.7 × 10⁻¹²
Recent acute peripheral vascular disease	27 (1.0)	7.3	8.1 × 10⁻¹²
Chronic peripheral vascular disease	181 (6.9)	0.0	−2.9 × 10⁻¹²
Respiratory disease
Chronic respiratory disease (including asthma and chronic obstructive pulmonary disease)	298 (11.4)	16.6	2.7 × 10⁻¹¹
Metabolic disease
Diabetes	378 (14.5)	7.5	1.6 × 10⁻¹¹
Liver and pancreatic disease
Mild or moderate liver disease	23 (0.9)	0.8	−5.4 × 10⁻¹³
Severe liver disease	16 (0.6)	−1.5	−5.2 × 10⁻¹²
Pancreatic disease	3 (0.1)	0.7	5.9 × 10⁻¹³
Renal disease
Chronic renal disease	168 (6.4)	6.5	1.2 × 10⁻¹¹
Dialysis	5 (0.2)	2.3	3.6 × 10⁻¹²
Kidney transplant	3 (0.1)	0.7	2.7 × 10⁻¹²
Immunosuppression
HIV infection	5 (0.2)	2.3	3.6 × 10⁻¹²
Solid organ transplant (except kidney)	1 (0.04)	—	—
Inflammatory and systemic disease
Inflammatory bowel disease	11 (0.4)	2.3	4.3 × 10⁻¹²
Inflammatory rheumatic disorder or psoriasis requiring immunosuppressive or immunomodulating agents	22 (0.8)	7.0	8.1 × 10⁻¹²
Connective tissue disease requiring immunosuppressive or immunomodulating agents	11 (0.4)	4.9	5.7 × 10⁻¹²
Cancer
Second cancer (other than melanoma)	410 (15.7)	−4.1	9.0 × 10⁻¹³
Neurological disease
Parkinson disease and extrapyramidal syndromes	34 (1.3)	2.0	3.4 × 10⁻¹²
Multiple sclerosis and related disorders	1 (0.04)	—	—
Paralysis	121 (4.6)	−9.1	1.0 × 10⁻¹¹
Neuromuscular disease	25 (1.0)	5.1	6.4 × 10⁻¹²
Epilepsy	67 (2.6)	−2.7	4.8 × 10⁻¹²
Dementia	42 (1.6)	−3.2	−2.7 × 10⁻¹²
Mental deficiency	2 (0.1)	—	—
Psychiatric disease
Hospitalization in a psychiatric hospital	33 (1.3)	0.9	−8.6 × 10⁻¹²
Depression and mood disorders	425 (16.3)	9.9	1.7 × 10⁻¹¹
Schizophrenia and delusional disorders	55 (2.1)	−9.5	−5.3 × 10⁻¹¹
Alcohol abuse	81 (3.1)	−0.3	8.9 × 10⁻¹³
Substance abuse	8 (0.3)	5.2	5.1 × 10⁻¹²

^aBefore overlap weighting. — = Covariates with zero values (no exposed or unexposed individual) were not included in the calculation of the propensity score.
^bAfter overlap weighting.

Authors and Disclosures

Florence Poizeau, MD, MSc^1,2, Sandrine Kerbrat, MSc³, Frédéric Balusson, MSc¹, Pierre Tattevin, MD, PhD⁴, Matthieu Revest, MD, PhD,^4,5, Vincent Cattoir, PharmD, PhD⁶, David Luque-Paz, MD, MSc⁴, Thierry Lesimple, MD⁷, Marc Pracht, MD,⁷, Monica Dinulescu, MD,⁸, David Russo, MD,⁸, Emmanuel Oger, MD, PhD³ and Alain Dupuy, MD, PhD^1,2,*

¹Univ Rennes, CHU Rennes, Inserm, EHESP, Institut de recherche en santé, environnement et travail (Irset) - UMR_S 1085, Rennes, France; ²Department of Dermatology, Univ Rennes, CHU Rennes, Rennes, France; ³Univ Rennes, CHU Rennes, Pharmacoepidemiology and Health Services Research (REPERES), Rennes, France; ⁴Univ Rennes, CHU Rennes, Infectious Diseases and Intensive Care Unit, Rennes, France; ⁵Univ Rennes, Inserm, Bacterial Regulatory RNAs and Medicine (BRM) - UMR_S 1230, Rennes, France; ⁶Department of Bacteriology, Univ Rennes, CHU Rennes, Rennes, France; ⁷Department of Medical Oncology, Centre Eugène Marquis, Rennes, France; and ⁸Department of Dermatology, CHU Rennes, Rennes, France

*Correspondence to
Alain Dupuy, MD, PhD, Department of Dermatology, CHU Rennes, 2 Rue Henri le Guilloux 35000 Rennes, France (e-mail: alain.dupuy@chu-rennes.fr).

Disclosures
VC reports reimbursement for travel and/or accommodation expenses for attending congresses from bioMérieux, Menarini, and Pfizer, and personal fees for expertise and conferences from Accelerate Diagnostics, bioMérieux, Correvio, Eumedica, Menarini, and Mylan, outside the submitted work. TL reports personal fees from BMS, MSD, Novartis, and Pierre Fabre Oncology, outside the submitted work. MD reports reimbursement for travel and/or accommodation expenses for attending medical meetings from BMS, MSD, Novartis, and Pierre Fabre Oncology and personal fees from Sanofi, outside the submitted work. AD reports reimbursement for travel and/or accommodation expenses for attending medical meetings from Sanofi and UCB Pharma, and personal fees from Sanofi, outside the submitted work. The other authors have no disclosures.

Author contributions
Conceptualization, methodology: FP, PT, MR, VC, DLP, EO, AD; Data curation, investigation, software: FP, SK, FB; Writing—original draft: FP, AD; Writing—review & editing: All authors; Formal analysis: FP, EO; Funding acquisition: FP, EO, AD; Project administration, resources: FP, SK, FB, EO, AD; Validation, supervision: EO, AD; Visualization: FP.