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Table 1 The relationship between antibiotic exposure and outcomes from immune checkpoint inhibitor therapy

From: Antibiotic therapy and outcome from immune-checkpoint inhibitors

StudyTumour SitesICPI
(n, %)
ATB exposureATB DurationATB TypeAdministration routeResponseSurvivalNotes
Derosa L et al. [9]NSCLC (239)PD-L1 (205, 86%)
PD-L1/ CTLA-4 (34, 14%)
pATB (within 30 days)
(48, 20%)
No ATB (191, 80%)
≤ 7 days
(35, 73%)
>  7 days
(13, 27%)
Beta-lactam
(15, 32%)
Quinolones
(14, 29%)
Macrolides
(4, 8%)
Sulfonamides (12, 25%)
Tetracyclines
(1, 2%)
Nitromidazole (1, 2%)
Others
(1, 2%)
Oral
(42, 87%)
IM/ IV
(5, 11%)
Unreported
(1, 2%)
PD in 52% exposed vs in 43% unexposed, P = 0.26ATB vs no ATB
median OS:
7.9 months vs 24.6 months,
HR 4.4, 95% CI 2.6–7.7, P < 0.01
median PFS:
1.9 months vs 3.8 months, HR 1.5, 95%
CI 1.0–2.2, P = 0.03
Significant impact supported by multivariate analysis
RCC (121)PD-L1 (106, 88%)
PD-L1/CTLA-4
(10, 8%)
PD-L1/Bevacizumab (5, 4%)
pATB (within 30 days) (16, 13%)
No ATB (105, 87%)
≤ 7 days
(8, 50%)
>  7 days
(8, 50%)
Beta-lactam
(13, 82%)
Quinolones
(1, 6%)
Tetracyclines
(1, 6%)
Aminoglycosides (1, 6%)
Oral
(15, 94%)
IV/ IM
(1, 6%)
PD in 75% exposed vs
in 22% unexposed, P < 0.01
ATB vs no ATB
median OS:
17.3 months vs 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03
median PFS:
1.9 months vs 7.4 months, HR 3.1, 95% CI 1.4–6.9, P < 0.01
Pinato DJ et al. [10]NSCLC
(119, 60%)
Melanoma (38, 20%)
Renal
(27, 14%)
Head & neck
(10, 5%)
Total n = 196
PD-1/PD-L1
(189, 96%)
pATB (29, 15%)
(within 30 days)
cATB (during ICPI therapy until cessation) (68, 35%)
no ATB
(99, 50%)
pATB
≤7 days
(26, 90%)
>  7 days
(3, 10%)
cATB
≤7 days
(39, 88%)
pATB
Beta-lactam
in 22, 75%
cATB
Beta-lactam
in 49, 72%
pATB:
PD in 80% exposed vs 44% unexposed, p < 0.001
cATB:
PD in 50% exposed vs 49% unexposed, p = 0.87
pATB (p < 0.001) but not cATB (p = 0.76) predicted worse OS (26 vs 2 months, HR 7.4, 95% CI 4.2–12.9) Multivariate analysis confirmed pATB as a predictor of OS (HR 3.4, 95%CI 1.9–6.1 p < 0.001)ICPI-refractory in 81% pATB vs 44% no pATB, p < 0.001
Hakozaki T et al. [11]NSCLC (90)PD-1 (90)pATB
(13, 14%)
(30 days before ICPI initiation)
no pATB (77, 86%)
≤7 days (1, 8%)
>  7 days (12, 92%)
Beta-lactam (8, 61%) Sulfonamides (4, 31%)
Quinolones (1, 8%)
Oral
(10, 77%)
IV
(3, 23%)
pATB vs no ATB
median PFS:
1.2 [95% CI, 0.5–5.8] vs 4.4 months [95% CI, 2.5–7.4], P = 0.04
median OS:
8.8 months vs not reached, P = 0.037
Unsupported by multivariate analysis of pATB and OS:
HR 2.02, (95% CI, 0.7–5.83, P = 0.19)
Galli G et al. [12]NSCLC (157)PD-1 (98, 62.4%)
PD-L1 (52, 33%)
CTLA4 (1, 0.6%)
PD-L1/CTLA4 (6, 4%)
ATB:
in EIOP (27, 17%)
in WIOP (46, 29%)
No ATB (111, 71%)
High AIER
23 (15%)
Low AIER
(134, 85%)
Median duration
7.0 days (5.0–33.0)
Quinolone (33, 72%)
Macrolide (8, 17%)
Beta-lactam (14, 30%)
Rifaximin (4, 8.7%)
Oral
(44, 98%) IM
(3, 6.5%), IV
(2, 4.4%).
Exposed in EIOP
RR: 11.1% vs 24.6%, p = 0.20; DCR: 51.9% vs 56.2%, p = 0.8319.
AIER (high vs low)
RR: 8.7%, vs 26.6%. p = 0.11
DCR: 47.8% vs 56.0%, p = 0.50,
High vs low AIER
median PFS:
1.9 [95% CI, 1.3–3.0] vs
3.5 months [95% CI, 2.6–5.0] p < 0.0001
median OS:
5.1 [95% CI, 3.8–5.9] vs 13.2 months [95% CI, 9.9–5.9] p = 0.0004
Exposed vs unexposed in EIOP
median PFS:
2.2 [95% CI, 1.8–3.2] vs 3.3 months [95% CI, 2.6–4.8]
P = 0.1772
median OS:
11.9 [95% CI, 9.2–15.6] vs 5.9 months [95% CI, 4.5–22.5]
P = 0.2492
Significant impact supported by multivariate analysis
Ahmed J et al. [13]NSCLC (34, 57%)
Renal (4, 7%)
HCC (5, 8%)
Urothelial (5, 8%)
Other (12 20%)
Total n = 60
ICPI with chemotherapy (8, 13%)
PD-1 (49, 82%)
PD-L1 (3, 5%)
pATB or cATB (2 weeks before or after ICPI initiation)
(17, 28%)
No ATB (43, 72%)
8–14 daysBeta-lactam (14, 82%)
Quinolone (5, 29%)
Vancomycin (7, 41%)
Daptomycin (1, 6%)
Linezolid (2, 12%)
Meropenem (3, 18%)
Tetracyclines (2, 12%)
Bactrim (1, 6%)
Azithromycin (1, 6%)
Nitrofurantoin (1, 6%)
RR: 29.4% in exposed vs 62.8% in unexposed,
p = 0.024
Decreased PFS with ATB
HR 1.6; 95% CI: 0.84–3.03, p = 0.048
Median OS:
24 in exposed vs 89 months in unexposed p = 0.003
Narrow-spectrum ATB alone did not affect the RR, but broad-spectrum ATB decreased RR (p = 0.02) and PFS (p = 0.012).
Multivariate analysis found that only ATB decreased RR (p = 0.0038) and PFS (p = 0.01)
Tinsley N et al. [14]Melanoma (206, 66%)
NSCLC (56, 18%)
Renal (46, 15%)
Total n = 303
pATB or cATB (2 weeks before or 6 weeks after ICPI initiation) (94,31%)The commonest ATBs: beta-lactam and macrolidesATB vs no ATB
PFS
97 (95% CI 84–122) vs 178 days (95% CI 155–304) p = 0.049
OS
317 days (95% CI 221–584) vs 651 days (95% CI 477–998) p = 0.001.
Cumulative ATB (>  10 days, multiple concurrent/successive courses) further shortened PFS to 87 days (95% CI 83–122) p = 0.0093 and OS to 193 days (95% CI 96–355) p = 0.00021
pATB exposed had shorter PFS and OS than cATB exposed (HR 1.37, p = 0.29 and HR 1.72, p = 0.08)
Khan U et al. [15]Lung (111, 46%)
Bladder (36, 15%)
Renal (35, 14%)
GI (16, 7%)
Other (44, 18%)
Total n = 242
PD-1 (189, 78%)
PD-L1 (52, 21%)
75, 46 and 32% received ATBs within 6 months, 60 days and 30 days of starting ICPIscATB use in the first 30- or 60-days of ICPI therapy associated with inferior ORR
(OR 0.40, p = 0.01 and OR 0.42, p = 0.005, respectively)
pATB or cATB use in the first 6 months of ICPI use had no impact
Routy B et al. [5]NSCLC (140, 56%), RCC (67, 27%)
urothelial carcinoma (42, 17%)
Total n = 249
PD-1/PD-L1 (249, 100%)pATB or cATB
(2 months before or 1 month after ICPI initiation)
(69, 28%)
no ATB (180, 72%)
β-lactam+/− inhibitors, fluoroquinolonesor macrolidesMostly oralATB vs no ATB
For all groups combined
median PFS:
3.5 vs 4.1 months
p = 0.017
median OS:
11.5 vs 20.6 months
p < 0.001
For individual cancer groups,
PFS and/or OS were also shorter in ATB group
Univariate and multivariate Cox regression analyses confirmed the negative impact of ATB, independent from other factors
Mielgo-Rubio X et al. [16]NSCLC (168)PD-1 (168,100%)pATB or cATB
(2 months before or 1 month after ICPI initiation)
(47.9%)
No ATB
(52.1%)
Oral (70%) IV (30%)ATB vs no ATB
OS:
8.1 (95%CI 3.6–12.5) vs 11.9 months (95%CI 9.1–14.7) p = 0.026
PFS:
5 (95%CI 3.1–6.9) vs 7.3 months (95%CI 2–12) p = 0.028
IV ATB had a more negative impact than oral ATB
OS:
2.9 (95%CI, 1.6–4.1) vs 14.2 months (95%CI, 7.9–20.6) p = 0.0001
PFS:
2.2 (95%CI 0.6–3.7) vs 5.9 months (95%CI 3.9–8) p = 0.001
Ouaknine J et al. [17]NSCLC (72)PD-1 (72,100%)pATB or cATB (2 months before or 1 month after ICPI initiation)
(30, 42%)
No ATB (42, 58%)
Median duration 9.5 days (IQR 7–14)The commonest ATBs:
β-lactam and vancomycin
Mostly oral (65%)ATB vs no pATB
ORR
37% vs 24% p = 0.276 Clinical benefit rate 27% vs 29% p = 0.859
ATB vs no ATB
median OS: 5.1  (IQR 3.4-not reached) vs 13.4 months (IQR 10.6-not reached) p = 0.03
median PFS:
2.8
(IQR 1.4–5.1) vs 3.3 months (IQR 1.8–7.3) p = 0.249
Kaderbhai C et al. [18]NSCLC (74)PD-1 (74, 100%)pATB
(within 3 months) (15, 20%)
No ATB
(59, 80%)
No difference in ORR
p = 0.75
No difference in PFS and p = 0.72,
Zhao S et al. [19]NSCLC (109)PD-1 (57, 52%)
PD-1/ chemotherapy (33, 30%)
PD-1/apatinib or bevacizumab (19, 18%)
pATB or cATB (1 month before or after ICPI initiation) (20, 18%)
No ATB (89, 82%)
The commonest ATBs:
β-lactam inhibitors and fluoroquinolones
Higher PD rates in ATB-treated group (p = 0.092)ATB decreased PFS, p < 0.0001
and OS, p = 0.0021
In multivariable analysis, ATB was associated with shorter PFS (HR = 0.29, 95%CI 0.15–0.56, p < 0.0001) and OS (HR = 0.35, 95%CI 0.16–0.77, p = 0.009)
Thompson et al. [20]NSCLC (74)PD-1 (74, 100%)pATB (within 6 weeks) (18, 24%)
No ATB (56, 76%)
Mostly fluoroquinolones (50%)ORR in ATB vs no ATB groups
25% vs 23% (adjusted OR 1.2, p = 0.20).
ATB vs no ATB
PFS
2.0 vs 3.8 months
p < 0.001)
OS
4.0 vs 12.6 months, p = 0.005
The impact of ATB on PFS and OS was independent of other factors (HR 2.5, p = 0.02), (HR 3.5, p = 0.004), respectively
Derosa L et al. [21]RCC (80)PD1/PD-L1 (67, 84%),
PD-1/CTLA-4 (10, 12%)
PD-L1/ bevacizumab (3, 4%)
pATB
(within 1 month)
(16, 20%)
No ATB (64, 80%)
Mostly β-lactam and fluoroquinolonesLower ORR in ATB group vs no ATB p < 0.002ATB vs no ATB
PFS
2.3 vs. 8.1 months, p < 0.001
Confirmed by multivariate analysis
Do TP et al. [22]Lung (109)PD-1 (109, 100%)pATB or cATB
(1 month before ICPI or concurrently)
(87, 80%)
No ATB (22, 20%)
β-lactam
(12, 13.8%) quinolones
(11,12.6%)
other
(7, 8.1%) multiple antibiotics
(57, 65.5%)
ATB vs no ATB
OS
5.4 vs 17.2 months
(HR 0.29, 95% CI 0.15–0.58 p = 0.0004)
 
Elkrief A et al. [23]Melanoma (74)PD-1 (54, 73%)
CTLA-4 (5, 6.8%)
CTLA-4/ carboplatin/paclitaxel (15, 20%)
pATB
(within 1 month)
(10, 13.5%)
No ATB
(64, 86.5%)
> 7 days (7, 70%)
< 7 days (3, 30%)
Mostly β-lactams± inhibitorsOral (40%)
IV (60%)
ORR
ATB vs no ATB
0% vs 34%
ATB vs no ATB
median PFS
2.4 vs 7.3 months
(HR 0.28, 95% CI 0.10–0.76
p = 0.01)
median OS
10.7 vs 18.3 months
(HR: 0.52, 95% CI 0.21–1.32
p = 0.17).
The multivariate analysis supported the impact of ATB on PFS
(HR 0.32 (0.13–0.83) 95% CI, p = 0.02).
Huemer F et al. [24]NSCLC (30)PD-1 (30, 100%)pATB or cATB
(1 month before or 1 month after ICPI initiation)
(11, 37%)
No ATB
(19, 63%)
β-lactam (7, 64%), fluoroquinolones (4, 36%) and carbapenems (2, 18%)ATB vs no ATB
median PFS
3.1 vs 2.9 months, (HR = 0.46 95%CI: 0.12–0.90 p = 0.031). median OS 15.1 vs 7.5 months (HR = 0.31 95%CI: 0.02–0.78 p = 0.026).
The multivariate analysis supported the impact of ATB on PFS (p = 0.028) and OS (p = 0.026).
Lalani A et al. [25]RCC (146)PD-1/PD-L1 (146, 100%)pATB or cATB
(2 months before or 1 month after ICPI initiation) (31, 21%)
No ATB
(115, 79%)
ATB vs no ATB
ORR
12.9 vs 34.8%
p = 0.026
ATB vs no ATB
2.6 (1.7–5.3) vs
8.1 (5.6–10.9) months
p = 0.008
  1. Abbreviations: EIOP (Early Immunotherapy Period): antibiotics given between 1 month before and 3 months after starting immunotherapy, WIOP (Whole immunotherapy Period): antibiotics given throughout immunotherapy, cumulative exposure to antibiotics; AIER defined as “days of antibiotic therapy/days of immunotherapy’: AIER stratified over the median (4.2%) into high and low AIER groups, RR Response rate, DCR Disease control rate, GI Gastrointestinal, ORR Overall response rate, IV Intravenous, IM Intramuscular