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

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 = 0.26

ATB 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 days

Beta-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 macrolides

–

–

ATB 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 ICPIs

–

–

–

cATB 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 macrolides

Mostly oral

–

ATB 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 fluoroquinolones

–

Lower ORR in ATB group vs no ATB p < 0.002

ATB 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± inhibitors

Oral (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

–