The relationship between antibiotic exposure and outcomes from immune checkpoint inhibitor therapy
| Study | Tumour Sites | ICPI(n, %) | ATB exposure | ATB Duration | ATB Type | Administration route | Response | Survival | Notes |
|---|---|---|---|---|---|---|---|---|---|
| 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 ATBmedian OS:7.9 months vs 24.6 months,HR 4.4, 95% CI 2.6–7.7, P < 0.01median 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 vsin 22% unexposed, P < 0.01 | ATB vs no ATBmedian OS:17.3 months vs 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03median 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%) | pATBBeta-lactamin 22, 75%cATBBeta-lactamin 49, 72% | – | pATB:PD in 80% exposed vs 44% unexposed, p < 0.001cATB: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 ATBmedian PFS:1.2 [95% CI, 0.5–5.8] vs 4.4 months [95% CI, 2.5–7.4], P = 0.04median 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 AIER23 (15%)Low AIER(134, 85%) | Median duration7.0 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 EIOPRR: 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 = 0.11DCR: 47.8% vs 56.0%, p = 0.50, | High vs low AIERmedian PFS:1.9 [95% CI, 1.3–3.0] vs3.5 months [95% CI, 2.6–5.0] p < 0.0001median 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 EIOPmedian PFS:2.2 [95% CI, 1.8–3.2] vs 3.3 months [95% CI, 2.6–4.8]P = 0.1772median OS:11.9 [95% CI, 9.2–15.6] vs 5.9 months [95% CI, 4.5–22.5]P = 0.2492Significant 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 ATBHR 1.6; 95% CI: 0.84–3.03, p = 0.048Median 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 ATBPFS97 (95% CI 84–122) vs 178 days (95% CI 155–304) p = 0.049OS317 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 = 0.00021pATB 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 ATBFor all groups combinedmedian PFS:3.5 vs 4.1 monthsp = 0.017median OS:11.5 vs 20.6 monthsp < 0.001For 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 ATBOS:8.1 (95%CI 3.6–12.5) vs 11.9 months (95%CI 9.1–14.7) p = 0.026PFS: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 ATBOS:2.9 (95%CI, 1.6–4.1) vs 14.2 months (95%CI, 7.9–20.6) p = 0.0001PFS: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 pATBORR37% vs 24% p = 0.276 Clinical benefit rate 27% vs 29% p = 0.859 | ATB vs no ATBmedian OS: 5.1 (IQR 3.4-not reached) vs 13.4 months (IQR 10.6-not reached) p = 0.03median 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 ORRp = 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 < 0.0001and 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 groups25% vs 23% (adjusted OR 1.2, p = 0.20). | ATB vs no ATBPFS2.0 vs 3.8 monthsp < 0.001)OS4.0 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 ATBPFS2.3 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 ATBOS5.4 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%) | ORRATB vs no ATB0% vs 34% | ATB vs no ATBmedian PFS2.4 vs 7.3 months(HR 0.28, 95% CI 0.10–0.76p = 0.01)median OS10.7 vs 18.3 months(HR: 0.52, 95% CI 0.21–1.32p = 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 ATBmedian PFS3.1 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 ATBORR12.9 vs 34.8%p = 0.026 | ATB vs no ATB2.6 (1.7–5.3) vs8.1 (5.6–10.9) monthsp = 0.008 | – |
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