NSCLC Care Could Benefit From Antibiotic Stewardship

Care for patients living with non–small cell lung cancer (NSCLC) could benefit greatly from implementing antiobiotic stewardship practices, particularly among patients treated for their cancer with anti-PD(L)-1 inhibition immunotherapy (IO) alone or IO plus platinum-doublet chemotherapy (chemo/IO).

The investigators of a new study published in NPJ Precision Oncology came to this conclusion after analyzing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) among patients with NSCLC and looking at their outcomes for 2 care windows of antibiotic administration: within 60 days prior to IO or chemo/IO and between 60 days before and 42 days after IO or chemo/IO.¹

“There is a growing body of evidence to suggest that antibiotic exposure prior to the initiation of IO disrupts the gut microbiota composition and negatively impacts the clinical outcomes of patients with NSCLC and other solid malignancies,” the authors wrote. “Given increasing use of chemo-IO as a mainstay first-line therapy in patients with NSCLC, and recent approvals of chemo-IO in the neoadjuvant setting 21, there is a need to further understand the role of antibiotic use in clinical outcomes prior to the initiation of chemo-IO.”

In this investigation, patients who received antibiotics prior to their immunotherapy or immunotherapy and chemotherapy had worse survival outcomes compared with patients who did not receive antibiotics | Image Credit: Елена Бутусова-stockk.adobe.com

NSCLC is not the only disease state in which the gut microbiota is thought have an impact. Its influence has also been investigated among patients who have myelodysplastic syndrome, hepatocellular carcinoma, myasthenia gravis, and melanoma, among others.^2-5

Of the 769 patients in the chemo/IO cohort, antibiotics were given to 183 patients in the 60 days before their treatment; and among the 1259 patients in the IO-alone cohort, antibiotics were given to 277 in that same 60-day window. Median (IQR) ages in these cohorts were very close, with those in the chemo/IO group being slightly younger: 66 (60-72) years vs 67 (59-73). Thirteen percent and 10%, respectively, had a baseline ECOG performance status (PS) of 2 or higher vs 87% and 90% whose baseline ECOG PS was 0 to 1.

The most common disease histologies were adenocarcinoma and squamous cell carcinoma, and a smoking history was evident in 87% of the chemo/IO group and 88% of the IO-alone group. A PD-L1 status of less than 1% was seen in 68% and 36%, respectively; 1% to 49% in 22% and 20%; and 50% or more, 11% and 44%. Also at baseline, brain metastases were not seen in 76% of the chemo/IO group or 66% of the IO-alone group, and liver metastases were not seen in 90% and 74%, respectively.

In general, the study authors noted that ephalosporins, sulfonamides, and quinolones were the most common single-agent antibiotics and antibiotic exposure was more common in younger patients overall (P < .001).

Specifically among the patients in the chemo/IO group who received antibiotics vs those who didn’t receive antibiotics in the 60 days before receipt of treatment:

• ORR was 27% vs 40% (P = .001)
• PFS was 3.9 vs 5.9 months, for a 35% greater risk of death (HR, 1.35; 95% CI, 1.1-1.6; P = .0012)
• OS was 10 vs 15 months, for a 50% greater risk of death (HR, 1.5; 95% CI, 1.2-1.8; P = .00014)
• Combination antibiotics led to the shortest overall PFS of 1.9 months
• Oral antibiotics vs no antibiotics resulted in a PFS of just 2.8 months
• OS after receiving oral or intravenous antibiotics was worse vs receiving no antibiotics

Overall results were similar when looking at outcomes from 60 days before to 42 days after treatment for ORR (P < .001), PFS (HR, 1.35; 95% CI, 1.15-1.59), and OS (HR, 1.58; 95% CI, 1.31-1.90).

Among the patients in the IO-alone group who received antibiotics vs those who didn’t receive antibiotics in the 60 days before receipt of treatment:

• ORR was 16% vs 22% (P = .045)
• PFS was 1.9 vs 2.8 months, for a 40% greater risk of death (HR, 1.40; 95% CI,1.2-1.6; P < .0001)
• OS was 5.3 vs 13 months, for a 47% greater risk of death (HR, 1.47; 95% CI, 1.3-1.7; P < .0001)
• Combination antibiotics were more common among those who received 2 or more lines of IO and had brain metastases at baseline

An additional meta-analysis they conducted of available studies that investigated antibiotic exposure’s impact on patients with NSCLC who received chemo/IO or IO found a 93% greater risk of death (HR, 19.3; 95% CI, 1.52-2.45) compared with no antibiotic exposure.

Beyond greater antibiotic stewardship in this NSCLC setting, the authors also recommend minimizing antibiotic exposure and selecting narrow-spectrum antibiotic classes when administration of such is unavoidable.

Potential limitations on these findings are patients’ poor performance status and the infections among those who received antibiotics. Also, that simply receiving an antibiotic may not lend itself to poor outcomes, due to their finding that patients receiving oral antibiotics having worse outcomes than patients who received intravenous antibiotics, “suggesting that antibiotic exposure may not merely act as a surrogate for overall ‘sickness’ or severity of infection.” In addition, patients may have been on nonantibiotic medications, and details were not available on the duration of antibiotic administration.

References

1. Elkrief A, Méndez-Salazar EO, Maillou J, et al. Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy. NPJ Precis Oncol. 2024;8(1):143. doi:10.1038/s41698-024-00630-w

2. Feng Z, Liao M, Guo X, Li L, Zhang L. Effects of immune cells in mediating the relationship between gut microbiota and myelodysplastic syndrome: a bidirectional two-sample, two-step Mendelian randomization study. Discov Oncol. 2024;15(1):199. doi:10.1007/s12672-024-01061-6doi:10.1007/s12672-024-01061-6

3. Tsai MC, Kuo YH, Tai WC, et al. Distinct gut microbiota alterations in patients with early-stage and advanced-stage hepatocellular carcinoma. Adv Digest Med. Published online February 1, 2024. doi:10.1002/aid2.13385

4. Su T, Yin X, Ren J, Lang Y, Zhang W, Cui L. Causal relationship between gut microbiota and myasthenia gravis: a bidirectional mendelian randomization study. Cell Biosci. 2023;13(1):204. doi:10.1186/s13578-023-01163-8

5. Witt RG, Cass SH, Tran T, et al. Gut microbiome in patients with early-stage and late-stage melanoma. JAMA Dermatol. 2023;159(10):1076-1084. doi:10.1001/jamadermatol.2023.2955