Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer

Abstract

IMPORTANCE Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. OBJECTIVE To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. DESIGN, SETTING, AND PARTICIPANTS This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials.MAIN OUTCOMES AND MEASURES Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. RESULTS Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status.CONCLUSIONS AND RELEVANCE Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment

“…The gut microbiome was also recently shown to have direct effects on the innate and adaptive immune responses, with broad‐spectrum antibiotic treatment adversely influencing the outcomes of ICI therapy through the modulation of the intestinal microbiota . A prospective study of 196 patients with NSCLC also concluded that antibiotic use before starting ICI therapy was associated with poorer rates of treatment response and survival . However, our findings suggest that corticosteroid or antibiotic use before ICI treatment was not related to RP.…”

The diagnostic value of a seven‐autoantibody panel and a nomogram with a scoring table for predicting the risk of non–small‐cell lung cancer

“…A recent study pointed out that antibiotic treatment is associated with a worse immune response, which may also be a potential reason for our study’s sensitivity. Even so, the sensitivity of our seven AAB panel was as high as that of the EarlyCDT‐Lung test and significantly higher than that of traditional tumor markers .…”

Vildagliptin‐induced ground‐glass nodules mimicking lung metastases in a cancer patient receiving Lactobacillus probiotic supplementation

“…Probiotics are micro‐organisms that could exert immunological effects by modulating a gut microbiota imbalance. Accumulated data have shown that gut microbiota contribute to the antitumor activity of immune checkpoint inhibitors . The association between gut microbiota and the lung immune system may be critical in the treatment outcome of lung cancer .…”