Dr. Lalani’s article entitled “Effect of Antibiotic Use on Outcomes with Systemic Therapies in Metastatic Renal Cell Carcinoma” was published in the June 2020 issue of the journal.1 The gut microbiome has emerged as a key component of the host immune system and a central player in anticancer immunosurveillance. Antibiotic use disrupts the microbial ecosystem, which has been shown to predispose individuals to various multi-system illnesses. There has been recent interest in how antibiotics may influence response to therapy in patients with various cancers, and thus Dr. Lalani and colleagues sought to evaluate the association of antibiotic use and clinical outcomes in metastatic renal cell carcinoma (mRCC) patients with the range of approved systemic therapies, including immune checkpoint inhibitors.
The authors analyzed two cohorts: an institutional cohort (n=146) receiving PD-1/ PD-L1-based immune checkpoint inhibitors and a clinical trial cohort (n=4,144) receiving interferon-α (n=510), mTOR inhibitors (n=660), and VEGF-TT (n=2974) on phase II/III clinical trials. The association of antibiotic use (defined as use from 8 weeks before to 4 weeks after the initiation of anticancer therapy) with progression-free survival and overall survival was evaluated using Cox regression, adjusted for known prognostic factors including IMDC risk factors.
The majority of patients were male (71.2% institutional cohort; 70.7% clinical trials cohort), had clear cell histology (84.9% institutional cohort; 89.6% clinical trials cohort), and were at intermediate risk (59.9% institutional cohort; 41.1% clinical trials cohort). In the institutional cohort, the median follow-up since initiation of immune checkpoint inhibitor therapy was 16.6 months (range 0.7-67.8), and the median duration of therapy was 5.1 months (range <1-61.4). The objective response rate was 30% (95% CI 23-38%), median PFS was 7.2 months (95% CI 3.5-8.8), and 1-yr OS rate was 77% (95% CI 68-83%). Antibiotic users (n=31, 21%) had a lower objective response rate (12.9% vs 34.8%, p=0.026) and shorter PFS (adjusted HR 1.96, 95% CI 1.20-3.20, p=0.007) than antibiotic nonusers:
Additionally, the negative association of antibiotic use with PFS was consistent across subgroups by type of therapy, line of therapy, and by IMDC risk group (all interaction p-values >0.35). There was no difference in overall survival between the two groups (HR 1.44, 95% CI 0.75-2.77):
In the clinical trials cohort, antibiotic use (n=709, 17%) adversely impacted overall survival in patients treated with interferon (HR=1.62, 95% CI 1.13-2.31, p=0.008) or with VEGF-TT and prior cytokines (HR=1.65, 95% CI 1.04-2.62, p=0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines.
This study demonstrated that antibiotic use was associated with worse clinical outcomes in mRCC patients treated with either contemporary PD-(L)1-based immune checkpoint inhibitors or cytokines. Antibiotic use did not appear to impact survival in patients treated with VEGF-TT without prior cytokines or mTOR inhibitors. Additionally, these findings are consistent with and build upon previous reports evaluating antibiotic use and outcomes with immunotherapy across other solid tumors, however, this data may better reflect the shift in the standard of care for mRCC therapy as in this study 43% received first-line immune checkpoint inhibitor and 45% received combination immune checkpoint inhibitors.
Dr. Lalani concluded with several important implications of this study:
- There is importance in antimicrobial stewardship in that prescribing patterns may affect subsequent outcomes of immune checkpoint inhibitor therapies
- Large scale prospective efforts are warranted to better capture and analyze on-treatment fecal samples and changes in bacterial subspecies
- This may lead to a deeper understanding of the host microbiome and elucidate meaningful strategies to optimize the efficacy and reduce toxicity of contemporary immune checkpoint inhibitors
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 18th Meeting of the EAU Section of Oncological Urology (ESOU21), January 29-31, 2021