Antibiotics linked to worse survival outcomes with atezolizumab in bladder cancer

Concomitant use of antibiotics and the immune checkpoint inhibitor atezolizumab (Tecentriq) was linked to worse overall survival (OS) outcomes in patients with locally advanced or metastatic urothelial bladder cancer, according to an analysis of data from the single-arm phase 2 IMvigor210 and phase 3 randomized IMvigor211 trials.¹

The analysis, which was published European Urology, found that among 847 patients receiving atezolizumab, use of antibiotics was associated with worse OS outcomes (HR, 1.44; 95% CI, 1.19-1.73), as well as worse progression-free survival (PFS) outcomes (HR, 1.24; 95% CI, 1.05-1.46). Among 415 patients who received chemotherapy, however, antibiotic use was not associated with poorer OS (HR, 1.15; 95% CI, 0.91-1.46) or PFS (HR, 1.09; 95% CI, 0.88-1.36) outcomes.

For the IMvigor211 data specifically, the investigators determined that among antibiotic users, the HR for OS was 0.95 (95% CI, 0.71-1.25) for atezolizumab versus chemotherapy compared with 0.73 for the comparison among nonusers.

"We demonstrated that antibiotic use is directly associated with worse survival in patients with urothelial carcinoma when they're treated with atezolizumab. But no antibiotic association was observed in patients treated with chemotherapy, suggesting that antibiotics may specifically reduce the effectiveness of cancer immunotherapies," Ashley Hopkins, PhD, a postdoctoral fellow working in the Precision Medicines Group at Flinders University in Australia, stated in a press release.²

The researchers suggested that their findings show that there are real consequences to overprescribing antibiotics in patients with cancer.

“The study does not justify a change in antibiotic selection for infections; however, antibiotic overuse occurs in cancer care and this needs to be evaluated for immune checkpoint inhibitors,” they wrote in their study conclusion.

For their analysis of antibiotic use and survival with atezolizumab, investigators used a Cox proportional hazard model. The study defined use of antibiotics as receiving them in the range of 30 days before to 30 days following the start of treatment.

Atezolizumab is currently FDA approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1; are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status; or have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy.

Data from the IMvigor210 trial supported the FDA’s accelerated approval of atezolizumab in bladder cancer. In the phase 2 single-arm study, there was a cohort of 310 patients with locally advanced or metastatic urothelial carcinoma who progressed after a platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Across this entire group, the objective response rate (ORR) was 14.8%, including ORRs of 26% in PD-L1–positive patients and 9.5% in PD-L1–negative patients.

The phase 3 III IMvigor211 trial was intended as a confirmatory trial for these phase 2 data. In IMvigor211, 931 patients with previously treated locally advanced or metastatic urothelial carcinoma were randomized to atezolizumab or investigator’s choice of chemotherapy, which included vinflunine, paclitaxel, or docetaxel. The results of the study showed that the PD-L1 inhibitor fell short and did not improve OS versus chemotherapy in this second-line setting.

Regarding the next steps following the antibiotic analysis, Hopkins said, "These results provide strong justification for prospective studies to tease out whether antibiotics are primarily a surrogate of an unfit or immunodeficient patient or whether antibiotic effects on the gut microbiota are having casual impacts on immune checkpoint inhibitor efficacy. If the latter is true, in patients at a high risk of recurrent infections, it may need to be considered whether immune checkpoint inhibitor therapy is the most appropriate way to go."

References

1. Hopkins AM, Kichenadasse G, Karapetis CS, et al. Concomitant antibiotic use and survival in urothelial carcinoma treated with atezolizumab [published online July 11, 2020]. Eur Urol. doi: 10.1016/j.eururo.2020.06.061

2. Antibiotic overuse reduces bladder cancer survival rates. Published August 16, 2020. https://bit.ly/2EmfEDT. Accessed August 20, 2020.