Survival in advanced non-small cell lung cancer (NSCLC) declined significantly in patients treated with antibiotics or a proton pump inhibitor (PPI) at the same time they received a PD-L1 inhibitor, pooled data from two randomized trials showed.

Overall, patients who received an antibiotic along with either docetaxel or atezolizumab (Tecentriq) had a 20% higher survival hazard, increasing to 26% for patients who received a PPI. Further analysis showed that the adverse associations were limited to patients randomized to atezolizumab, according to Fernanda Herrera, MD, of Lausanne University Hospital in Switzerland, and colleagues.

Concomitant use of antibiotics or a PPI did not affect progression-free survival (PFS) or OS in patients randomized to docetaxel, they reported in the Annals of Oncology.

"Whether ATB [antibiotics] and PPI are purely prognostic or contributing to resistance to checkpoint inhibition remains a matter of debate," the authors concluded. "However, these data should encourage physicians to carefully evaluate the need for comedications, such as PPI and ATB in their patients. Validation of these results from other randomized controlled trials is needed, considering that prospective testing of ATB and PPI on outcome after ICI (immune checkpoint inhibitors) may not be feasible."

The findings added to an emerging clinical story about the two drug classes' potentially negative effects on immune checkpoint inhibitors. Beginning with an 80-patient retrospective chart review reported in 2017, more than a dozen studies have documented worse outcomes with antibiotic use temporally related to immunotherapy for cancer, primarily anti-PD-1/L1 agents but also CTLA-4 inhibitors. Most of the studies involved patients with NSCLC, but similar adverse effects of antibiotics have been observed in patients with melanoma, urothelial cancer, and renal cell carcinoma treated with checkpoint inhibitors.

The data have been less consistent for PPI use and outcomes with immune checkpoint inhibitors. A study reported in 2018 showed that PPIs adversely affected the efficacy of combination therapy for melanoma with nivolumab (Opdivo) and ipilimumab (Yervoy), but not single-agent ipilimumab.

A small single-center retrospective study reported in 2019 showed no evidence of adverse effects of PPI therapy in patients with various types of cancer treated with pembrolizumab (Keytruda), nivolumab, or ipilimumab. Another recent single-center retrospective review showed no difference in PFS, OS, or immune-related adverse events by PPI use among patients treated with PD-1/L1 inhibitors.

The rationale for investigating the effects of antibiotics and PPIs on cancer immunotherapy has come from studies showing that the composition of the gut microbiome influences immune checkpoint inhibitor efficacy. Antibiotics and PPIs can alter the microbiome makeup.

The evidence linking antibiotic use to reduced efficacy of checkpoint inhibitors is not widely recognized in the oncology community, said thoracic oncologist Fred R. Hirsch, MD, PhD, of Mount Sinai Medical Center in New York City. Additionally, no clear direction has been provided with respect to applying the information in the clinic.

"I don't think we're clear about what it really means in terms of interpreting it clinically, but oncologists need to start paying more attention to it," Hirsch, who was not involved in the study, told MedPage Today. "From an academic point of view, we need to better understand what it is all about."

Herrera and colleagues retrospectively reviewed pooled data from POPLAR and OAK randomized trials comparing atezolizumab and docetaxel in patients with previously treated NSCLC. The analysis comprised a total of 1,512 patients, 757 randomized to atezolizumab and 755 to docetaxel. The primary objective of the analysis was to determine the impact of antibiotic and PPI use on OS and PFS.

The data showed that 169 (22.3%) patients in the atezolizumab group and 202 (26.8%) in the docetaxel arm received antibiotics, whereas 234 (30.9%) and 260 (34.4%), respectively, received PPIs. In a multivariate analysis, both antibiotic use and PPI use had significant adverse associations with OS.

Additional analysis showed that antibiotics and PPIs were associated with significantly shorter median OS in patients treated with atezolizumab: 8.5 versus 14.1 months (HR 1.32, 95% CI 1.06-1.63) and 9.6 versus 14.5 months (HR 1.45, 95% CI 1.20-1.75), respectively. An exploratory analysis suggested that the adverse effect on OS was seen across all classes of antibiotics.

Patients randomized to atezolizumab also had a briefer PFS if they received a PPI (1.9 vs 2.8 months, HR 1.30, 95% CI 1.10-1.53), but antibiotic use did not influence PFS.

Neither antibiotic use nor PPI use had a significant association with OS or PFS in the docetaxel group, the authors reported. However, hazard ratios exceeded 1.0 for antibiotics and PPIs.

The authors acknowledged that the findings were based on an exploratory retrospective analysis of subgroups that were not prespecified. Additionally, they did not characterize biological mechanisms by which antibiotics or PPIs affected the efficacy of atezolizumab.

Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow