A recent post-hoc analysis of the phase I/III IMpower133 trial examined the potential impact of prior antibiotic, proton pump inhibitor (PPI), and probiotic use on outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with immune checkpoint inhibitors. The study, published in the International Journal of Cancer in January 2025, aimed to determine if exposure to these medications affected clinical outcomes differently between patients receiving immunotherapy plus chemotherapy versus chemotherapy alone.
The IMpower133 trial was a randomized, double-blind, placebo-controlled phase I/III study conducted at multiple international sites. It was funded by Roche, the manufacturer of atezolizumab. The original trial randomized patients with ES-SCLC to receive first-line carboplatin and etoposide chemotherapy with either atezolizumab immunotherapy or placebo. This post-hoc analysis used data from that trial to investigate a different research question.
The researchers analyzed data from 393 patients who received treatment in the IMpower133 trial - 198 in the atezolizumab plus chemotherapy arm and 195 in the placebo plus chemotherapy arm. They examined antibiotic and probiotic use within 42 days prior to treatment initiation, as well as PPI use within 30 days prior. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS).
Patients were included if they had received treatment in the original IMpower133 trial. The analysis excluded patients who did not receive the assigned treatment and one patient with missing concomitant medication data. Baseline characteristics were well-balanced between the two treatment arms. The patient population was predominantly white (around 80%) and male (around 65%), with a median age of 64 years. Most patients were current or former smokers.
In the atezolizumab arm, 17 patients (8.6%) had prior antibiotic exposure, 43 (21.7%) had prior PPI exposure, and 3 (1.5%) had prior probiotic exposure. In the placebo arm, 14 patients (7.2%) had antibiotic exposure, 55 (28.2%) had PPI exposure, and 5 (2.6%) had probiotic exposure. The specific probiotic bacterial species were unknown in most cases.
The key finding was that exposure to antibiotics, PPIs, or probiotics was not associated with overall survival or progression-free survival in either treatment arm. There were no statistically significant interactions between these medications and treatment modality (atezolizumab vs. placebo) for either OS or PFS outcomes.
For antibiotics, the hazard ratio for OS was 0.73 (95% CI 0.43-1.33) in the placebo arm and 1.01 (95% CI 0.60-1.70) in the atezolizumab arm, with an interaction p-value of 0.4618. For PPIs, the OS hazard ratio was 1.03 (95% CI 0.70-1.51) for placebo and 0.90 (95% CI 0.63-1.29) for atezolizumab, with an interaction p-value of 0.6254. Results were similar for PFS and for probiotic exposure.
The study had several important limitations. As a post-hoc analysis, it was not powered specifically to detect differences based on concomitant medication use. The sample sizes for patients exposed to antibiotics, PPIs, and especially probiotics were small, limiting the ability to draw firm conclusions. The retrospective nature of the analysis also introduces potential for bias. Additionally, details on antibiotic types, duration of use, and indications were not available.
Despite these limitations, the authors concluded that baseline use of antibiotics, PPIs, or probiotics did not appear to influence clinical outcomes in ES-SCLC patients treated with first-line atezolizumab plus chemotherapy or placebo plus chemotherapy. They suggest these medications may not have a notable impact on efficacy in this patient population and could be considered for use when clinically necessary.
This study provides important clinical insights, as patients with ES-SCLC often require multiple medications and experience treatment-related adverse events necessitating antibiotics or PPIs. The findings are somewhat surprising, as prior research in other cancer types has suggested negative impacts of antibiotics and PPIs on immunotherapy efficacy. However, the authors note that SCLC is a highly aggressive cancer with poor prognosis, which may explain the lack of impact from these medications.
The potential clinical implications are significant. If confirmed in larger prospective studies, these results suggest oncologists may not need to avoid antibiotics, PPIs, or probiotics in ES-SCLC patients receiving immunotherapy, as long as there is a clear clinical indication. This could allow for better management of comorbidities and treatment-related toxicities without compromising cancer outcomes.
However, the authors caution that further research is still needed given the limitations of this analysis. They suggest additional studies with larger sample sizes to more definitively evaluate potential interactions between concomitant medications and immunotherapy in SCLC. Future research could also examine impacts of specific antibiotic classes, longer durations of use, or timing relative to immunotherapy initiation.
In conclusion, this post-hoc analysis provides preliminary evidence that commonly used medications like antibiotics, PPIs, and probiotics may not negatively impact immunotherapy efficacy in ES-SCLC. While not practice-changing on its own, the study offers reassurance to clinicians managing complex patients and highlights an important area for further investigation as immunotherapy combinations become standard of care in SCLC treatment.
References
Takada K, Takamori S, Shimokawa M, Pinato DJ, Cortellini A. Prior antibiotics, proton pump inhibitors, and probiotics in patients with extensive stage small cell lung cancer treated with immune checkpoint blockade: A post-hoc analysis of the phase I/III IMpower 133 trial. Int J Cancer. 2025;156(5):914-919. doi:10.1002/ijc.35249
