Background: Antibiotic exposure has been associated with reduced benefit from immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). However, evidence in patients with KRAS-mutated NSCLC remains limited. This study evaluated the associations of antibiotic and probiotic exposure with survival outcomes in patients with advanced KRAS-mutated NSCLC receiving ICIs. Methods: This multicenter retrospective study included patients with advanced KRAS-mutated NSCLC who received at least one dose of ICI-based therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were performed to evaluate factors associated with survival outcomes. Results: A total of 101 patients were included, of whom 23 were exposed to antibiotics and 18 received probiotics. All patients had documented KRAS mutations. Eight patients received KRAS-targeted inhibitors after ICI progression, and none received KRAS-targeted inhibitors before or during ICI treatment. The median PFS was 9.0 months in the antibiotic-exposed group and 14.4 months in the non-antibiotic group (p = 0.041). The median OS was 23.5 and 38.4 months, respectively (p = 0.017). After multivariable adjustment, antibiotic exposure remained associated with shorter PFS (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.08–3.84; p = 0.029) and OS (HR, 2.85; 95% CI, 1.30–6.22; p = 0.009). Probiotic exposure was not significantly associated with PFS or OS. Conclusions: Antibiotic exposure was associated with shorter PFS and OS in patients with advanced KRAS-mutated NSCLC receiving ICIs, whereas probiotic exposure was not significantly associated with survival outcomes.
- Open Access
- Article
Association of Antibiotic Exposure with Survival Outcomes in Patients with Advanced KRAS-Mutated NSCLC Receiving Immune Checkpoint Inhibitors
- Qianlin Huang 1,2,†,
- Weichi Luo 1,†,
- Yichen Zhang 1,†,
- Zhihong Chen 1,
- Qiuyi Zhang 3,
- Fen Wang 4,
- Jianhua Chang 3,*,
- Qing Zhou 1,2,*
Author Information
Received: 25 Jun 2026 | Revised: 06 Aug 2026 | Accepted: 10 Aug 2026 | Published: 24 Aug 2026
Abstract
Keywords
non-small cell lung cancer | immune checkpoint inhibitors | KRAS mutation | antibiotics | probiotics
References
- 1.
Bray, F.; Laversanne, M.; Sung, H.; et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024, 74, 229–263. https://doi.org/10.3322/caac.21834.
- 2.
Assi, H.I.; Kamphorst, A.O.; Moukalled, N.M.; et al. Immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer 2018, 124, 248–261. https://doi.org/10.1002/cncr.31105.
- 3.
Adderley, H.; Blackhall, F.H.; Lindsay, C.R. KRAS-mutant non-small cell lung cancer: Converging small molecules and immune checkpoint inhibition. EBioMedicine 2019, 41, 711–716. https://doi.org/10.1016/j.ebiom.2019.02.049.
- 4.
Mazieres, J.; Drilon, A.; Lusque, A.; et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry. Ann. Oncol. 2019, 30, 1321–1328. https://doi.org/10.1093/annonc/mdz167.
- 5.
West, H.J.; McCleland, M.; Cappuzzo, F.; et al. Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: Subgroup results from the phase III IMpower150 trial. J. Immunother. Cancer 2022, 10, e003027. https://doi.org/10.1136/jitc-2021-003027.
- 6.
Skoulidis, F.; Byers, L.A.; Diao, L.; et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015, 5, 860–877. https://doi.org/10.1158/2159-8290.CD-14-1236.
- 7.
Skoulidis, F.; Goldberg, M.E.; Greenawalt, D.M.; et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018, 8, 822–835. https://doi.org/10.1158/2159-8290.CD-18-0099.
- 8.
Ricciuti, B.; Arbour, K.C.; Lin, J.J.; et al. Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status. J. Thorac. Oncol. 2022, 17, 399–410. https://doi.org/10.1016/j.jtho.2021.10.013.
- 9.
Gao, G.; Liao, W.; Ma, Q.; et al. KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma. Lung Cancer 2020, 149, 41–45. https://doi.org/10.1016/j.lungcan.2020.09.004.
- 10.
Routy, B.; Le Chatelier, E.; Derosa, L.; et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018, 359, 91–97. https://doi.org/10.1126/science.aan3706.
- 11.
Hakozaki, T.; Richard, C.; Elkrief, A.; et al. The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non-Small Cell Lung Cancer. Cancer Immunol. Res. 2020, 8, 1243–1250. https://doi.org/10.1158/2326-6066.CIR-20-0196.
- 12.
Finlay, B.B.; Goldszmid, R.; Honda, K.; et al. Can we harness the microbiota to enhance the efficacy of cancer immunotherapy? Nat. Rev. Immunol. 2020, 20, 522–528. https://doi.org/10.1038/s41577-020-0374-6.
- 13.
Derosa, L.; Routy, B.; Thomas, A.M.; et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat. Med. 2022, 28, 315–324. https://doi.org/10.1038/s41591-021-01655-5.
- 14.
Fathi, Z.; Mousavi, S.A.J.; Roudi, R.; et al. Distribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients. PLoS ONE 2018, 13, e0200633. https://doi.org/10.1371/journal.pone.0200633.
- 15.
Dearden, S.; Stevens, J.; Wu, Y.L.; et al. Mutation incidence and coincidence in non-small-cell lung cancer: Meta-analyses by ethnicity and histology (mutMap). Ann. Oncol. 2013, 24, 2371–2376. https://doi.org/10.1093/annonc/mdt205.
- 16.
Loong, H.H.F.; Du, N.; Cheng, C.; et al. KRAS G12C mutations in Asia: A landscape analysis of 11,951 Chinese tumor samples. Transl. Lung Cancer Res. 2020, 9, 1759–1769. https://doi.org/10.21037/tlcr-20-455.
- 17.
Zhao, S.; Gao, G.; Li, W.; et al. Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer. Lung Cancer 2019, 130, 10–17. https://doi.org/10.1016/j.lungcan.2019.01.017.
- 18.
Derosa, L.; Hellmann, M.D.; Spaziano, M.; et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann. Oncol. 2018, 29, 1437–1444. https://doi.org/10.1093/annonc/mdy103.
- 19.
Abdelhamid, A.; Tuminello, S.; Ivic-Pavlicic, T.; et al. Antibiotic treatment and survival in non-small cell lung cancer patients receiving immunotherapy: A systematic review and meta-analysis. Transl. Lung Cancer Res. 2023, 12, 2427–2439. https://doi.org/10.21037/tlcr-23-597.
- 20.
Chalabi, M.; Cardona, A.; Nagarkar, D.R.; et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: Pooled post hoc analyses of the OAK and POPLAR trials. Ann. Oncol. 2020, 31, 525–531. https://doi.org/10.1016/j.annonc.2020.01.006.
- 21.
Takada, K.; Shimokawa, M.; Takamori, S.; et al. Clinical impact of probiotics on the efficacy of anti-PD-1 monotherapy in patients with nonsmall cell lung cancer: A multicenter retrospective survival analysis study with inverse probability of treatment weighting. Int. J. Cancer 2021, 149, 473–482. https://doi.org/10.1002/ijc.33557.
- 22.
Tomita, Y.; Ikeda, T.; Sakata, S.; et al. Association of Probiotic Clostridium butyricum Therapy with Survival and Response to Immune Checkpoint Blockade in Patients with Lung Cancer. Cancer Immunol. Res. 2020, 8, 1236–1242. https://doi.org/10.1158/2326-6066.CIR-20-0051.
- 23.
Takada, K.; Buti, S.; Bersanelli, M.; et al. Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade. Eur. J. Cancer 2022, 172, 199–208. https://doi.org/10.1016/j.ejca.2022.06.002.
- 24.
Taioli, E.; Flores, R.M.; Abdelhamid, A.; et al. Antibiotic use and survival in patients with late-stage NSCLC treated with chemoimmunotherapy. JTO Clin. Res. Rep. 2024, 5, 100710. https://doi.org/10.1016/j.jtocrr.2024.100710.
- 25.
Pinato, D.J.; Howlett, S.; Ottaviani, D.; et al. Association of Prior Antibiotic Treatment with Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients with Cancer. JAMA Oncol. 2019, 5, 1774–1778. https://doi.org/10.1001/jamaoncol.2019.2785.
- 26.
Hamada, K.; Yoshimura, K.; Hirasawa, Y.; et al. Antibiotic Usage Reduced Overall Survival by over 70% in Non-small Cell Lung Cancer Patients on Anti-PD-1 Immunotherapy. Anticancer Res. 2021, 41, 4985–4993. https://doi.org/10.21873/anticanres.15312.
- 27.
Nyein, A.F.; Bari, S.; Hogue, S.; et al. Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer. BMC Cancer 2022, 22, 101. https://doi.org/10.1186/s12885-022-09210-2.
- 28.
Ochi, N.; Ichihara, E.; Takigawa, N.; et al. The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression. Eur. J. Cancer 2021, 149, 73–81. https://doi.org/10.1016/j.ejca.2021.02.040.
- 29.
Metselaar-Albers, M.; Meijerman, I.; Engels, F.; et al. No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: An observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC. J. Immunother. Cancer 2024, 12, e008269. https://doi.org/10.1136/jitc-2023-008269.
- 30.
Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018, 359, 97–103. https://doi.org/10.1126/science.aan4236.
- 31.
Matson, V.; Fessler, J.; Bao, R.; et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018, 359, 104–108. https://doi.org/10.1126/science.aao3290.
- 32.
Zhang, C.; Wang, J.; Sun, Z.; et al. Commensal microbiota contributes to predicting the response to immune checkpoint inhibitors in non-small-cell lung cancer patients. Cancer Sci. 2021, 112, 3005–3017. https://doi.org/10.1111/cas.14979.
- 33.
Vétizou, M.; Pitt, J.M.; Daillère, R.; et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015, 350, 1079–1084. https://doi.org/10.1126/science.aad1329.
- 34.
Hersi, F.; Elgendy, S.M.; Al Shamma, S.A.; et al. Cancer immunotherapy resistance: The impact of microbiome-derived short-chain fatty acids and other emerging metabolites. Life Sci. 2022, 300, 120573. https://doi.org/10.1016/j.lfs.2022.120573.
- 35.
Sivan, A.; Corrales, L.; Hubert, N.; et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015, 350, 1084–1089. https://doi.org/10.1126/science.aac4255.
- 36.
Lee, K.A.; Thomas, A.M.; Bolte, L.A.; et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat. Med. 2022, 28, 535–544. https://doi.org/10.1038/s41591-022-01695-5.
- 37.
McCulloch, J.A.; Davar, D.; Rodrigues, R.R.; et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat. Med. 2022, 28, 545–556. https://doi.org/10.1038/s41591-022-01698-2.
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