Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications

Abstract

The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers. Here, we sought to more broadly survey cancers to identify those in which the microbiome will play a role using retrospective analyses. We created a causal model for the relationship between medications, the microbiome and ICI response and used it to guide the abstraction of electronic health records of 690 patients who received ICI therapy for advanced cancer. Medications associated with changes to the microbiome including antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins were abstracted. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for antibiotics classes to taxa correlated with ICI response and a literature review of culture-based antibiotic susceptibilities. Of the medications assessed, only antibiotics and corticosteroids significantly associated with lower OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers. The timing and strength of these effects after controlling for confounding factors are consistent with role for the microbiome in response to ICIs.

Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma

“…CS use during these later CPI treatment periods may have different biological implications and different underlying reasons, such as management of immune-mediated adverse events. 18 , 23 Our findings are consistent with recent reports of clinical outcomes associated with CPI treatment and bCS use in many of the same tumor types, including shorter OS and/or progression-free survival (PFS) in patients who received concomitant CSs with CPI 20 – 22 , 27 , 30 , 38 , 39 – although some differences have emerged in smaller study populations or subgroups, such as those receiving CSs related versus unrelated to cancer care. 24 , 30 , 38 …”

“…Nevertheless, six studies consistently reported significantly shorter OS and PFS with CS use during CPI treatment in final or multivariable models adjusting for baseline characteristics and conditions (Table S4). 20 – 22 , 26 , 27 , 39 Spakowicz and colleagues evaluated the effect of five types of concomitant medications (antibiotics, CSs, proton pump inhibitors, histamine 2 blockers, and non-steroid anti-inflammatory drugs) on OS among 690 CPI-treated patients with advanced/metastatic melanoma (29%), NSCLC (23%), or other cancers. Multivariate HRs showed associations of OS with CS use within 28 days of the CPI start date for patients with melanoma (HR, 1.57; P = .01) or NSCLC (HR, 1.85; P < .01).…”

“…Multivariate HRs showed associations of OS with CS use within 28 days of the CPI start date for patients with melanoma (HR, 1.57; P = .01) or NSCLC (HR, 1.85; P < .01). 22 In a study of 640 patients with NSCLC, Arbor and colleagues compared those who received ≥10 mg/day prednisone equivalent at the start of CPI treatment with those who received <10 mg and found significantly shorter OS (5.4 vs. 12.1 months; P < .001) and PFS (1.9 vs. 2.6 months; P = .001) in analyses adjusting for smoking history, performance status, and brain metastases (HR for OS, 1.66 [ P < .001]; HR for ORR, 0.42 [ P = .053]; HR for PFS, 1.31 [ P = .03]). 21 Martínez Bernal also reported a significantly worse OS (3 vs 10 months; P = .002) and more progressive disease ( P = .011) in patients with NSCLC receiving ≥20 mg daily prednisone during CPI treatment.…”

“…The mechanisms of PD-L1/PD-1 inhibitors counteract immune suppression in the tumor microenvironment by restoring antitumor activity of T cells; 19 immunosuppression from CSs administered prior to or at the start of CPI treatment, or “baseline” CS use (bCS), may counteract the CPI-driven antitumor immune response. 20 – 22 On the other hand, CSs used to manage immune-mediated adverse events later in the course of CPI treatment may not hinder its efficacy. 18 , 23–25 In fact, differences in survival outcomes and peripheral blood immune cells associated with CSs may be limited to use within the first 28 days of CPI treatment.…”

“… 18 , 23–25 In fact, differences in survival outcomes and peripheral blood immune cells associated with CSs may be limited to use within the first 28 days of CPI treatment. 20 , 22 …”