Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer.

Importance: Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective: To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants: This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures: Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results: Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status. Conclusions and Relevance: Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

The pharmacokinetics of high-dose methotrexate in people living with HIV on antiretroviral therapy.

PURPOSE: Clinical outcomes for lymphoma in people living with HIV (PLWH) are similar to those in the general public. However, a number of concerns remain including pharmacological interactions between cytotoxic chemotherapy and antiretroviral therapy (ARVs). Much attention has focussed on pharmacokinetic interactions attributable to effects on hepatic microsomal enzymes, but not on competition for the renal organic anion transport system. High-dose (3 g/m(2)) intravenous methotrexate (MTX) is part a of (R)-CODOX-M/IVAC chemotherapy regimen for HIV-associated Burkitt/Burkitt-like lymphoma (BL/BLL). We investigated MTX pharmacokinetics and evaluated the effects of renal function (eGFR), age and use of different classes of ARVs. METHODS: Forty-three PLWH treated with ARVs and (R)-CODOX-M/IVAC are included in the analysis. Plasma MTX concentration was measured (ARK TM MTX assay, VITROS(®) 5600) daily after administration until levels were <0.04/mmol/L. MTX elimination half-life was correlated with age, renal function and antiretroviral regimen. RESULTS: One hundred and fifty timed plasma MTX levels were collected. The median MTX elimination half-life was 21.7 h (range 9.4-204.4). MTX elimination half-life was not influenced by age (p = 0.71), eGFR (p = 0.67) or use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) or integrase inhibitors (p = 0.15). Similarly, different NRTI backbones did not affect MTX elimination kinetics (p = 0.68), despite the potential overlapping competition for active renal tubular transporters between MTX and tenofovir. CONCLUSION: Although there is potential competition for active renal tubular transporters between MTX and tenofovir, no prolongation of MTX half-life was observed. These findings are reassuring to clinicians managing patients with dual diagnoses.