Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab–ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab–ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05–0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.
BackgroundThe clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between PBRM1 mutations and response with immunotherapy (IO). We sought to determine genomic predictors of differential response to vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKIs) and IO.MethodsConsecutive patients who underwent genomic profiling were identified; patients receiving either VEGF-TKIs or IO were included. Clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test were performed using a Clinical Laboratory Improvement Amendments (CLIA)-certified assay (Ashion Analytics; Phoenix, Arizona, USA). Genomic findings were compared between patients with clinical benefit (CB; complete/partial response or stable disease for >6 months) and no clinical benefit (NCB) in VEGF-TKI-treated patient cohort and IO-treated patient cohort.Results91 patients received genomic profiling and 58 patients received VEGF-TKI and/or IO therapy. 17 received sequenced treatment involving both VEGF-TKI and IO, resulting in 32 patients in the IO cohort and 43 patients in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (66%) and sunitinib (40%). The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038); transcriptomic analysis revealed multiple differentially regulated pathways downstream of TERT. TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. While PBRM1 mutations were more prevalent in patients with CB with IO and VEGF-TKIs, no statistically significant association was found.ConclusionsOur analysis found that TERT promoter mutations may be a negative predictor of outcome with IO and are mutually exclusive with PBRM1 loss-of-function mutations.
BackgroundPatient‐reported outcomes have been used to assess treatment effectiveness and actively engage patients in their disease management. This study was designed to describe the patient‐reported performance status (PS) and the provider‐reported PS.MethodsPatients with metastatic genitourinary cancers were recruited from a single cancer center before the initiation of a new line of treatment. PS (Eastern Cooperative Oncology Group [ECOG]), quality of life (Functional Assessment of Chronic Illness Therapy–General), and distress (Patient‐Reported Outcomes Measurement Information System Anxiety and Depression) were self‐reported by patients. Clinical data (eg, age, sex, diagnosis, and physician‐reported ECOG PS) were extracted from medical records. Multivariate analysis was used to determine the association between PS, quality of life, and psychological symptoms.ResultsOne hundred forty‐five patients were enrolled (76.6% male, 70.3% White, 81.4% married, and 76.6% well educated). The median age was 67 years; 66.9% were diagnosed with renal cell carcinoma, 20.0% were diagnosed with urothelial carcinoma, and 13.1% were diagnosed with prostate cancer. Clinicians more frequently classified patients' ECOG PS as 0 in comparison with the patients themselves (92.4% vs 64.1%; P = .001). Higher clinician‐reported ECOG PS was associated with poorer physical and functional well‐being and higher rates of depression (P < .01), whereas higher patient‐reported ECOG PS was associated with worse psychosocial outcomes (P < .01).ConclusionsDiscrepancies were noted between the patient‐ and provider‐reported ECOG PS, with clinicians overestimating the ECOG PS in comparison with the patients themselves. This study's findings suggest that patients incorporate their social and emotional well‐being into their PS score in addition to their physical well‐being. This information is not immediately accessible to most clinicians from just a standard patient interview and likely accounts for the overestimation of the patients' ECOG PS by the clinicians.
BackgroundCirculating cytokines and angiogenic factors have been associated with clinical outcomes in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in parallel cohorts receiving either immunotherapy or targeted therapy.MethodsIn this prospective correlative study, we enrolled 56 patients who were planned for treatment with either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Eligibility requirements permitted any RCC histologic subtype, International Metastatic Renal Cell Carcinoma risk classification, and line of therapy. Immunologic profile was assessed at baseline and after 1 month on treatment using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit was defined as complete response, partial response, or stable disease ≥6 months per RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria.ResultsClinical benefit was similar between VEGF-TKI and ICI arms (65% vs 54%). Patients with clinical benefit from VEGF-TKIs had lower pretreatment levels of interleukin-6 (IL-6) (p=0.02), IL-1RA (p=0.03), and granulocyte colony-stimulating factor (CSF) (p=0.02). At 1 month, patients with clinical benefit from ICIs had higher levels of interferon-γ (IFN-γ) (p=0.04) and IL-12 (p=0.03). Among patients on VEGF-TKIs, those with clinical benefit had lower 1 month IL-13 (p=0.02) and granulocyte macrophage CSF (p=0.01) as well as higher 1 month VEGF (p=0.04) compared with patients with no clinical benefit.ConclusionFor patients receiving VEGF-TKI or ICI therapy, distinct plasma cytokines were associated with clinical benefit. Our findings support additional investigation into plasma cytokines as biomarkers in metastatic RCC.
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