CA : A Cancer Journal for Clinicians

BackgroundNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. MethodsA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. ResultsThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The haz...

/pdf/nivolumab-versus-everolimus-in-advanced-renal-cell-carcinoma-4qkp9zdhuq.pdf

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.

Cancer immunotherapy using checkpoint blockade

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

http://science.sciencemag.org/content/sci/359/6371/91.full.pdf

Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

https://www.cell.com/cancer-cell/pdf/S1535-6108(15)00089-6.pdf

Immune checkpoint blockade: a common denominator approach to cancer therapy

472 Background: Timely initiation of NAC is critical to improve outcomes in MIBC. Medicaid expansion through the Affordable Care Act improved racial disparities in healthcare access for patients with advanced cancers. This study aimed to assess the association of Medicaid expansion with racial disparities in time-to-NAC in MIBC. Methods: This case-control study queried the National Cancer Database for 18-64 years old Black and White adults who were diagnosed with stage II&III bladder cancer and treated with NAC from Jan 1, 2008 to Dec 31, 2018. The primary endpoint was the timely receipt of NAC, defined as initiation within 45 days from the diagnosis of resectable MIBC. Racial disparity was defined as percentage-point (PP) difference for Black vs. White patients, adjusted for age, sex, income level, clinical stage, and year of diagnosis. Results: The study included 5053 patients (7.2% Black, n = 391). In states without Medicaid expansion, Black patients became less likely to receive timely NAC than their White counterparts (2008-2013: Black 59.6% vs White 63.8%, p = 0.53; 2014-2018: Black 47.9% vs White 61.2%, p < 0.01). In contrast, the racial disparity was narrowed in states with Medicaid expansion (2008-2013: Black 35.7% vs White 62.9%, p < 0.01; 2014-2018: Black 53.4% vs White 59.5%, adjusted PP difference -2.4; p = 0.20). The adjusted difference-in-differences estimate revealed a 26.0 PP reduction in racial disparity (95% CI, 8.1%-44.0%; p < 0.01). Conclusions: Medicaid expansion was associated with significant reduction in racial disparity between Black and White patients in the timely receipt of NAC for MIBC.

Association of Medicaid expansion with racial disparities in timely neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC).

Plain language summary Targeted immunotherapy refers to a new class of drugs that boost the body's immune system to fight against cancer. Studies have shown that immunotherapy increases the survival of kidney cancer patients, but it has certain side effects that can affect any organ in the body, including the heart, lungs, skin, bowel and thyroid. Most side effects can be managed with drugs that can suppress the immune system, such as steroids; however, some side effects can be fatal if not diagnosed in a timely manner. It is vital to have a proper understanding of the side effects of immunotherapy drugs when making decisions about treatment for kidney cancer.

Saby George

Papers

Association of Medicaid expansion with racial disparities in timely neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC).

Management of immune-mediated toxicities and their implications in the outcomes of advanced kidney cancer.