Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Landscape of Immunotherapy in Genitourinary Malignancies.

The past decade has witnessed a revolution in the development of immune checkpoint inhibitors for the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors have notably improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established except for microsatellite instability high (MSI-H) tumors. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This book chapter is a comprehensive review of immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.

Nivolumab for the Treatment of Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma (nccRCC): A Single-Institutional Experience and Literature Meta-Analysis.

INTRODUCTION: Nivolumab alone and in combination with ipilimumab is approved for the treatment of patients with metastatic renal cell carcinoma (RCC) who received prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) and those who are treatment naive, respectively. However, the clinical activity of nivolumab in non-clear cell RCC (nccRCC) is unknown, as these patients were excluded from the trials. MATERIALS AND METHODS: We reviewed the records of patients who received nivolumab for nccRCC and ccRCC with >20% rhabdoid with the primary endpoint to assess the objective response rate (ORR). We assessed radiographic response using RECIST, v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also reviewed the literature to identify studies reporting on the clinical activity of immune checkpoint inhibitors in nccRCC, and performed a meta-analysis of proportions for ORR and disease control rate (DCR). RESULTS: Twelve patients (30%) had papillary histology, 11 (27.5%) had unclassified, 8 (20%) had ccRCC with rhabdoid component, 5 (12.5%) had chromophobe, 3 (7.5%) had translocation, and 1 (2.5%) had mucinous tubular and spindle cell carcinoma. Overall, seven patients (21.6%, 95% confidence interval [CI], 8.7%-37.9%) had an objective response, including three patients (8.8%, 95% confidence interval [CI], 1.9%-23.7%) who achieved a complete remission. At a median follow-up of 24.5 monoths (95% CI, 17.7-32.6), median PFS was 4.9 monoths (95% CI, 3.53-10.27) and median OS was 21.7 monoths (95% CI, 7.83 mo to not reached). There were no treatment-related deaths. We also identified two retrospective studies reporting best ORR in patients with nccRCC receiving PD-1/PD-L1 checkpoint blockade. The ORR and DCR for the total cohort were, respectively, 18.6% (95% CI, 11.9%-26.4%) and 53.4% (95% CI, 44.2%-62.5%). CONCLUSION: Nivolumab demonstrated activity in unclassified nccRCC and ccRCC with >20% rhabdoid; further randomized clinical trials are warranted. IMPLICATIONS FOR PRACTICE: This article reports on the clinical activity and safety of immune checkpoint inhibitors in non-clear cell kidney cancer. The retrospective data with the meta-analysis provides a summary that will help guide the treatment of this rare and heterogeneous group of kidney cancers.

Current Landscape of Immunotherapy in Genitourinary Malignancies.

The past decade has witnessed a revolution of immune checkpoint inhibitors in the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established, but clinical trials investigating their use are ongoing. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is a great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This chapter is a comprehensive review of the immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.

Implementing an immunotherapy toxicity (IOTOX) GI service improves outcomes in patients with immune-mediated diarrhea and colitis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can lead to GI toxicity, termed immune-mediated diarrhea and colitis (IMDC). Standardization of IMDC management and early GI consultation is imperative to control symptoms and prevent delays in cancer care. Therefore, we implemented an inpatient algorithm and a focused IOTOX GI service to measure outcomes. METHODS: Patients who received ICIs and were hospitalized with severe IMDC were grouped into a pre-interventional cohort in 2017, followed by implementation of the standardized algorithm in 2018, and then a post-interventional cohort of patients in 2019. Clinical data and patient outcomes were compared using univariate and multivariate analysis to determine the morbidity, and overall survival. RESULTS: Our sample comprised 126 hospitalized patients with IMDC, with 59 patients in the pre-interventional 2017 cohort, and 67 patients in the post-interventional 2019 cohort. We found no significant differences in the clinical severity of IMDC symptoms between the two cohorts (p = 1.03) or median time from ICI exposure to development of IMDC (p = 0.495, respectively). After implementing the standardized algorithm, we observed higher rates of GI consultation (p < 0.001) in the post-treatment group. Patients in the post-treatment cohort showed decreased time to clinical remission (4 vs 10 days, p = 0.046), higher rate of GI follow-up after hospital discharge (p = 0.038), fewer hospital re-admissions (p = 0.002), and significantly fewer recurrences of IMDC symptoms (p = 0.002). Overall survival was significantly higher for at least 2 years in patients who followed with GI post-discharge compared to those without follow-up (p = 0.003). CONCLUSION: Prompt GI consultation and monitoring of IMDC using a regimented approach can provide efficacious management, decrease time to clinical remission of symptoms, decrease re-admissions to the hospital, and improve overall patient outcomes.

A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy.

The accumulation of immune-suppressive myeloid cells is a critical determinant of resistance to anti-programmed death-1 (PD-1) therapy in advanced clear cell renal cell carcinoma (ccRCC). In preclinical models, the tyrosine kinase inhibitor sitravatinib enhanced responses to anti-PD-1 therapy by modulating immune-suppressive myeloid cells. We conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab in 42 immunotherapy-naïve patients with ccRCC refractory to prior antiangiogenic therapies. The combination demonstrated no unexpected toxicities and achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80.1% of patients alive after a median follow-up of 18.7 months. Baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with response to sitravatinib and nivolumab. Patients with liver metastases showed durable responses comparable to patients without liver metastases. In addition, correlative studies demonstrated reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib treatment. This study provides a rationally designed combinatorial strategy to improve outcomes of anti-PD-1 therapy in advanced ccRCC.

Management of Advanced Bladder Cancer: An Update.

Bladder cancer is the sixth most common cancer in the United States; therefore, the majority of clinicians working in the oncology setting will care for this patient population. Unfortunately, treatment plans, especially in the advanced setting, lack consistency. This, along with the advanced age and comorbidities of most bladder cancer patients, can provide challenges for clinicians when developing treatment plans. In the past 2 years, new drug approvals, specifically those for immune checkpoint inhibitors, have changed the treatment landscape for bladder cancer for the first time since the 1980s. This review article outlines the current management for muscle-invasive and metastatic bladder cancer, while also highlighting future considerations in this disease space. It is imperative that oncology advanced practice providers are up to date with these new changes and have a sound understanding of treatment principles for patients with advanced bladder cancer in order to deliver the safest and most effective care.