The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patients Progressing after VEGF Inhibition

Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first-line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs

Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B)

Background To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naive patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy.Methods Eligible patients with treatment-naive nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies.Results 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of = 5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death.Conclusions Nivolumab monotherapy has limited activity in treatment-naive nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity

Combination strategies in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) consist of an array of clonal hematological malignancies resulting from disorders of pluripotent hematopoietic stem cells. MDS is associated with a poor overall prognosis and patients are categorized as higher risk and lower risk on the basis of the International Prognostic Scoring System. Currently, lenalidomide, azacitidine, and decitabine are the only three FDA-approved drugs for MDS. Traditional therapies for MDS involve the administration of single agents providing either supportive measures or disease-modifying effects directed to slowing progression to acute myeloid leukemia (AML) and improving survival. Recently, however, there has been increasing evidence suggesting that the combination of drugs with different mechanisms of action offers substantial benefit in the form of diminished side effects, improved overall survival, and delayed progression to AML. Multiple studies indicate that when compared with traditional monotherapies, combining various medications with non-overlapping mechanisms of action and toxicities may result in significant benefit for patients with MDS. A variety of combination therapies with growth factors, DNA methytransferase inhibitors, histone deacetylase inhibitors, and immunosuppressant treatments provide encouraging data indicating that the successful future of MDS treatment rests in the combination of multiple treatments modalities to achieve improved clinical outcomes

Addition of Salvage Immunotherapy to Targeted Therapy in Patients with Metastatic Renal Cell Carcinoma

There have been significant advances in the treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy (IO)-based combinations as the standard-of-care treatment in the front-line setting. IO in this setting is paired with another IO agent or with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI). One IO/IO combination and four IO/TKI combinations are currently approved. However, the role of the salvage IO in patients with disease progression on TKI monotherapy is uncertain. Here, we present a case series of five patients who were on single-agent TKI therapy for treatment-refractory mRCC and upon disease progression had an IO agent added to their TKI. The median duration of TKI monotherapy was 11.2 months (range, 1.7–31.1 months), and the median duration of response after the addition of IO was 4 months (range, 2.8–10.5 months). Although IO salvage therapy has a plausible rationale, this case series did not show a clear benefit to this approach. Further clinical trials are needed to determine the clinical utility of IO salvage therapy in mRCC

More is better: combination therapies for myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS

Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC

Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab

Abstract Background Nivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking. Methods A retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015–2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS). Results Ninety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1–6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05–3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30–0.98; p = 0.042). Conclusion Brain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count

Assessing the Value of Echocardiograms for Patients with Acute Myeloid Leukemia (AML) Receiving Anthracyclines

Abstract Background AML is a life-threatening disease that requires prompt administration of anthracycline-based induction chemotherapy, particularly in younger adults. Prior to treatment initiation, patients (pts) undergo routine echocardiography (echo) screening to assess cardiac ejection fraction (EF) as a measure of induction tolerability, despite American Society of Clinical Oncology and National Comprehensive Cancer Center guidelines which state that only pts with prior cardiac disease or exposure to cardiotoxic drugs or radiation therapy require such evaluation This is costly to the health-care system and may be unnecessary. In this study, we assess whether the use of echo prior to anthracycline-based therapy in AML has a major effect on pt outcomes. Methods We reviewed clinical data on AML pts treated with anthracycline-based induction chemotherapy regimens at our institution from 2002-2014. EF was obtained by 2D echo prior to induction chemotherapy initiation. Charlson comorbidity index was used to evaluate comorbidities prior to therapy. A cox proportional hazard model was used to analyze the impact of baseline echo on overall survival, with p-values <.05 denoting significance. Results: Of the 120 pts included, 60 (50%) were female. At diagnosis, median age was 57 years (range, 23-85), white blood cell count (WBC) 8.9 x 109/L (0.3-227), hemoglobin 9.1g/dL (4.7-13.8), platelets 85 x 103 (8-277), bone marrow blasts 48% (14-95%). Cytogenetic risk categories per CALGB 8461 criteria: 12 pts (10%) were favorable, 63 (53%) indeterminate, and 41 (34%) unfavorable. Charlson morbidity index was > 1 in 23 pts (19%) and 50 (38%) were current or former smokers. All pts received induction chemotherapy with either idarubicin (38%), daunorubicin (38%), or mitoxantrone (23%) combined with cytarabine (7+3). In 116 pts (97%), the baseline echo showed a left ventricular ejection fraction (LVEF) >50% (+/- 5). In the 4 remaining pts (3%), the EF was < 40%. In a multivariable analysis controlling for age, WBC, cytogenetic risk group, Charlson comorbidity index, and smoking exposure, LVEF was not associated with overall survival (HR 1.05 with 95% CI 0.99-1.12 and p=.09). Among the 4 pts with EF<40% (age 57-71 years), all received full dose anthracycline and only the 71-year-old patient experienced congestive heart failure during treatment. Six pts (5%) died during induction therapy (4 weeks) and none of these had an EF <40%. Conclusion Among AML pts who received anthracycline-based induction chemotherapy, results from echocardiography did not impact outcome in >99% in this cohort. It is not clear that echocardiography, particularly in younger pts, provides value, and may delay treatment initiation. Disclosures No relevant conflicts of interest to declare