New advancements and developments in treatment of renal cell carcinoma: focus on pazopanib

With the recent approval of pazopanib, an oral multitargeted tyrosine kinase inhibitor which potently targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor, and c-kit, six agents are now available for use in the management of metastatic renal cell carcinoma (RCC). Pazopanib has shown improved progression-free survival compared with placebo in treatment-naïve or cytokine-treated patients with metastatic RCC in large Phase II and Phase III clinical trials. Pazopanib has demonstrated a tolerable side effect profile and is currently being compared with sunitinib in a Phase III noninferiority trial. In this review, the outcomes of the clinical testing of pazopanib are discussed, as well as a perspective on the placement of pazopanib among other approved agents

Using molecular biology to develop drugs for renal cell carcinoma

Renal cell carcinoma is a disease marked by a unique biology which has governed it’s long history of poor response to conventional cancer treatments. The discovery of the signaling pathway activated as a result of inappropriate constitutive activation of the hypoxia inducible factors (HIF), transcription factors physiologically and transiently stabilized in response to low oxygen, has provided a primary opportunity to devise treatment strategies to target this oncogenic pathway

HIF1α and HIF2α Exert Distinct Nutrient Preferences in Renal Cells

Background: Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells. Methods: We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene. Results: Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media. Conclusion: HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients

real world treatment outcomes in patients with metastatic merkel cell carcinoma treated with chemotherapy in the usa

Aim: This retrospective study of patients in the USA with metastatic Merkel cell carcinoma (mMCC) aimed to assess patient responses to second-line and later (2L+) and first-line (1L) chemotherapy. Patients & methods: Out of 686 patients with MCC identified in The US Oncology Network, 20 and 67 patients with mMCC qualified for the 2L+ and 1L study, respectively; the primary analysis population was restricted to immunocompetent patients. Results: In the 2L+ primary analysis population, objective response rate (ORR) was 28.6%, median duration of response (DOR) was 1.7 months and median progression-free survival was 2.2 months. In the 1L primary analysis population, ORR was 29.4%, median DOR was 6.7 months and median progression-free survival was 4.6 months. Conclusion: The low ORR and brief DOR underscore the need for novel therapies

Neoadjuvant Clinical Trial With Sorafenib for Patients With Stage II or Higher Renal Cell Carcinoma

The multitargeted tyrosine kinase inhibitor sorafenib is used for the treatment of advanced-stage renal cell carcinoma. However, the safety and efficacy of this agent have yet to be evaluated in the preoperative period, where there may be potential advantages including tumor downstaging. This prospective trial evaluates the safety and feasibility of sorafenib in the preoperative setting

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

945 patients with inoperable stage III or stage IV melanoma were randomised to ipilimumab plus nivolumab (ipi/nivo)(314), nivolumab (nivo) (316) or ipilimumab (Ipilimumab) (315). The minimum follow up from randomisation of the last patient was 60 months. Objective responses were seen in 58% of Ipilimumab/nivo, 45% of nivo and 19% of Ipilimumab patients. Complete responses were seen in 22% (Ipilimumab/nivo), 19% (nivo) and 6% (Ipi) patients. Overall survival (OS) at five years was 52% (Ipilimumab/nivo), 44% (nivo) and 26% (Ipi). In patients with and without bras mutations the OS at five years was 60 & 48% (Ipilimumab/nivo), 46 & 43% (nivo) and 30 & 25% (Ipi) respectively. OS curves were flat beyond three years indicating that these treatments lead to sustained long term survival of these patients

Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

PURPOSE In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. PATIENTS AND METHODS Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated. RESULTS Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF–wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed. CONCLUSION These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy

Health-related quality of life results from the phase III CheckMate 067 study

Background Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.Patients and methods HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.Results Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.Conclusion These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.Study number NCT01844505

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival.

Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial. Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups. From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm. Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident. NCT02388906

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

This is the three year update of a randomised phase III trial in patients with locally advanced inoperable stage III or stage IV melanoma. 1296 patients were radomised to receive either ipilimumab (Ipi), nivolumab (Nivo) or both antibodies (Ipi+Nivo). Complete responses were seen in 5, 16 & 19% of patients in the Ipi, Nivo and Ipi+Nivo groups respectively. Partial responses were seen in 14, 28 & 29% of patients respectively. With a minimum follow up of 28 months 3 year overall survivals were 32, 52 & 58% in the Ipi, Nivo & Ipi+Nivo respectively. In patients with braf mutations the three year survivals were 37, 56 & 68% in the three groups. This compares with a three year survival of 44% in the dabrafenib plus trametinib arm of the COMBI-D trial (J. Clin. Oncol. 2017 Dob: 10.1200/JCO.2017.74.1025). These data represent practice changing data for oncologist who treat melanoma and life changing treatment for patients with metastatic melanoma