Daniel Cho

The Role of Mammalian Target of Rapamycin Inhibitors in the Treatment of Advanced Renal Cancer

Inhibitors of the mammalian target of rapamycin (mTOR) have shown promising efficacy in early-stage trials in patients with advanced renal cell carcinoma (RCC). Most RCCs have been shown to possess biallelic alterations in the von Hippel-Lindau (VHL) gene, resulting in accumulation of hypoxia-inducible factors 1α and 2α, as well as their downstream targets including vascular endothelial growth factor (VEGF). The observed clinical efficacy of mTOR inhibitors in patients with RCC may be mediated in part by the dependence of efficient hypoxia-inducible factor translation on the mTOR pathway. mTOR inhibitors have entered more advanced phase clinical trials either as single agents or in combination with other targeted agents or IFN, which might ultimately result in regulatory approval of one or more agents. Given the likely nonoverlapping mechanism of action of mTOR inhibitors and VEGF pathway–targeted agents, mTOR inhibitors may prove useful if administered in combination or after resistance to VEGF inhibitors. With an increasing number of active agents for treatment of patients with RCC, efforts must continue to develop patient selection models based on predictive biomarkers to direct therapy to appropriate patients.

Treatment Selection for Patients With Metastatic Renal Cell Carcinoma

The availability of approved agents with distinct mechanisms of action has encouraged investigations to identify optimal treatment strategies for specific patients and specific tumor features. Study of tumors from patients treated with interleukin‐2 (IL‐2) has suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into 2 groups of roughly equal size, with 96% of the responding patients being in the favorable prognostic group. Additional studies have begun to identify molecular features that might predict response to IL‐2 therapy. In contrast, clinical trial data suggest that temsirolimus was relatively more active than interferon in patients with tumors containing non–clear cell features. Furthermore, pathologic examination showed no correlation of response with CAIX expression, but an apparent association with high expression of either phospho‐AKT or phospho‐S6, proteins either upstream or downstream of mammalian target of rapamycin. Preliminary investigations of tumor specimens from patients receiving vascular endothelial growth factor–targeted therapy suggested that high hypoxia‐inducible factor expression might predict response. In addition, response appeared more likely in tumors with mutated or methylated VHL genes; however, substantial antitumor activity was still observed in patients with VHL wild‐type tumors, particularly in patients treated with either sunitinib or axitinib, rather than bevacizumab or sorafenib. Although these data provide some guidance in treatment selection, considerably more research is needed to identify and validate selection models for particular treatment approaches, and to enable rational and optimal utilization of the available treatment options. Cancer 2009;115(10 suppl):2327‐33.

Phase 2 trial of linifanib (ABT-869) in patients with advanced renal cell cancer after sunitinib failure.

PURPOSEnThis study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma (RCC) who were previously treated with sunitinib.nnnMATERIALS AND METHODSnThis open-label, multicentre, phase 2 trial of oral linifanib 0.25 mg/kg/day enrolled patients who had prior nephrectomy and adequate organ function. The primary end-point was objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) by central imaging. Secondary end-points were progression-free survival (PFS), overall survival (OS) and time to progression (TTP). Safety was also assessed.nnnRESULTSnFifty-three patients, median age 61 years (range 40-80) were enrolled (August 2007 to October 2008) across 12 North-American centres. Median number of prior therapies was 2 (range 1-4); 43 patients (81%) had clear-cell histology. ORR was 13.2%, median PFS was 5.4 months (95% Confidence Interval (CI): 3.6, 6.0) and TTP was the same; median OS was 14.5 months (95% CI: 10.8, 24.1). The most common treatment-related adverse events (AEs) were diarrhoea (74%), fatigue (74%) and hypertension (66%), and the most common treatment-related Grade 3/4 AE was hypertension (40%).nnnCONCLUSIONSnLinifanib demonstrated clinically meaningful activity in patients with advanced RCC after sunitinib failure. At 0.25 mg/kg/day, significant dose modifications were required. An alternative, fixed-dosing strategy is being evaluated in other trials.

Response of renal cell carcinoma pancreatic metastasis to sunitinib treatment: a retrospective analysis.

PURPOSEnPancreatic metastasis accounts for 2% of metastatic renal cell carcinoma cases. Surgical management is typically recommended because of the limited value of immunotherapy as an effective treatment. Sunitinib recently showed clinical efficacy in patients with advanced renal cell carcinoma. We report a series of patients with pancreatic metastasis treated with sunitinib.nnnMATERIALS AND METHODSnWe retrospectively studied a population of 15 adults with pancreatic metastasis of renal cell carcinoma at 1 center in France and at 2 in the United States who were treated with sunitinib between 2005 and 2007. Sunitinib monotherapy was given at a dose of 50 mg orally in 6-week cycles, consisting of 4 weeks of treatment followed by 2 weeks of rest. All clinical and radiological data were analyzed.nnnRESULTSnAt a median followup of 20 months the overall tumor response using Response Evaluation Criteria in Solid Tumors was 34%. Median time to relapse was 20 months. Two deaths were noted and median survival was not attained. Responses in the pancreatic metastasis were seen in 28% of patients and were stable in 72%. The main grade 3 and 4 adverse events were diarrhea in 7% of cases and fatigue in 7%. Only grade 1 increased lipase was noted in 27% of patients and no increase in amylase was noted.nnnCONCLUSIONSnSunitinib is effective in patients with pancreatic metastasis. This raises the question of whether patients with metastatic renal cell carcinoma limited to the pancreas may derive greater clinical benefit from anti-angiogenic agents, rather than from aggressive surgical resection. However, surgery remains the only potential cure in patients with isolated pancreatic metastasis.

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial

BACKGROUNDnThe combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma.nnnMETHODSnThe JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751.nnnFINDINGSnBetween Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily.nnnINTERPRETATIONnThe safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy.nnnFUNDINGnPfizer and Merck.

PI3K/Akt/mTOR Pathway: A Growth and Proliferation Pathway

The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway regulates numerous cellular processes such as growth, proliferation, cell cycle progression, motility, adhesion, and angio-genesis, and appears to be constitutively active in a majority of renal cell carcinoma (RCC). The integrity of the pathway is clearly vital to the survival and growth of RCC as pharmacologic inhibition of PI3K or Akt induces apoptosis in RCC tumor cells and tumor regression in vivo. These observations suggest that the PI3K/Akt/ mTOR pathway may be an attractive target for drug development in the treatment of RCC. The recently demonstrated clinical efficacy of inhibitors of mTOR supports this hypothesis and demonstrates the relevance of this pathway in RCC. As Akt activates numerous kinases, transcription factors and other proteins associated with cell growth and survival in addition to mTOR, it is possible even greater clinical responses may be achieved with agents that disrupt the PI3K/Akt/mTOR pathway upstream of mTOR. Concurrent with the development of inhibitors of PI3K or Akt for clinical application are efforts to identify predictive biomarkers of response to agents targeting elements of the PI3K/Akt/mTOR pathway so as to develop more individualized patient selection strategies. In this chapter, we will review the molecular biology of the PI3K/Akt/mTOR pathway, its relevance to RCC, and its potential as a therapeutic target in RCC.

Abstract A27: The combination of navitoclax and PLX4720 in melanoma in vitro and in vivo.

Introduction: Approximately 40–50% of patients with melanoma have a tumor which harbors a BRAF mutation (BRAF+). Vemurafenib is a highly selective inhibitor of mutant BRAF which has recently been FDA-approved for the treatment of patients with BRAF+ advanced melanoma. While response rates to vemurafenib are high, the vast majority of patients will develop resistance. Identification of therapeutic strategies to enhance the efficacy of vemurafenib is a high priority. Navitoclax is a BH3-only mimetic which has single agent activity in tumors with low Mcl-1 and enhances the toxicity of agents which inhibit or downregulate MCL-1. As recent data suggests that selective BRAF inhibitors inactivate Mcl-1 through upregulation of BIM, we therefore studied the effects of combining PLX4720, a selective BRAF inhibitor very similar to vemurafenib, with navitoclax in vitro and in vivo. Methods: Three BRAF mutant melanoma cell lines (A2058, A375, SKMel5) were selected for in vitro analysis and treated for 6 hours with DMSO, navitoclax (1 uM), PLX4720 (1 uM), or the combination. Cells were then lysed after 6 hours of treatment and western blot analysis was performed probing for vinculin, PARP, total and phosphorylated Erk, Mcl-1, BIM, BID, AKT, pS6, and NOXA. Xenografts were generated from the A375 and A2058 cell lines in nude beige mice and grown to 10 mm in size. Mice were then treated with vehicle, navitoclax (100 mg/kg/day), PLX4720 (100 mg/kg/day), or the combination once daily by gavage for 14 days. Tumor measurements were taken daily. Results: Treatment of melanoma cell lines with PLX4720 resulted in downmodulation of Mcl-1 and induction of BIM both in vitro and in vivo. In vitro, the combination of navitoclax and PLX4720 led to greater PARP cleavage than either agent alone. In vivo, the navitoclax enhanced the efficacy of PLX4720 in both xenograft models. Interestingly, the two xenograft models showed differential sensitivity to treatment with the respective single agents. Conclusion: The combination of a selective BRAF inhibitor with a BH3-mimetic may be a promising therapeutic strategy to enhance the clinical efficacy of BRAF inhibitors. Efforts are underway to assess such a combination clinically. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A27.