Louise Lim

Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer

Purpose: To test the hypothesis that sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant. Experimental Design: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. 18F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUVmax) at 4 and 16 weeks with overall survival (OS). Results: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUVmax = 6.8, range: <2.5–18.4). In multivariate analysis, a high SUVmax and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36–8.45) and 3.67 (95% CI: 1.43–9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40–1.99) or OS (HR for responders = 0.80; 95% CI: 0.34–1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43–19.02) and HR = 12.13 (95% CI: 3.72–46.45), respectively]. Conclusions: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant. Clin Cancer Res; 17(18); 6021–8. ©2011 AACR.

Sunitinib and other targeted therapies for renal cell carcinoma.

Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years.

A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer

BACKGROUND Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach. MATERIALS AND METHODS This study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed. RESULTS Sixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break. CONCLUSIONS Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.

The Effect of Sunitinib on Immune Subsets in Metastatic Clear Cell Renal Cancer

Background: Sunitinib is standard first-line therapy for metastatic clear cell renal cancer (MCRC). It is associated with leucopenia; however, its effects on specific immune cell subsets are unclear. Alterations in immune cell subsets may contribute to tumour progression. Methods: Lymphocyte subsets (CD3, 4, 8, 19 and 56) were measured in 43 untreated MCRC patients who received sunitinib. The protocol included a structured treatment interruption of 5 weeks. Cell populations were measured at specific time points during sunitinib treatment and the treatment break. Results: Sunitinib was associated with significant declines in total leucocyte (–48%), neutrophil (–62%), CD3 total T cell (–31%) and CD4 counts (32%; p < 0.05). There was no significant change in CD19 B lymphocyte, CD8 or CD56 natural killer cells. During the sunitinib-free interval, all parameters recovered to baseline. No patients developed opportunistic infections or neutropenic sepsis. The level of specific immune subsets at presentation or occurrence of a fall in specific counts had an effect on progression-free survival (p > 0.05). Conclusions: Sunitinib is associated with reversible inhibition of specific lymphocyte subsets which has implications for the immunological control of MCRC and its use in combination with other agents. Despite suppressive effects, there was no evidence of predisposition to immune suppressive-related infection.

A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer

BACKGROUND Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study. METHODS Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n=15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response. RESULTS Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5mg orally (PO) once daily (OD) and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1-4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2-11 months). Pharmacokinetic data at the MTD showed stable kinetics with time. CONCLUSION Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.

Low-dose induction chemotherapy with Baby-BOP in patients with metastatic germ-cell tumours does not compromise outcome: a single-centre experience

BACKGROUND In some institutions advanced metastatic germ-cell tumour (GCT) is treated with low-dose induction chemotherapy in specific settings. There is a lack of published data supporting its use. The data presented here specifically address this issue for the first time. PATIENTS AND METHODS Twenty patients with metastatic GCT treated were with low-dose induction chemotherapy [Baby-BOP (bBOP)] between 1998 and 2009. We report the toxicity and outcome and compare it with a control group. RESULTS bBOP was well tolerated with no treatment-related deaths and a lack of chemotherapy-related toxicity. It was associated with a significant fall in tumour markers (median HCG fell from 35 195 to 11 028 IU/l). The first subsequent cycle of standard chemotherapy was administered a median of 9.5 days after initial treatment and was not associated with excess toxicity. The 2-year overall survival of the poor-prognosis patients treated with bBOP was 79.0% [95% confidence interval (CI) 48% to 93%], which is not significantly different from the 2-year overall survival of 80% [95% CI 55% to 92%] of the poor-prognosis patients, who did not receive bBOP. CONCLUSION Low-dose induction chemotherapy can be given safely in selected individuals and does not adversely affect subsequent chemotherapy or outcome.

Single-agent carboplatin AUC10 for metastatic seminoma with IGCCCG good prognosis disease; a feasibility study of the Orchid Clinical Trials Group

Patients with metastatic seminoma exhibit excellent long-term cure rates [1], with the focus of recent investigations being the reduction of toxicity associated with standard cisplatinbased combination regimens. Carboplatin, a cisplatin analogue with improved toxicity profile, has been examined by a number of metastatic seminoma studies [2–7]. These have generally concluded that although progression-free survival is inferior to that seen with standard therapy, overall survival does not differ due to effective salvage treatment and toxicity is substantially reduced. The aim of this study was to assess higher doses of carboplatin monotherapy in order to improve efficacy while maintaining minimal toxicity.

Increased haematopoietic progenitor cells are associated with poor outcome in patients with metastatic renal cancer treated with sunitinib

BACKGROUND Haematopoietic progenitor cells (HPCs) are present in blood in metastatic renal cell cancer (mRCC). We investigate their expression in mRCC patients treated with sunitinib and correlate their expression with plasma growth factor levels [insulin-like growth factor (IGF)-1]. METHODS Circulating HPCs (CD34(+)/CD45(+)) and plasma IGF-1 levels were measured at specific sequential time points (0, 6, 18 and 28 weeks) in 43 untreated mRCC patients receiving sunitinib (50 mg for 28 days followed by 14-day off treatment). Univariate and multivariate analysis assessed the prognostic significance of HPCs and IGF-1. RESULTS HPCs levels were raised in 40 of 43 (93%) of patients. IGF-1 levels were raised in 9 of 43 patients (21%). Univariate and multivariate analysis revealed that high HPCs before treatment were associated with a significantly shorter overall survival (hazard ratio 3.3, 95% confidence interval 1.23-8.8, P=0.01), which was not the case for IGF-1 levels. Both HPC and IGF-1 levels fell with sunitinib (61% and 14% fall, respectively, P <0.05 for both). A positive correlation between the falls in HPC and IGF-1 occurred (P<0.001). CONCLUSIONS HPCs are over expressed in the peripheral blood in the majority of patients with mRCC. Higher levels are associated with poor prognosis. A concurrent fall in HPCs and growth factor expression (IGF-1) with sunitinib occurs.

The application of the National Institute of Clinical Excellence guidelines for treatment of metastatic renal cell carcinoma in the United Kingdom: friend or foe?

Targeted therapy has replaced immunotherapy as standard treatment in metastatic renal cell carcinoma (mRCC). Both firstand second-line targeted therapy is associated with clinical benefit in this setting. The National Institute of Clinical Excellence (NICE) focuses on the cost of drugs as well as their efficacy. It does this by calculation of the cost per quality adjusted life year (QALY) of an agent. NICE has recently assessed targeted therapy in RCC and approved sunitinib in isolation in the first-line metastatic setting, while rejecting other firstand second-line agents. Several clinical issues have arisen from this decision, including when to commence and discontinue therapy and how to treat patients who are not eligible for sunitinib. These issues, which are likely to become more prevalent in the era of healthcare economics, are addressed in this article.

The hazards of cross comparing the drug toxicity results from different trials in metastatic renal cancer: In response to a letter from Dr. Catalá-López

Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK Department of Medical Oncology, The Beatson Hospital, Glasgow, UK Department of Medical Oncology, The Royal Free Hospital, London, UK Department of Medical Oncology, John Radcliffe Hospital, London, UK Department of Medical Oncology, University of Southampton, Southampton, UK Department of Oncology, University Hospitals Coventry and Warwickshire NHS Trust, UK Department of Oncology, Mount Vernon Hospital, London, UK Guys and St Thomas’ Hospital, London, UK