Ulrika Harmenberg

Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma

BACKGROUND Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. METHODS We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. RESULTS Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons). CONCLUSIONS Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

PURPOSE Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. PATIENTS AND METHODS Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. RESULTS One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. CONCLUSION Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

Detection of pancreatic cancer using antibody microarray-based serum protein profiling

The driving force behind oncoproteomics is to identify protein signatures that are associated with a particular malignancy. Here, we have used a recombinant scFv antibody microarray in an attempt to classify sera derived from pancreatic adenocarcinoma patients versus healthy subjects. Based on analysis of nonfractionated, directly labeled, whole human serum proteomes we have identified a protein signature based on 19 nonredundant analytes, that discriminates between cancer patients and healthy subjects. Furthermore, a potential protein signature, consisting of 21 protein analytes, could be defined that was shown to be associated with cancer patients having a life expectancy of <12 months. Taken together, the data suggest that antibody microarray analysis of complex proteomes will be a useful tool to define disease associated protein signatures.

2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial

BACKGROUND Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. METHODS Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. FINDINGS 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). INTERPRETATION Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. FUNDING Sanofi.

Additive/synergistic antitumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronic acid

Once bone metastasized and androgen independent, prostate cancer is often associated with skeletal morbidity and disability. New treatment modalities that can palliate symptoms from the skeleton and inhibit further progression are warranted. In this study, the antitumoral effects following treatment with a combination of docetaxel and the new generation bisphosphonate, zoledronic acid, were investigated on two hormone-refractory prostate cancer cell lines: PC3 and DU145. The prostate cancer cells were treated with increasing concentrations of zoledronic acid in the absence or presence of docetaxel. Toxicity was measured using fluorometric microculture cytotoxic assay technique. A concentration of 25 µM, zoledronic acid reduced the viable cell number to 68% and 98% for PC3 and DU145 cells respectively. Docetaxel, on the other hand, at a concentration of 0.1 ng/ml, had no effect on the viability. However, a combination of zoledronic acid and docetaxel reduced the cell number to 60% and 81% respectively. Furthermore, zoledronic acid in the concentration range 12.5 µM–50 µM enhanced the antitumoral effects of docetaxel (0.01–1 ng/ml) in an additive and/or synergistic manner for both cell lines. These data support the hypothesis that zoledronic acid, in addition to having bone resorption inhibiting properties, also exhibits anti-tumoral effects. It also appears that combined treatment with docetaxel causes additive and/or synergistic cytostatic effects on prostate cancer cells.

Autoantibodies against the tumour-associated antigen GA733-2 in patients with colorectal carcinoma

Abstract The tumour-associated antigen (TAA) GA733-2 is expressed as a non-secreted surface molecule on the majority of human colorectal carcinoma cells. The antigen has been used as a target for passive and active immunotherapy during the last decade. To determine the incidence of autoantibodies against this antigen, sera from 1068 patients with colorectal carcinoma were analysed for naturally occurring IgG antibodies against the baculovirus-produced GA733-2E protein. A total of 14.5% of the patients had IgG antibodies against the antigen. In 519 patients, sera were collected at the time of diagnosis and 15% of those patients had anti-GA733-2E IgG antibodies. There was a tendency to a higher frequency of patients with antibodies among those in the advanced Dukes stages: 11% in stage A and 32% in stage D respectively (P = 0.06). Antibodies could be detected for up to 10 years after the diagnosis. Patients with Crohns disease or colitis ulcerosa (n = 20) did not elicit anti-GA733-2E antibodies. No healthy control donor (n = 45) had detectable antibodies against the antigen. The specificity of GA733-2E-reactive serum IgG was indicated by significant inhibition of mAb17-1A (originally used to define GA733-2) binding to the GA733-2E antigen. Sera of positive patients bound to the GA733-2-expressing human colorectal carcinoma cell line, SW948. No significant correlation was found between the presence of antibodies and survival in the present patient population. However, the high incidence of autoantibodies against this tumour antigen in colorectal carcinoma patients confirms its antigenicity in humans and supports the use of the GA733-2 antigen as a target for immunotherapy.

T-cell-epitope mapping of the idiotypic monoclonal IgG heavy and light chains in multiple myeloma

The idiotypic structures of the myeloma protein might be regarded as tumor‐specific antigens. The present study was designed to map T‐cell epitopes of the idiotypic myeloma protein to prove the existence of naturally occurring major‐histocompatibility‐complex‐dependent idiotype (peptide)‐specific T cells in multiple myeloma. The fine specificity of idiotype‐reactive, interferon‐γ‐producing blood T cells of a patient with multiple myeloma stage I was characterized by identification of idiotype (heavy and light chains)‐derived MHC‐restricted T‐cell epitopes. T cells specifically reacting with peptides corresponding to each of the 3 complementarity‐determining regions (CDRs) of the heavy‐chain variable part (VH) of the autologous idiotype were found. In contrast, none of the peptides corresponding to the 3 CDRs of the light chain (VL) induced a specific T‐cell response. The idiotype amino‐acid sequence corresponding to the junction of the VH, diversity (D), and joining (J) gene segments of the VH appeared to be an important target for T cells, since the sequence expressed MHC‐class‐I‐ as well as MHC‐class‐II‐restricted epitopes. The study provides further support for the existence of MHC‐restricted idiotype‐specific T cells, which may target immunogenic CDR peptides in multiple myeloma. Such T cells could be an important part of the specific anti‐tumor immune responses induced in idiotype vaccination protocols. Int. J. Cancer 80:671–680, 1999.

Treatment and overall survival in renal cell carcinoma: a Swedish population-based study (2000-2008).

Background:This retrospective register study assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients.Methods:Using three merged national health registers, Cox proportional-hazards analysis was conducted and, in three models, it was used to assess the impact of cytokine (interferon-α and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatment on OS in metastatic (m)RCC.Results:From 2000 to 2008, 8009 patients were diagnosed with RCC and 2753 with mRCC (2002–2008). Median OS in RCC patients diagnosed from 2006 to 2008 compared with 2000–2005 was not reached vs 47.9 months (P<0.001), and in mRCC patients diagnosed from 2006 to 2008 compared with 2002–2005, was 12.4 vs 9.6 months, respectively (P=0.004). Factors associated with significantly improved OS in RCC were female gender, lower age, and previous nephrectomy, and, in mRCC female gender, previous nephrectomy, and any TKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients) vs 9.7 months (non-TKI patients); hazard ratio, 0.621; P<0.001).Conclusion:OS was improved in Swedish patients diagnosed with RCC and mRCC in the period 2006–2008 compared with 2000–2005 (RCC) and 2002–2005 (mRCC). Although multifactorial in origin, results suggest that increased nephrectomy rates and the use of TKIs contributed to the improvement seen in mRCC patients.

Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025

BACKGROUND Response patterns to nivolumab differ from those seen with other approved targeted therapies. OBJECTIVE To investigate the efficacy of nivolumab in previously treated patients with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression. DESIGN, SETTING, AND PARTICIPANTS This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for ≥4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression. INTERVENTIONS Nivolumab 3mg/kg intravenously every 2 wk. RESULTS AND LIMITATIONS Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had ≥30% tumor burden reduction including patients with preprogression and postprogression tumor measurements (n=142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis. CONCLUSIONS A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.gov Identifier: NCT01668784. PATIENT SUMMARY A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile.

Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma.

Study Type – Therapy (economic)