Advanced pancreatic cancer remains a lethal, incurable malignancy. Chemotherapy is the mainstay of systemic therapy consideration in metastatic pancreas cancer. Homologous recombinant DNA repair ...mutations are reported in about 7% of pancreas cancer cases and have rapidly emerged as actionable mutations.
A review was conducted of publications of PARP inhibitors in pancreatic malignancies with a focus on clinical trials with olaparib. This included a review of the phase II and phase III clinical trials of olaparib in pancreatic cancer.
Olaparib was compared to placebo in a randomized double blind trial in cases with advanced pancreatic cancer and germline
mutations, with a clinical response or stable disease after at least 16 weeks of platinum based chemotherapy. Olaparib significantly improved progression free survival, HR = -.53,
= 0.0035 but did not improve overall survival. No differences in quality of life were noted between the two arms. Adverse events from olaparib were noted in 40% of treated patients. Objective response rate was 20% in olaparib arm and 10% in placebo treated arm. A careful consideration of the risks and benefits of this personalized therapy is advisable, prior to clinical application in germline BRCA1/2 mutated advanced pancreatic cancer.
Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, ...dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC).
Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety.
A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs.
Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.
Purpose of Review
Due to the rapidly changing field of kidney cancer therapeutics, addressing the state of the art systemic therapy regimens, and sequencing with cytoreductive nephrectomy are the ...primary focus of this review. We will also discuss the role of biomarkers and novel therapeutic targets in the management of renal cell carcinoma.
Recent Findings
The management of metastatic renal cell cancer has undergone a paradigm shift with immune checkpoint inhibitors being used in the frontline setting. Over the last 4 years, programmed cell death-1 (PD-1) inhibitors as well as programmed cell death ligand-1 inhibitors have become available in various combinations with cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors and tyrosine kinase inhibitors (TKIs). These drugs have improved outcomes in patients with renal cell cancer and more work is being done to refine these targets as well as discover newer ones.
Summary
Despite the availability of several new treatment options, some questions that still need to be addressed in the management of kidney cancer include the sequencing of treatment options, treatment of patients who progress on immune checkpoint inhibitors, and role of biomarkers to ascertain the best treatment options to minimize costs and improve outcomes.
Summary Background The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy ...of the model in an external population and compared it with other prognostic models. Methods We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit. Findings Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6–21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68–0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4–50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7–25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5–9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639–0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636–0·687), of the French model 0·640 (0·614–0·665), of the IKCWG model 0·668 (0·645–0·692), and of the MSKCC model 0·657 (0·632–0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models. Interpretation The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis. Funding None.
Summary Background Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to ...compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. Methods We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov , number NCT01108445. Findings Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months 80% CI 5·8–11·4 vs 5·6 months 5·5–6·0; hazard ratio 1·41 80% CI 1·03–1·92; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3–4 adverse events were hypertension (12 24% of 51 patients in the sunitinib group vs one 2% of 57 patients in the everolimus group), infection (six 12% vs four 7%), diarrhoea (five 10% vs one 2%), pneumonitis (none vs five 9%), stomatitis (none vs five 9%), and hand-foot syndrome (four 8% vs none). Interpretation In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors. Funding Novartis and Pfizer.
Cabozantinib is a small molecule tyrosine kinase inhibitor that initially showed activity in medullary thyroid cancer and was recently approved by the Food and Drug Administration for the treatment ...of metastatic renal cell carcinoma after progression on first line therapy. Areas covered: In the METEOR trial, cabozantinib demonstrated significantly improved efficacy in all three endpoints; response rates, progression free survival and overall survival in a randomized trial with everolimus as an active comparator. Cabozantinib also showed activity in the front line setting in RCC within the CABOSUN trial. The study randomized untreated metastatic RCC patients to either cabozantinib or sunitinib and the former showed improved progression free survival which was the primary endpoint. The future holds promise for indications in other malignancies, given the preliminary efficacy and unique mechanism of action of cabozantinib. In this review we address the mechanism of action, pharmacodynamics and pharmacokinetics of cabozantinib, and also review the development pathway of this agent in the treatment of advanced renal cell carcinoma. The potential benefit in specific patient populations, such as poor risk patients and bone metastases subgroups is also discussed. Expert commentary: The clinical applications of cabozantinib will be addressed within the context of the current competitive therapeutic landscape of RCC.
Summary Background Previous prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of targeted therapy. We sought to ...validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in patients with metastatic renal cell carcinoma receiving next-line targeted therapy after progression on first-line targeted therapy. Methods In this population-based study, we analysed patients who received second-line targeted therapy for metastatic renal cell carcinoma at 19 centres in Canada, USA, Greece, Japan, Singapore, South Korea, and Denmark. The primary endpoint was overall survival since the initiation of second-line therapy. We compared the prognostic performance of the IMDC model with the three-factor MSKCC model used for previously treated patients for overall survival since the start of second-line targeted therapy. Findings Between Jan 1, 2005, and Nov 30, 2012, we included 1021 patients treated with second-line targeted therapy. Median overall survival since the start of second-line targeted therapy was 12·5 months (95% CI 11·3–14·3). Five of six predefined factors in the IMDC model (anaemia, thrombocytosis, neutrophilia, Karnofsky performance status KPS <80, and <1 year from diagnosis to first-line targeted therapy) were independent predictors of poor overall survival on multivariable analysis. The concordance index using all six prognostic factors (ie, also including hypercalcaemia) was 0·70 (95% CI 0·67–0·72) with the IMDC model and was 0·66 (95% CI 0·64–0·68) with the three-factor MSKCC model. When patients were divided into three risk categories using IMDC criteria, median overall survival was 35·3 months (95% CI 28·3–47·8) in the favourable risk group (n=76), 16·6 months (14·9–17·9) in the intermediate risk group (n=529), and 5·4 months (4·7–6·8) in the poor risk group (n=261). Interpretation The IMDC prognostic model can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy. The IMDC prognostic model in the second-line targeted therapy setting has an improved prognostic performance and is applicable to a more contemporary patient cohort than that of the three-factor MSKCC model. Funding DF/HCC Kidney Cancer SPORE P50 CA101942-01, Kidney Cancer Research Network of Canada, Canadian Institute for Health Research, Trust Family, Loker Pinard, Michael Brigham, and Gerald DeWulf.
Abstract Background The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). Objective To analyze outcomes based on the presence of ...bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. Design, setting, and participants We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. Outcome measurements and statistical analysis We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. Results and limitations The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively ( p < 0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) ( p = 0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval CI, 1.22–1.62) for BMs, 1.42 (95% CI, 1.17–1.73) for LMs, and 1.82 (95% CI, 1.47–2.26) for both BMs and LMs compared with other metastatic sites ( p < 0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p < 0.0001). Data in this analysis were collected retrospectively. Conclusions The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in ...patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.
Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.
One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).
Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
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