In patients with renal-cell carcinoma at high risk for relapse after nephrectomy, the rate of disease-free survival was significantly higher among those receiving sunitinib than among those receiving ...placebo, at the cost of a higher rate of toxic events.
Each year, approximately 300,000 persons worldwide are diagnosed with renal-cell carcinoma, resulting in 129,000 deaths.
1
,
2
The prognosis for patients with renal-cell carcinoma is dependent on the stage of disease and other risk factors. The 5-year survival rate is 53% for locoregional (stage III) disease and 8% for metastatic disease.
3
Overall, locoregional disease is diagnosed in 16% of patients with renal-cell carcinoma,
4
and up to 40% of these patients have a relapse with metastasis after nephrectomy.
5
,
6
The relapse risk can be assessed with the use of two validated models, the University of California Los Angeles Integrated Staging System (UISS) . . .
Summary Background In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer ...progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. Methods Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov , number NCT00678392. Findings Median overall survival was 20·1 months (95% CI 16·7–23·4) with axitinib and 19·2 months (17·5–22·3) with sorafenib (hazard ratio HR 0·969, 95% CI 0·800–1·174; one-sided p=0·3744). Median investigator-assessed PFS was 8·3 months (95% CI 6·7–9·2) with axitinib and 5·7 months (4·7–6·5) with sorafenib (HR 0·656, 95% CI 0·552–0·779; one-sided p<0·0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 17%), diarrhoea (40 11%), and fatigue (37 10%) in 359 axitinib-treated patients and hand–foot syndrome (61 17%), hypertension (43 12%), and diarrhoea (27 8%) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20·7 months (95% CI 18·4–24·6) versus 12·9 months (10·1–20·4) in the axitinib group (p=0·0116), and 20·2 months (17·1–32·0) versus 14·8 months (12·0–17·7) in the sorafenib group (one-sided p=0·0020). Interpretation Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. Funding Pfizer Inc.
Summary Background The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the ...effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. Methods We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov , number NCT00678392. Findings A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. Interpretation Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. Funding Pfizer Inc.
Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial ...targeted therapy in patients with metastatic renal cell carcinoma (RCC).
Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review.
A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio HR, 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%).
Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.
The efficacy and safety of combining bevacizumab (7.5 and 15 mg/kg) with docetaxel as first-line therapy for human epidermal growth factor receptor 2 (HER2) -negative, locally recurrent or metastatic ...breast cancer (MBC) was investigated in a three-arm, placebo-controlled, phase III trial.
Patients (N = 736) were randomly assigned to docetaxel 100 mg/m(2) plus either placebo or bevacizumab 7.5 or 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS); secondary end points included best overall response, duration of response, time to treatment failure, overall survival, and safety.
Combination of bevacizumab 15 mg/kg, but not 7.5 mg/kg, with docetaxel showed superior median PFS (mPFS) to placebo plus docetaxel in unstratified analysis (placebo mPFS, 8.2 months; 7.5 mg/kg mPFS, 9.0 months hazard ratio (HR), 0.86; P = .12; 15 mg/kg mPFS, 10.1 months HR, 0.77; P = .006) and stratified analysis (placebo mPFS, 8.1 months; 7.5 mg/kg mPFS, 9.0 months HR, 0.80; P = .045; 15 mg/kg mPFS, 10.0 months HR, 0.67; P < .001). Response rates in patients with measurable disease at baseline also increased with bevacizumab 15 mg/kg (46% placebo v 55% 7.5 mg/kg; P = .07 and 64% 15 mg/kg; P < .001). Combination with bevacizumab had limited impact on the known toxicity profile of docetaxel.
Combination of bevacizumab with docetaxel did not significantly impact on the safety profile of docetaxel. Bevacizumab 15 mg/kg every 3 weeks significantly increased PFS when combined with docetaxel as first-line therapy for MBC compared with docetaxel plus placebo.
A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-alpha) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell ...carcinoma (RCC). Final survival analyses and updated results are reported.
Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-alpha 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up.
Median overall survival was greater in the sunitinib group than in the IFN-alpha group (26.4 v 21.8 months, respectively; hazard ratio HR = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-alpha group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).
Sunitinib demonstrates longer overall survival compared with IFN-alpha plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.
Summary Background Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. ...Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. Methods Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov , number NCT00664326. Findings The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7–34·4, IQR 2·5–18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7–52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. Interpretation Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring. Funding Bayer HealthCare Pharmaceuticals.
Abstract only
546
Background: PD-1/L1 pathway inhibitors are effective in clear cell (cc)RCC, but efficacy of PD-1 inhibitors (or any therapy) in nccRCC has not been established. KEYNOTE-427 is a ...single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced ccRCC (cohort A) and nccRCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed nccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts were followed after PD for overall survival. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Secondary end points included duration of response (DOR) and population description by International Metastatic RCC Database Consortium (IMDC) risk. Exploratory end points: ORR by histology and PD-L1 expression (combined positive score CPS ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). 68% of patients were at intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At a median follow-up duration of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 4.8% CRs, 33 20% PRs); median DOR was not reached. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified nccRCC. ORR (95% CI) was 28.3% (16.8-42.3) with favorable and 23.2% (15.8-32.1) with intermediate/poor IMDC risk and 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS<1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts; 6% discontinued due to TRAEs. 6 pts died due to AEs, 2 of which were TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in nccRCC, especially with papillary or unclassified histology. Safety profile of pembro was generally as expected. Clinical trial information: NCT02853344.
We reexamine the Kosterlitz-Thouless phase transition in the ground state |Ψ0⟩ of an antiferromagnetic spin-1/2 Heisenberg chain with nearest- and next-nearest-neighbor interactions λ from a ...different perspective: After defining winding number (topological charge) W in the basis of resonating valence bond states, the finite-size scaling of ⟨Ψ0|W|Ψ0⟩, ⟨Ψ0|W|∂λΨ0⟩, ⟨∂λΨ0|W|∂λΨ0⟩ leads to the accurate value of critical coupling λc = 0.2412 ± 0.0007 and to the value of subleading critical exponent ν = 2.000 ± 0.001 . This approach should be useful when examining the topological phase transitions in all systems described in the basis of resonating valence bonds.
PDF
