A number of agents are now approved for the treatment of renal cancer. A comparison of two agents, pazopanib and sunitinib, showed similar levels of antitumor activity but distinct side-effect ...profiles. Symptoms affecting quality of life were somewhat worse with sunitinib.
Renal-cell carcinoma is the most common kidney cancer.
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Up to 30% of patients have metastases at the time of the initial diagnosis.
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Systemic treatment for patients who have metastatic renal-cell carcinoma with a clear-cell histologic component has shifted from cytokines to drugs targeting angiogenesis. Sunitinib, pazopanib, and five other agents have been approved by the Food and Drug Administration for the treatment of clear-cell, metastatic renal-cell carcinoma.
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Among the tyrosine kinase inhibitors, pazopanib and sunitinib are first-line treatment options.
Sunitinib has been compared with interferon alfa in patients who had not previously received systemic therapy for renal-cell carcinoma,
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whereas . . .
Renal cell carcinoma still carries a poor prognosis despite therapeutic advancements. Detection of genetic mutations is vital in improving our understanding of this disease as well as potential role ...in targeted therapy. Here we present a case of a 49 year old man with an aggressive renal cell carcinoma bearing a novel pathogenic
fusion. We will explore the clinical presentation, histological and molecular diagnostics, treatment and disease progression. We will discuss the relevance of this unique fusion and comparisons with cancer cases with similar genetic mutations. Further research is warranted for such cases, in order to facilitate better targeted treatments.
Highlights • Crizotinib is a standard of care for ALK-positive lung cancer. • Crizotinib-associated AEs are mostly mild to moderate in severity. • Appropriate monitoring and supportive therapies ...reduce the need for dosing modifications. • Patients may have prolonged benefit from crizotinib after disease progression. • Crizotinib should be continued for as long as the patient derives benefit.
The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.
To establish the safety and efficacy of upfront pazopanib therapy prior to ...cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.
Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.
Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.
The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.
Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median interquartile range age, 64 56-71 years). Overall, 84 of 100 (84% 95% CI, 75%-91%) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 95% CI, 2.6-10.8 and 3.9 95% CI, 0.5-9.1 months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.
Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.
Following ipilimumab/nivolumab treatment, cytoreductive nephrectomy to achieve no evidence of disease resulted in durable disease-free survival and median treatment-free survival of 21 mo.
Upfront ...cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories.
To investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN.
This was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED.
We measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined.
At median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo.
CN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety.
In our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.
Abstract Background Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)–refractory metastatic renal cell carcinoma (mRCC). It acts on only ...part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). Objective The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. Design, setting, and participants Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. Intervention Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. Outcome measurements and statistical analysis Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. Results and limitations Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 95% confidence interval (CI), 1.2–6.5; p = 0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus ( p < 0.001). Grade 3–4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients ( p = 0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1–8.4; p < 0.02). Conclusions The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. Patient summary There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.
Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free ...interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma.
This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was –0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16.
Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 73% male and 251 27% female; 885 96% White and 23 3% non-White). The median follow-up time was 58 months (IQR 46–73 months) in the ITT population and 58 months (46–72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 95% CI 0·83 to 1·12 in the ITT population; 0·94 0·80 to 1·09 in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 95% CI –0·11 to 0·23 for the ITT population; 0·04 –0·14 to 0·21 for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 26% of 485 patients in the conventional continuation strategy group vs 127 29% of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 11% vs 48 11%); and fatigue (39 8% vs 63 15%). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1).
Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma.
UK National Institute for Health and Care Research.
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