In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell ...carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up.
This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group not reported in this updated analysis) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861.
Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 26% female, 796 74% male; median age 62 years IQR 55–69) were randomly assigned: 355 (33%) patients (255 72% male and 100 28% female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 77% male and 82 23% female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3–33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5–32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8–27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0–11·0) in the sunitinib group (stratified hazard ratio HR 0·42 95% CI 0·34–0·52). Median overall survival follow-up was 33·7 months (IQR 27·4–36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7–36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached 95% CI 41·5–not estimable) versus sunitinib (median not reached 38·4–not estimable; HR 0·72 95% CI 0·55–0·93).
Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma.
Eisai and Merck Sharp & Dohme.
Approximately 70% of cases of kidney cancer are localized or locally advanced at diagnosis. Among patients who undergo surgery for these cancers, 30-35% will eventually develop potentially fatal ...metachronous distant metastases. Effective adjuvant treatments are urgently needed to reduce the risk of recurrence of kidney cancer and of dying of metastatic disease. To date, almost all of the tested adjuvant agents have failed to demonstrate any benefit. Only two trials of an autologous renal tumour cell vaccine and of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor sunitinib have shown positive results, but these have been criticized for methodological reasons and conflicting data, respectively. The results of two additional trials of targeted agents as adjuvant therapies have not yet been published. Novel immune checkpoint inhibitors are promising approaches to adjuvant therapy in kidney cancer, and a number of trials are now underway. An important component of the management of patients with kidney cancer, particularly those who undergo radical resection for localized renal cell carcinoma, is the preservation of kidney function to reduce morbidity and mortality. The optimal management of these patients therefore requires a multidisciplinary approach involving nephrologists, oncologists, urologists and pathologists.
To our readers:
With deep regrets, we inform our Readers that the article The biological mechanism involved in anticancer properties of amniotic membrane (DOI: ...https://doi.org/10.4081/oncol.2020.429), which has been published in the current issue of Oncology Reviews (2020-1), contains verbatim text plagiarized from another paper.1 The manuscript must be considered as retracted. On behalf of the Editorial Board of Oncology Reviews, I apologize to the Author of the manuscript whose text was plagiarized by Ameneh Jafari, Hassan Niknejad, Mostafa Rezaei-Tavirani, Caitlin D’Amico, Hakimeh Zali that this was not picked up in the peer review process. I also apologize to the affected journal for the violation of copyright due to plagiarism. Unfortunately we were not able to detect it before publication due to the language of the original paper (Slovenian). Oncology Reviews is uncompromising in its commitment to scientific integrity. When credible evidence of misconduct is brought to our attention, our commitment to the scientific record and to our readership requires immediate notification. Oncology Reviews is increasingly employing sophisticated software to detect plagiarism. Other journals use similar tools. Authors should be aware that most journals routinely employ plagiarism detection software, and that any plagiarism is likely to be detected.
Camillo Porta, Editor-in-Chief Oncology Reviews
Reference1. Ramuta TZ, Cirman T, Erdani Kreft M. Celično-biološki mehanizmi delovanja amnijske membrane proti raku in možnosti za njeno uporabo pri zdravljenju raka Cell-biological mechanisms of amniotic membrane anticancer activity and the possibilities of its use in anticancer therapy. Slovenian Medical Journal (Zdravniški vestnik) 2018;87(9-10):483-92. (DOI: 10.6016/ZdravVestn.2674).
Lenvatinib plus either pembrolizumab or everolimus was compared with sunitinib as first-line therapy for advanced renal cell cancer. Progression-free survival was significantly longer with lenvatinib ...plus pembrolizumab than with sunitinib. Lenvatinib plus everolimus was also more effective than sunitinib, but the difference was smaller.
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 ...alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2′s role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.
Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal ...cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treatment with ICIs, the most common adverse kidney effect is represented by the development of acute kidney injury (AKI) with the acute tubulointerstitial nephritis as recurrent histological feature. The mechanisms involved in ICIs-induced AKI include the re-activation of effector T cells previously stimulated by nephrotoxic drugs (i.e. by antibiotics), the loss of tolerance versus self-renal antigens, the increased PD-L1 expression by tubular cells or the establishment of a pro-inflammatory milieu with the release of self-reactive antibodies. For renal transplant recipient treated with ICIs, the increased incidence of rejection is a serious concern. Therefore, the combination of ICIs with mTOR inhibitors represents an emerging strategy. Finally, it is relevant to anticipate which patients under ICIs would experience severe irAEs and from a kidney perspective, to predict patients with higher risk of AKI. Here, we provide a detailed overview of ICIs-related nephrotoxicity and the recently described multicenter studies. Several factors have been reported as biomarkers of ICIs-irAEs, in this review we speculate on potential biomarkers for ICIs-associated AKI.
Cell lines are still a tool of choice for many fields of biomedical research, including oncology. Although cancer is a very complex disease, many discoveries have been made using monocultures of ...established cell lines. Therefore, the proper use of in vitro models is crucial to enhance our understanding of cancer. Therapeutics against renal cell cancer (RCC) are also screened with the use of cell lines. Multiple RCC in vitro cultures are available, allowing in vivo heterogeneity in the laboratory, but at the same time, these can be a source of errors. In this review, we tried to sum up the data on the RCC cell lines used currently. An increasing amount of data on RCC shed new light on the molecular background of the disease; however, it revealed how much still needs to be done. As new types of RCC are being distinguished, novel cell lines and the re-exploration of old ones seems to be indispensable to create effective in vitro tools for drug screening and more.
Summary Background Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, ...particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. Methods Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov , NCT00130897. Findings As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1–25). Reasons for discontinuation included lack of efficacy (n=1168 27%) and adverse events (n=362 8%). The most common treatment-related adverse events were diarrhoea (n=1936 44%) and fatigue (n=1606 37%). The most common grade 3–4 adverse events were fatigue (n=344 8%) and thrombocytopenia (n=338 8%) with incidences of grade 3–4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 12%), ECOG performance status 2 or higher (29 of 319 9%), non-clear-cell RCC (48 of 437 11%) and age 65 years or more (176 of 1056 17%). Median progression-free survival was 10·9 months (95% CI 10·3–11·2) and overall survival was 18·4 months (17·4–19·2). Interpretation In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials. Funding Pfizer Inc.
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