Daniel YC Heng’s research while affiliated with Tom Baker Cancer Centre and other places

The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 ( ClinicalTrials.gov )

Radiotherapy is living a second life in Renal Cell Carcinoma (RCC) patients, mainly due to the introduction of immunocheckpoint inhibitors, such as anti-Programmed-death (PD)-1, alone or in combination with anti-Cytotoxic T-Lymphocyte Antigen (CTLA)-4. Several trials are investigating the efficacy/safety of immunocheckpoint inhibitors in sequential or combined strategies with radiotherapy. Chimeric Antigen Receptor (CAR)-T cells therapy as a promising approach in cancer patients has opened the way to novel possibilities of integrating therapies. The identification of biomarkers of tumor response to these combinations represents a challenge in RCC, together with the research for the best partner for immunotherapy in metastatic patients. In this review we illustrated preclinical/clinical data on the integration of radiotherapy with immunocheckpoint inhibitors or CAR-T cells in RCC.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

Real-world evidence has played an important role in expanding our knowledge on the treatment and prognostication of advanced renal cell carcinoma. This type of data has been particularly helpful in providing a better understanding of groups that are traditionally excluded from randomized controlled trials. The International mRCC Database Consortium (IMDC) represents the largest collection of real-world data on patients with advanced kidney cancer treated with targeted therapies. The IMDC prognostic model has been used to stratify patients in contemporary clinical trials and to provide risk-directed treatment selection in everyday clinical practice. More recently, it has been shown to predict response to first-line combination immunotherapy in the phase III CheckMate 214 clinical trial. In this review, we highlight the real-world evidence associated with the treatment of mRCC. We focus on first-line therapy, as well as second-line and third-line therapeutic options, including novel immuno-oncology agents. We also address the real-world evidence for the use of cytoreductive nephrectomy in advanced renal cell carcinoma in the targeted therapy era.

Over the last number of years, the treatment of metastatic renal cell cancer has evolved tremendously with the advent of targeted therapy. Previously, immunotherapies, such as interferon alpha and interleukin-2, were the only treatment options available for this chemoresistant malignancy. Currently, seven additional agents, including sunitinib, sorafenib, axitinib, pazopanib, bevacizumab, everolimus and temsirolimus, have been approved for use in metastatic renal cell cancer, with several more in development. The efficacy of these agents depends primarily on inhibition of the vascular endothelial growth factor and mammalian target of rapamycin pathways, and have drastically improved the outcomes of patients diagnosed with metastatic renal cell cancer. This article reviews the major treatment advances that have occurred for metastatic renal cell cancer with the advent of targeted treatments, summarizes the evidence to support their use and addresses clinical issues that have arisen with them. To help guide clinicians in their decision-making with these emerging therapeutic choices, the evidence for sequencing and combining these agents, and the need for biomarkers will be addressed. The role of surgical management options, such as cytoreductive nephrectomy and metastectomy, in the era of targeted treatment is also reviewed. Several novel treatments are also on the horizon, which might serve as future avenues for treatment advancement in metastatic renal cell cancer.

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.

s: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA Background: SB939 is a potent oral inhibitor of class I, II and IV histone deacetylases (HDACs) with high tumor tissue selectivity. These 3 classes of HDAC are highly expressed in prostate cancer and associated with poor clinical outcomes. HDAC inhibition has been shown to abrogate androgen receptor signaling via inactivation of HSP90, and may have relevance particularly in TMPRSS2-ERG fusion positive prostate cancer. Methods: In this multicenter phase II study, pts with CRPC received SB939 60mg every other day 3 times per week × 3 weeks on a 28-day cycle. Primary endpoints were PSA response rate (RR) (>50% decline from baseline for > 4 weeks) and progression free survival (PFS). Secondary endpoints included objective response rate; response duration, overall survival; circulating tumor cell (CTC) enumeration at baseline, 6 and 12 weeks; TMPRSS2-ERG fusion analysis; correlative analysis of archival tissue; and safety. Planned sample size was 29 pts, the hypotheses (PSA RR <2% vs. ≥15%) could be tested at 10% and levels. Results: Twenty-nine pts have been accrued. Median age is 69, 25 pts had received no prior chemotherapy, ECOG performance status was 0/1 in 48%/52% of pts. Bone/lymph node/visceral metastases were present in 86%/69%/10% of pts. The median number of cycles of SB939 administered is 2 (range 1–6) with 7 pts still continuing treatment. Adverse events were generally grade 1–2, with 5 patients experiencing grade 3 events (fatigue (5 pts), vomiting (1 pt) and dyspnea (1pt)). To date, a confirmed PSA response has been noted in 2 pts (7%). In 8 RECIST-evaluable pts, there were no objective responses, and 3 pts had stable disease lasting from 3.4 to 5.6 months. CTC favorable conversion (from ≥5 at baseline to 5) at 6 weeks correlated with PSA progression. RT-PCR for presence of TMPRSS2-ERG transcripts from whole blood and FISH analyzes of CTC and archival tissue for TMPRSS2-ERG fusion and PTEN deletion status are ongoing. Conclusion: SB939 is well tolerated and has shown early evidence of activity in CRPC. Analysis of more mature data will be required to determine whether this agent warrants further study, and whether TMPRSS2-ERG status might predict for response to SB939. Supported by grants from the Canadian Cancer Society and the Ontario Institute for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A221.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) signaling cascades may play an important role in this peripheral tolerance and their inhibition may be a possible mechanism for the treatment of metastatic renal cell carcinoma.