Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to
gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor ...2α (HIF-2α).
In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.
After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients 77%) and central nervous system hemangioblastomas (15 of 50 patients 30%). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl).
Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a ...combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.
In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg two 300-mg tablets twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.
The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).
In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).
There has been substantial evolution in the treatment of metastatic renal cell carcinoma with notable changes in the first-line setting. Currently, doublet combination therapy with either two immune ...checkpoint inhibitors or a combination of an immune checkpoint and tyrosine kinase inhibitor is considered the standard of care. The doublet combination therapies have demonstrated significantly improved clinical outcomes. A recently conducted trial (COSMIC-313) showed superior efficacy with a triplet combination of cabozantinib, nivolumab, and ipilimumab when compared to a placebo, nivolumab, and ipilimumab but at the cost of additional toxicity. Many other combination treatments, such as pembrolizumab plus lenvatinib plus belzutifan (NCT04976634), are being investigated, possibly leading to more options in the first-line setting in the future.
Purpose of Review
Historically, kidney cancer was diagnosed as either clear cell renal carcinoma (ccRCC) or non-clear cell renal carcinoma (nccRCC). With further research into the pathophysiology of ...nccRCC, multiple distinct subtypes have emerged creating distinct diagnosis, such as papillary renal cell carcinoma (PRCC), chromophobe renal cell carcinoma (crRCC), or unclassified carcinoma (cRCC). Many other kidney cancer subtypes are now included in the WHO classification system.
Recent Findings
The prognosis for each of the more frequently diagnosed types is discussed here along with treatment recommendations. The available clinical trial results and salient retrospective studies of each subtype are reviewed here to guide clinicians on the optimal treatment selection for patients with these rare histologic types or RCC.
Summary
Many nccRCC types are now recognized and each has unique molecular drivers which are different than ccRCC. The optimal treatment strategy is different for each subtype. The prognosis also differs based on the histology.
Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and ...enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.
Opinion statement
PRCC is a unique histologic entity compared to other forms of renal cell carcinoma, harboring distinct molecular drivers. The WHO 2022 classification is further emphasizing the ...molecular biology by making molecular classifications of PRCC subclassifications and discontinuing the morphologic type 1 and type 2 classification system. We agree with this functional classification system and encourage all future clinical trials to only include patients with similar diagnosis instead of conducting basket trials (including all nccRCC together) which limits the scientific value of those conclusions. Based on recent disease-specific clinical trial (S1500, PAPMET), the current standard of care for patients with treatment naïve PRCC is cabozantinib. Prospective clinical trials clearly establish that immune checkpoint inhibitor therapy has meaningful activity in PRCC. The data to date include only single-arm clinical trials of combination immune therapy. Despite the positive and encouraging results, we need validation through randomized studies because of the overestimation of effect size seen in single-arm trials. These randomized trials are currently underway and enrolling. We strongly encourage all physicians to support these studies and enroll patients with PRCC to these trials in order to continue improving the standard of care.
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