Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the ...treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.
Patients with cancer have been disproportionately affected by the COVID-19 pandemic. This effect has included the adverse outcomes in patients with cancer who develop COVID-19, the impact of the ...COVID-19 pandemic on the delivery of cancer care, and the severe disruption to cancer research. However, patients with cancer are a heterogeneous population, and recent studies have now documented factors that allow risk stratification of patients with cancer in order to optimize care. In this review, we highlight data at the intersection of COVID-19 and cancer, including the biological interplay between the two diseases and practical recommendations for the treatment of patients with cancer during the pandemic. We additionally discuss the potential long-lasting impact of the pandemic on cancer care due to its deleterious effect on cancer research, as well as biological insights from the cancer research community that could help develop novel therapies for all patients with COVID-19.
Patients with cancer have been disproportionately affected by the COVID-19 pandemic. This effect has included the adverse outcomes in patients with cancer who develop COVID-19, the impact of the COVID-19 pandemic on the delivery of cancer care, and the severe disruption to cancer research. However, patients with cancer are a heterogeneous population, and recent studies have now documented factors that allow risk stratification of patients with cancer in order to optimize care. In this review, we highlight data at the intersection of COVID-19 and cancer, including the biological interplay between the two diseases and practical recommendations for the treatment of patients with cancer during the pandemic. We additionally discuss the potential long-lasting impact of the pandemic on cancer care due to its deleterious effect on cancer research, as well as biological insights from the cancer research community that could help develop novel therapies for all patients with COVID-19.
In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients ...with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.
We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.
A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval CI, 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.
Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck Darmstadt, Germany; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).
PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed ...592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8
T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8
T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.
Systemic therapy for metastatic clear cell renal cell carcinoma (mccRCC) has greatly evolved over the last 15yr. More recently, combination strategies involving contemporary immunotherapy have ...emerged as key opportunities to further shift the treatment landscape.
To review the evidence regarding the efficacy and safety of standard therapeutic options in mccRCC as well as combination immunotherapy options on the horizon.
PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to February 2018 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed.
Twenty-six studies were included regarding therapies for metastatic RCC including vascular endothelial growth factor (VEGF)-directed therapy (n=9), mTOR inhibitors (n=2), cytokines (n=3), vaccines (n=3), and immune checkpoint inhibitors (ICIs, n=9). VEGF tyrosine kinase inhibitor monotherapy had been the standard therapy, and its use is evolving in the front-line setting with ICIs; cabozantinib provides superior progression-free survival versus sunitinib in intermediate- and poor-risk patients, by International Metastatic RCC Database Consortium criteria. The mTOR therapy is largely inferior to VEGF-directed therapy, although it has a role in combination strategies. Cytokines have largely been replaced in current practice throughout most regions, and vaccines have failed to show improved survival in phase III studies to date. ICIs have now become standard care in untreated patients with intermediate and poor risks, given overall survival benefit seen with CheckMate-214 study; survival data from IMmotion 151 are not yet mature. Several ongoing phase III combination trials, with promising early-phase data, are due to be read out.
The treatment landscape for mccRCC has evolved since the introduction of VEGF inhibitors. Combination therapies involving checkpoint inhibitors could be the next standard of care.
With the expanding role of immune checkpoint inhibitors in metastatic renal cell carcinoma, the treatment paradigm has shifted to include combination therapy in the untreated setting. As the field advances, the bar has been raised in evaluating ongoing combination strategies.
With the expanding role of immune checkpoint inhibitors in metastatic renal cell carcinoma, the treatment paradigm has shifted to include combination therapy in the untreated setting. As the field advances, the bar has been raised in evaluating ongoing combination strategies.
Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen ...accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.
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