Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic ...features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk‐predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed.
Patients with high‐risk renal cell carcinoma are at increased risk of disease recurrence. There is an unmet need for effective adjuvant therapies in this setting to improve overall survival.
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.
Purpose of Review
In this review, the importance of the hypoxia inducible factor (HIF) pathway in tumorigenesis and cancer treatment outcomes will be discussed. The outcomes of phase II and III ...clinical trials of direct HIF inhibitors in the treatment of cancer will be reviewed.
Recent Findings
The HIF signaling pathway is activated by tumor-induced hypoxia or by inactivating mutations of the VHL gene. HIF is a transcription factor which regulates the expression of genes involved in adjusting mechanisms to hypoxia such as angiogenesis or apoptosis as well as tumor growth, invasion, and metastasis. The HIF pathway has a key role in development of resistance to different treatment modalities and higher expression of the HIF molecule is associated with poor prognosis.
Summary
Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies of the HIF inhibitors either as a single agent or in combination with other therapeutic agents.
Summary Therapeutic targeting of integral biological pathways, including those involving vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), has produced robust ...clinical effects and revolutionised the treatment of metastatic renal-cell carcinoma (RCC). However, some patients are inherently resistant to these approaches and most, if not all, patients acquire resistance over time. As such, the biological basis for resistance to these targeted therapies and the clinical approach in this setting is of heightened interest. Emerging preclinical evidence suggests resistance is mediated via tumour and environmental changes, which allow for continued perfusion and tumour growth that is less reliant on VEGF. Furthermore, elements upstream of receptor blockade, such as hypoxia-inducible factor (HIF) and protein kinase B (AKT), in addition to pathways independent of VEGF or mTOR, could drive tumour growth despite adequate target blockade. These considerations provide a rational basis for combination or sequential therapy targeting these elements. Clinical data support activity of several agents in resistant patient populations, with large-scale clinical trials ongoing to more thoroughly test several postulations regarding the optimum clinical approach.
Clear cell renal carcinoma (ccRCC) is a heterogeneous disease with a variable post-surgical course. To assemble a comprehensive ccRCC tumor microenvironment (TME) atlas, we performed single-cell RNA ...sequencing (scRNA-seq) of hematopoietic and non-hematopoietic subpopulations from tumor and tumor-adjacent tissue of treatment-naive ccRCC resections. We leveraged the VIPER algorithm to quantitate single-cell protein activity and validated this approach by comparison to flow cytometry. The analysis identified key TME subpopulations, as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant populations, undetectable by gene-expression analysis. Specifically, we uncovered a tumor-specific macrophage subpopulation characterized by upregulation of TREM2/APOE/C1Q, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, these markers were significantly enriched in tumors from patients who recurred following surgery. The study thus identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential prognostic biomarker for ccRCC recurrence, as well as a candidate therapeutic target.
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•We present a robust pipeline for scRNA-seq analysis by protein activity inference•Our pipeline identifies a C1Q+TREM2+APOE+ macrophage population enriched in ccRCC•Protein activity signature of these cells is prognostic of post-surgical recurrence•C1Q+ Macrophage association with recurrence is validated by immunohistochemistry
Analysis of the tumor microenvironment using tumor and tumor-adjacent tissue of treatment-naive clear cell renal carcinoma resections from patients by combining single-cell sequencing and single-cell protein activity uncovers a tumor-specific infiltrating macrophage subpopulation associated with disease recurrence.
The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The ...exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.
In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.
Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2–34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months 95% CI 33·3–not reached with sunitinib); hazard ratio HR 0·68 95% CI 0·55–0·85, p=0·0003) and progression-free survival (median 15·4 months 12·7–18·9 vs 11·1 months 9·1–12·5; 0·71 0·60–0·84, p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 22% of 429 patients in the pembrolizumab plus axitinib group vs 84 20% of 425 patients in the sunitinib group), alanine aminotransferase increase (54 13% vs 11 3%), and diarrhoea (46 11% vs 23 5%). No new treatment-related deaths were reported since the first interim analysis.
With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.
Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced ...renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib.
In the phase 3, randomised, controlled, CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment.
Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25·2 months (IQR 23·0–27·4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4·00 (95% CI 1·91 to 6·09) for nivolumab plus ipilimumab versus −3·14 (−6·03 to −0·25) for sunitinib (p<0·0001), and for FACT-G total score being 4·77 (1·73 to 7·82) for nivolumab plus ipilimumab versus −4·32 (−8·54 to −0·11) for sunitinib (p=0·0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10·07 (95% CI 4·35 to 15·80) for nivolumab plus ipilimumab and 6·40 (−1·36 to 14·16) for sunitinib (p=0·45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio HR 0·54; 95% CI 0·46–0·63), FACT-G total score (0·63, 0·52–0·75), and EQ-5D-3L VAS score (HR 0·75, 95% CI 0·63–0·89) and UK utility scores (0·67, 0·57–0·80).
Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.
Bristol-Myers Squibb and ONO Pharmaceutical.
...the control cabozantinib monotherapy group had a higher objective response rate and longer progression-free survival than previous trials.12 CONTACT-03 does not address whether immunotherapy ...rechallenge after a delayed period since previous immunotherapy (eg, after adjuvant PD-1 inhibitor therapy or in later lines of therapy) is of benefit and this will require additional investigation. ...testing novel immunotherapy in a refractory setting might be suboptimal. There are no wider data from other cancers to support sequenced immunotherapy. ...this rechallenge approach, which was being increasingly adopted in clinical practice, should be avoided until and unless positive data are available.
In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell ...carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.
In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.
Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months IQR 13·4–36·3), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached 95% CI 35·6–not estimable vs 26·6 months 22·1–33·4; hazard ratio HR 0·66 95% CI 0·54–0·80, p<0·0001), progression-free survival (median 8·2 months 95% CI 6·9–10·0 vs 8·3 months 7·0–8·8; HR 0·77 95% CI 0·65–0·90, p=0·0014), and the proportion of patients achieving an objective response (178 42% of 425 vs 124 29% of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached 95% CI not estimable vs 37·9 months 32·2–not estimable; HR 0·71 95% CI 0·59–0·86, p=0·0003), progression-free survival (median 9·7 months 95% CI 8·1–11·1 vs 9·7 months 8·3–11·1; HR 0·85 95% CI 0·73–0·98, p=0·027), and the proportion of patients achieving an objective response (227 41% of 550 vs 186 34% of 546 p=0·015). In all treated patients, the most common grade 3–4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 10% of 547), increased amylase (31 6%), and increased alanine aminotransferase (28 5%), whereas in the sunitinib group they were hypertension (90 17% of 535), fatigue (51 10%), and palmar-plantar erythrodysaesthesia (49 9%). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.
The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.
Bristol-Myers Squibb and ONO Pharmaceutical.
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