Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial.

BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.

Efficacy of avelumab plus axitinib versus sunitinib by numbers of IMDC risk factors and target tumor sites at baseline in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline. METHODS: Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed. RESULTS: In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage. CONCLUSIONS: In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites.

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma.

BACKGROUND: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed. RESULTS: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization. CONCLUSIONS: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing. TRIAL REGISTRATION: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006.

Efficacy and safety of avelumab plus axitinib in elderly patients with advanced renal cell carcinoma: extended follow-up results from JAVELIN Renal 101.

BACKGROUND: In the phase III JAVELIN Renal 101 trial, first-line avelumab plus axitinib demonstrated a progression-free survival (PFS) and objective response rate (ORR) benefit versus sunitinib in patients with advanced renal cell carcinoma (aRCC). However, efficacy in elderly patients remains unclear. We report efficacy and safety by age group from the second interim analysis of overall survival (OS). PATIENTS AND METHODS: PFS and ORR as per blinded independent central review (RECIST 1.1), OS, and safety were assessed in patient groups aged <65, ≥65 to <75, and ≥75 years. RESULTS: In the avelumab plus axitinib and sunitinib arms, 271/138/33 and 275/128/41 patients aged <65, ≥65 to <75, and ≥75 years, respectively, were randomized. At data cut-off (January 2019), median PFS [95% confidence interval (CI)] with avelumab plus axitinib versus sunitinib in these respective age groups was 11.6 (8.4-19.4) versus 6.9 (5.6-8.4) months [hazard ratio (HR), 0.63; 95% CI 0.501-0.786], 13.8 (11.1-18.0) versus 11.0 (7.8-16.6) months (HR, 0.88; 95% CI 0.627-1.231), and 13.8 [7.0-not estimable (NE)] versus 9.8 (4.3-NE) months (HR, 0.76; 95% CI 0.378-1.511). Median OS (95% CI) in the respective age groups was not reached (NR) (NE-NE) versus 28.6 (25.5-NE) months (HR, 0.74; 95% CI 0.541-1.022), 30.0 (30.0-NE) versus NR (NE-NE) months (HR, 0.89; 95% CI 0.546-1.467), and 25.3 (19.9-NE) versus NR (19.4-NE) months (HR, 0.87; 95% CI 0.359-2.106). ORR (95% CI) in the respective age groups was 49.4% (43.3% to 55.6%) versus 27.3% (22.1% to 32.9%), 60.9% (52.2% to 69.1%) versus 28.9% (21.2% to 37.6%), and 42.4% (25.5% to 60.8%) versus 22.0% (10.6% to 37.6%). In the avelumab plus axitinib arm, grade ≥3 adverse events (AEs) and immune-related AEs occurred in 76.9%/81.2%/72.7% and 45.5%/48.1%/36.4% in the respective age groups. CONCLUSIONS: First-line avelumab plus axitinib demonstrated favorable efficacy across age groups, including patients aged ≥75 years. OS data were still immature; follow-up is ongoing. The safety profile was generally consistent across age groups.

Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial.

BACKGROUND: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. METHODS: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. RESULTS: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. CONCLUSIONS: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) 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 PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. PATIENTS AND METHODS: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used. RESULTS: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. CONCLUSIONS: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors.

Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint inhibitors), are used to treat various malignancies. Their mechanism of action involves the inhibition of negative regulators of immune activation, resulting in immune-related adverse events (irAEs) including endocrinopathies, pneumonitis, colitis, hepatitis and dermatological events. Dermatological irAEs include maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia secondary to immune checkpoint inhibitors has been reported in 1·0-2·0% of treated patients. Our objective is to characterize for the first time the clinicopathology of patients with alopecia areata (AA) secondary to immune checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced AA, and review of the literature. Four cases of patients who developed partial or complete alopecia during treatment with immune checkpoint inhibitors for underlying cancer were identified from our clinics. Methods include the review of the history and clinicopathologic features. Three patients (75%) had AA and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy. This report describes a series of four patients who developed partial or complete alopecia (i.e. areata and universalis) during treatment with immune checkpoint inhibitor therapies for cancer. The recognition and management of hair-related irAEs are important for pretherapy counselling and interventions that contribute to maintaining optimal health-related quality of life in patients.

Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma.

Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.

Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.

Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.

BACKGROUND: Dermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known. METHODS: We conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented. RESULTS: Rash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab. CONCLUSION: We found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.

Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. PATIENTS AND METHODS: Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. RESULTS: The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. CONCLUSIONS: Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.

Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).

BACKGROUND: RECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting. METHODS: Patients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis. RESULTS: Enrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7-11.0]; in the cohorts, it was 5.7 months (95% CI 3.7-11.3) with previous sunitinib, 7.8 months (95% CI 5.7-11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6-not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0-NE) and, in the cohorts, it was 23.8 months (95% CI 13.7-NE) with previous sunitinib, 17.2 months (95% CI 11.9-NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9-NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug). CONCLUSIONS: These results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience. CLINICAL TRIAL NAME AND IDENTIFIER: Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.

IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.

BACKGROUND: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC). METHODS: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3). RESULTS: In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients. CONCLUSIONS: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.