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.

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.

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.

Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial.

BACKGROUND: In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines. METHODS: In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ⩾median), and tumour burden (baseline sum of the longest diameter < vs ⩾median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated. RESULTS: Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy. CONCLUSIONS: AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC.

Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma.

BACKGROUND: We retrospectively analyzed sunitinib outcome as a function of age in metastatic renal cell carcinoma (mRCC) patients. METHODS: Data were pooled from 1059 patients in six trials. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were compared by log-rank test between patients aged <70 (n=857; 81%) and ≥70 (n=202; 19%) years. RESULTS: In first-line patients, median PFS was comparable in younger and older patients, 9.9 vs 11.0 months, respectively (HR, 0.89; 95% CI: 0.73-1.09; P=0.2629), as was median OS, 23.6 vs 25.6 months (HR, 0.93; 95% CI: 0.74-1.18; P=0.5442). Similarly, in cytokine-refractory patients, median PFS was 8.1 vs 8.4 months (HR, 0.79; 95% CI: 0.49-1.28; P=0.3350), while median OS was 20.2 vs 15.8 months (HR, 1.14; 95% CI: 0.73-1.79; P=0.5657). Some treatment-emergent adverse events were significantly less common in younger vs older patients, including fatigue (60% vs 69%), cough (20% vs 29%), peripheral edema (17% vs 27%), anemia (18% vs 25%), decreased appetite (13% vs 29%), and thrombocytopenia (16% vs 25%; all P<0.05). Hand-foot syndrome was more common in younger patients (32% vs 24%). CONCLUSIONS: Advanced age should not be a deterrent to sunitinib therapy and elderly patients may achieve additional clinical benefit.

Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies.

BACKGROUND: The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. PATIENTS AND METHODS: Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS: Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. CONCLUSIONS: A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.

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.

Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma.

BACKGROUND: Prognostic factors for progression-free survival (PFS), overall survival (OS), and long-term OS (≥30 months) were investigated in sunitinib-treated patients with metastatic renal cell carcinoma (RCC). METHODS: Data were pooled from 1059 patients in six trials. Baseline variables, including ethnicity, were analysed for prognostic significance by Cox proportional-hazards model. RESULTS: Median PFS and OS were 9.7 and 23.4 months, respectively. Multivariate analysis of PFS and OS identified independent predictors, including ethnic origin, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, prior cytokine use, haemoglobin, lactate dehydrogenase, corrected calcium, neutrophils, platelets, and bone metastases (OS only). Characteristics of long-term survivors (n=215, 20%) differed from those of non-long-term survivors; independent predictors of long-term OS included ethnic origin, bone metastases, and corrected calcium. There were no differences in PFS (10.5 vs 7.2 months; P=0.1006) or OS (23.8 vs 21.4 months; P=0.2135) in white vs Asian patients; however, there were significant differences in PFS (10.5 vs 5.7 months; P<0.001) and OS (23.8 vs 17.4 months; P=0.0319) in white vs non-white, non-Asian patients. CONCLUSION: These analyses identified risk factors to survival with sunitinib, including potential ethnic-based differences, and validated risk factors previously reported in advanced RCC.

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 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.

Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma.

BACKGROUND: In a randomized phase III trial of sunitinib vs interferon-alfa (IFN-α) in metastatic renal cell carcinoma (mRCC), better baseline quality of life (QoL) was predictive of longer survival. Using this dataset, we have developed a novel prognostic tool that establishes a relationship between baseline QoL scores and median survival time. METHODS: Baseline QoL was assessed using the FACT-Kidney Symptom Index-15 item (FKSI-15), its disease-related symptoms (FKSI-DRS) subscale, and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. Weibull models estimated median progression-free survival (mPFS) and overall survival (mOS) as a function of baseline QoL. RESULTS: Longer PFS and OS were associated with higher baseline FKSI-15, FKSI-DRS, and FACT-G scores (P<0.05), and baseline FKSI-15 score was the best predictor of survival. For example, for a baseline FKSI-15 score of 60, the predicted mPFS was 67.9 weeks, and predicted mOS was 240.6 weeks. The magnitude of benefit was greater with sunitinib vs IFN-α for a given baseline QoL score. CONCLUSION: This novel tool indicates that baseline FKSI-15 scores were linked to mPFS and mOS in a clear and interpretable way. The results support evaluation of patient-reported QoL symptoms at baseline as a prognostic indicator of survival in clinical research and practice.

Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-α.

BACKGROUND: In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis. METHODS: In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes. RESULTS: Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α. CONCLUSION: Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.

Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma.

The administration of mammalian target of rapamycin (mTOR) inhibitors can give rise to a potentially life-threatening adverse event, often referred to as 'non-infectious pneumonitis' (NIP), which is characterized by non-infectious, non-malignant, and non-specific inflammatory infiltrates. Patients usually present with cough and/or dyspnoea. We provide a brief description of the mechanism of action of mTOR inhibitors and their overall safety in patients with metastatic renal cell carcinoma (mRCC) and review the literature on mTOR inhibitor-associated NIP in patients with solid tumours. The review was used to derive questions on the diagnosis, management, and monitoring of mRCC patients with NIP, and to develop a decision tree for use in routine clinical practise. A key recommendation was the subdivision of grade 2 NIP into grades 2a and 2b, where grade 2a is closer to grade 1 and grade 2b to grade 3. This subdivision is important because it takes into account the nature and severity of clinical symptoms potentially related to NIP, either the onset of new symptoms or the worsening of existing symptoms, and thus determines the type and frequency of follow-up. It also helps to identify a subgroup of patients in whom treatment, if effective, may be continued without dose adjustment.

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.

Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: Analysis of prognostic factors for progression-free survival (PFS) and overall survival (OS) was performed using final data from a randomized phase III trial of sunitinib versus interferon-α (IFN-α) as first-line metastatic renal cell carcinoma (RCC) therapy. DESIGN: A multivariate Cox regression model analyzed baseline variables for prognostic significance. Each variable was investigated univariately and then multivariately using a stepwise algorithm. RESULTS: Each treatment arm comprised 375 patients. For sunitinib, multivariate analysis of PFS identified five independent predictors, including serum lactate dehydrogenase (LDH) level, presence of ≥2 metastatic sites, no prior nephrectomy, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline platelet count, while multivariate analysis of OS identified serum LDH level, corrected serum calcium level, time from diagnosis to treatment, hemoglobin level, ECOG performance status, and presence of bone metastasis as predictors. For IFN-α, LDH level and presence of ≥2 metastatic sites were common predictors of PFS to those for sunitinib, as were all predictors of OS except ECOG status. CONCLUSIONS: This analysis identified prognostic factors for PFS and OS with sunitinib as first-line metastatic RCC therapy and confirmed that the Memorial Sloan-Kettering Cancer Center model is applicable in the era of targeted therapy.