Search

Background: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. Methods: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. Results: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). Conclusion: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids. [ABSTRACT FROM AUTHOR]

Background: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan. Methods: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints. Results: The Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred. Conclusions: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population. [ABSTRACT FROM AUTHOR]

Background: Sequential treatment starting with target therapy is still the standard care for metastatic renal cell carcinoma (mRCC), even in the era of immune checkpoint inhibitors. Our objective was to compare the clinical outcomes between axitinib and nivolumab as second-line therapy following prior targeted therapy in mRCC patients. Methods: We identified 41 patients treated with axitinib and 39 patients treated with nivolumab as a second-line regimen after targeted therapy, and retrospectively compared the treatment efficacy and safety in these patients. Results: The clinical benefit rate of axitinib was significantly higher than that of nivolumab (82.9% versus 56.4%; p = 0.014) and patients who received axitinib tended to show longer progression-free survival (PFS) than those who received nivolumab (10.3 months versus 7.3 months; p = 0.067). There was no difference in the overall survival (OS) of the two groups (both not reached; p = 0.581). The incidence of grade ≥ 3 adverse events (AEs) was similar between the two groups, but one patient in the nivolumab group died due to an immune-related AE. In addition, a Cox proportional hazards model showed that the pre-treatment KPS, the baseline neutrophil-to-lymphocyte ratio (NLR), and an objective response in second-line therapy were significantly associated with PFS, while the pre-treatment KPS, the number of metastatic organs, and an objective response in second-line therapy significantly contributed to the predicted OS. Conclusions: Although the prognosis did not differ markedly between the two groups, axitinib resulted in a better tumor response rate. Further randomized prospective studies are needed for the ideal order of this sequential treatment. [ABSTRACT FROM AUTHOR]

Background Clinical benefits of presurgical axitinib therapy for renal cell carcinoma (RCC) extending into the inferior vena cava (IVC) remain unclear. We aimed to investigate surgical benefits and pathological antitumor effects of presurgical axitinib therapy for RCC with IVC thrombus. Methods Of 56 consecutive RCC patients with IVC thrombus between January 1994 and December 2016, 41 patients who underwent radical nephrectomy (RN) were categorized as upfront RN (Upfront group) or presurgical axitinib followed by RN (Presurgical group). We retrospectively evaluated safety, radiologic tumor responses, and Ki-67 proliferation index before and after axitinib administration in the Presurgical group. Surgical outcomes, postoperative complications, and fibrosis within the IVC thrombus were compared between the Upfront and Presurgical groups. Results The number of patients in the Upfront and Presurgical groups was 31 and 10, respectively. Major presurgical axitinib-related adverse events were grade 2 or 3 hypertension (50%). The median radiological tumor response in the renal tumor, IVC thrombus length, and IVC thrombus volume were -19%, -21 mm, and -54%, respectively. The fibrosis within the IVC thrombus was significantly higher in the Presurgical group (10%) than in the Upfront group (3.4%). The Ki-67 proliferation index was significantly decreased in RN specimens (7.3%) versus needle biopsy specimens (23%) in the Presurgical group. Blood loss and operative duration were significantly lower and shorter, respectively, in the Presurgical group than in the Upfront group. Conclusions Presurgical axitinib therapy enhanced tumor reduction accompanied by fibrosis and may contribute to surgical risk reduction for selected patients. [ABSTRACT FROM AUTHOR]

Background: No report has evaluated axitinib-induced proteinuria as a biomarker for predicting treatment efficacy and survival of patients with metastatic renal cell carcinoma (mRCC). Methods: The subjects were patients with mRCC treated with axitinib at Kinki University Hospital from February 2008 to November 2014. Clinical records were retrospectively reviewed including baseline patient characteristics, time-dependent changes of urinary protein status, computed tomography scans of metastatic lesions, treatment duration with axitinib, and survival time. Results: A total of 45 patients were evaluable. Median tumor shrinkage rates were 32.3 and 35.0 % in patients with urinary protein increases ≥+2 and <+2, respectively ( p = 0.496). Objective response rates were also similar between the two groups. Median progression-free survival (PFS) times with axitinib were 13.5 months [95 % confidence interval (CI) 0.0-27.5] and 11.0 months (95 % CI 0.0-26.7) in patients with urinary protein increases ≥+2 and <+2, respectively ( p = 0.975). The maximum tumor shrinkage rate with axitinib was significantly associated with PFS with axitinib as a result of multivariate analysis ( p = 0.002). Median overall survival (OS) times were 39.8 months (95 % CI 12.7-67.0) and 25.4 months (95 % CI 11.2-39.6) in patients with axitinib-induced urinary protein increases ≥+2 and <+2, respectively ( p = 0.250). The number of metastatic sites ( p = 0.006), the MSKCC risk ( p = 0.009), and the maximum tumor shrinkage rate with axitinib ( p = 0.019) were significantly associated with OS as a result of multivariate analysis. Conclusions: The degree of urinary protein increase during axitinib treatment was not associated with objective response, PFS, and OS in mRCC patients treated with axitinib. [ABSTRACT FROM AUTHOR]

Background: To investigate the impact of proteinuria on the renal function of patients with metastatic renal cell carcinoma (mRCC) who received axitinib, a tyrosine kinase inhibitor specifically targeting vascular endothelial growth factor receptors. Methods: This study included 65 consecutive Japanese patients who were diagnosed with mRCC and were subsequently treated with axitinib for at least 12 weeks. The association between the changes in the estimated glomerular filtration rate (eGFR) and proteinuria in these 65 patients was retrospectively assessed. Results: Of the 65 patients, 41 (63.1 %) were judged to be positive for proteinuria. There were no significant differences between the eGFR value before the introduction of axitinib and that at the last clinic visit in either group with or without proteinuria. Furthermore, no significant correlation was noted between the changes in eGFR and the urine protein to creatinine ratio in the group positive for proteinuria, and there was no significant effect of the duration of treatment with axitinib on the changes in eGFR in the proteinuria group. Of several factors examined, univariate analysis identified age, eGFR prior to the introduction of axitinib, and timing of axitinib introduction, but not the presence of proteinuria, as predictors of a decrease in eGFR of >10 %; however, only age appeared to be independently associated with a decrease in eGFR of >10 %. Conclusions: These findings suggest that treatment with axitinib may not have a significant adverse impact on the renal function in patients with mRCC, irrespective of the presence of proteinuria. [ABSTRACT FROM AUTHOR]

The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.