Months For Sunitinib Research Articles

Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214

BackgroundImmunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of...

Overall survival and long-term safety in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Updated analyses from INTRIGUE.

11524 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the first interim analysis (IA) for overall survival (OS) in the INTRIGUE trial, data were immature (OS event rate, 22.3%), and median OS was not reached in either arm for the KIT exon 11 intent-to-treat (ITT) and all-patient (AP) ITT populations (S Bauer, et al. J Clin Oncol. 2022). Additionally, ripretinib had a more favorable safety profile with fewer grade 3/4 treatment-emergent adverse events (TEAEs) than sunitinib. Here, we present the second IA of OS and updated safety from INTRIGUE. Methods: INTRIGUE is a global, open-label, phase 3 study that enrolled adult pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint; data cutoff for the second IA was Sept 1, 2022. Results: Of 453 pts in the AP ITT population, 444 received treatment; 51 remain on treatment (33/223 [14.8%] with ripretinib and 18/221 [8.1%] with sunitinib). Common reasons for treatment discontinuation were progressive disease (PD) assessed by independent radiologic review (55.4%), PD assessed by investigator (10.6%), clinical PD (5.9%), withdrawal of consent (5.4%), and adverse event (AE; 4.5%); fewer pts discontinued due to an AE for ripretinib vs sunitinib (2.7% vs 6.3%). Following study treatment discontinuation, 58 pts (25.6%) from the sunitinib arm received ripretinib; 139 pts (61.5%) from the ripretinib arm later received sunitinib. There were 185 OS events (40.8%) in the AP ITT population; median duration of follow-up was 28.7 and 28.5 months for ripretinib and sunitinib, respectively. OS was similar with ripretinib vs sunitinib in the AP ITT (median 35.5 vs 30.9 months; HR 0.88, 95% CI 0.66 to 1.18; nominal P = 0.39) and KIT exon 11 ITT populations (median 34.0 vs 31.5 months; HR 1.05, 95% CI 0.75 to 1.48; nominal P = 0.77). The updated safety profile was consistent with the primary analysis; fewer pts had grade 3/4 TEAEs with ripretinib vs sunitinib (95 [42.6%] vs 149 [67.4%]). Dose interruptions and reductions were lower with ripretinib vs sunitinib. The median (range) treatment duration was 7.9 (0.2–38.2) months for ripretinib and 6.5 (0.2–38.3) months for sunitinib. Conclusions: In the second IA from INTRIGUE, OS was similar between treatment arms. The safety profile remained consistent with additional data, and results demonstrate favorable safety with ripretinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 .

Outcomes and safety of subsequent treatments after immune- and anti-VEGF therapy in patients with metastatic clear-cell renal cell carcinoma: Outcomes from a tertiary referral hospital.

e16533 Background: Immune checkpoint inhibitors (ICIs) and anti-VEGFs, either in combination or sequentially, are the standard of care in first- and second-line (2L) setting for metastatic clear-cell renal cell carcinoma (mRCC); however, there is uncertainty about the subsequent lines. We describe real-world outcomes and safety of using anti-VEGFs such as cabozantinib (CABO), axitinib (AXI), and sunitinib (SUN) after ICIs and anti-VEGF therapies in patients (pts) with mRCC. Methods: A retrospective audit was performed on pts with mRCC treated between June 2014 and June 2022 at the St Bartholomew’s Hospital, London, UK. Baseline patient and treatment characteristics, best response, dose modifications and survival outcomes were collected. Kaplan-Meier methods were used to evaluate the progression-free survival (PFS) and overall survival (OS). Results: Overall, 188 pts with mRCC were treated. We analysed 69 pts of whom 45 (65%), 16 (23%) and 8 (12%) pts received CABO, AXI, and SUN, respectively, as subsequent treatment after prior ICIs and anti-VEG. Baseline characteristics are described. Median follow-up was 36 months (95% CI: 31.6 - 55.3). Overall, the partial response (PR) and stable disease (SD) rates were 9% and 45%, respectively. Eleven percent, 12% and 0% pts achieved PR and 53%, 25% and 31% achieved SD on CABO, SUN and AXI, respectively. In general, the median PFS was 9.9 months (95% CI: 6.5-14.2) and the median OS was 16.5 months (95% CI: 11.6-23.5). One-year PFS and 1-year OS was 36% and 51%, respectively. PFS and OS by treatment are reported. The number of pts who experienced toxicities that required dose reductions was higher with CABO (58%) and SUN (37%) than with AXI (6%). The median time to dose reduction was 2.4, 1.4, and 1.4 months for CABO, SUN and AXI. Conclusions: In our centre, CABO was the most common subsequent treatment after previous ICIs and anti-VEGF. Taking into account the retrospective and single-centre nature of the collected data these results support the activity of CABO, AXI and SUN in this setting. AXI was well tolerated with less dose modifications. [Table: see text]

Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma.

A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.

Efficacy and safety of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2 multicenter, randomized, open-label study in China.

803 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for the fourth-line therapy for GIST. In the INTRIGUE study (NCT03673501), ripretinib as second-line (2L) treatment demonstrated similar progression-free survival (PFS) and fewer Grade 3/4 treatment-emergent adverse events (TEAEs) compared to sunitinib in the overall population. It showed a numerically longer PFS and a nominally higher objective response rate (ORR) than sunitinib in patients (pts) with KIT exon 11 mutations. This study aims to evaluate the efficacy and safety of ripretinib vs sunitinib as 2L treatment in GIST pts in China. Methods: This multicenter, randomized, open-label phase 2 study (NCT04633122) enrolled adults with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 42-day cycles. Randomization was stratified by KIT mutational status. The primary endpoint was PFS by independent radiologic review (IRR) using modified RECIST version 1.1. Secondary endpoints included ORR by IRR, overall survival (OS) and safety. Efficacy analysis was performed in all-patients intent-to-treat (AP ITT) and KIT exon 11 mutation intent-to-treat (Ex11 ITT) populations. This study was designed to bridge the global trial (INTRIGUE) to show consistency in the efficacy of ripretinib between the two studies. No statistical testing was pre-specified and nominal p-values were presented for descriptive purpose. Results: Overall, 108 pts were randomized to ripretinib (AP ITT n= 54; Ex11 ITT n=35) or sunitinib (AP ITT n= 54; Ex11 ITT n=35). Median age was 59.0 years (range 25–82); 63.9% of pts were male and 57.4% had ECOG PS≥1. By primary data cut-off (20 Jul 2022), PFS by IRR was similar between ripretinib and sunitinib in AP ITT population (HR 0.99, 95% CI 0.57, 1.69; p=0.92; median PFS [mPFS] 10.3 vs 8.3 months). ORR by IRR was numerically higher for ripretinib than sunitinib (29.6% vs 20.4%). Median OS was not reached in either arm. In Ex11 ITT population, a longer PFS by IRR (HR 0.46, 95% CI 0.23, 0.92; p=0.03; mPFS not reached for ripretinib and 4.9 months for sunitinib) and a numerically higher ORR by IRR (37.1% vs 22.9%) were observed for ripretinib vs sunitinib. Fewer Grade 3/4 treatment-related TEAEs were reported with ripretinib than with sunitinib (16.7% vs 55.6%), as were treatment-related TEAEs leading to dose interruption (7.4% vs 42.6%), dose reduction (20.4% vs 29.6%) and treatment discontinuation (1.9% vs 7.4%). Conclusions: Similar to the INTRIGUE trial, ripretinib demonstrated comparable overall efficacy and favorable safety vs sunitinib as 2L therapy in Chinese pts with advanced GIST. 2L GIST pts harboring a KIT exon 11 mutation may benefit from ripretinib vs sunitinib. Clinical trial information: NCT04633122 .

Phase II study of avelumab plus intermittent axitinib in previously untreated patients with metastatic renal cell carcinoma (Tide-A study).

TPS762 Background: The combination of avelumab plus axitinib has been recently reported to be superior than sunitinib alone for treatment of previously untreated mRCC patients (Motzer, NEJM 2019). The study reported a median PFS of 13.8 for the combination of avelumab plus axitinib compared to 8.4 months for sunitinib (p&lt;0.001) with an ORR of 48% vs 24%, respectively. To improve treatment efficacy and safety, TKI discontinuation has been considered in patients treated with sunitinib leading to a longer definitive progression free survival (22.4 months) and overall survival (34.8 months) with a better safety profile (Ornstein, JCO 2017). Despite a new tumor response at TKI reintroduction, many patients progressed after the first months of treatment discontinuation suggesting the necessity to maintain the previous response. This study aims to test if patients achieving a tumor response with the combination of avelumab plus axitinib, can discontinue the TKI in order to delay the resistance and decrease the toxicity related to the combination of therapies. Methods: The single arm, phase II TIDE-A trial, aims to evaluate the activity of avelumab as maintenance therapy in patients with mRCC who achieved a tumor response after the induction phase of therapy with the combination of avelumab and axitinib. Eligible patients have clear cell carcinoma, ECOG performance status 0 or 1, measurable, no bulky disease without tumor-related symptoms or hepatic metastases. Eligible patient will receive the combination of avelumab plus axitinib for 36 weeks. Patients achieving RECIST 1.1 partial response discontinue the axitinib and continue avelumab. At tumor progression, the axitinib will be restarted for at least six months. If a new tumor response is achieved, axitinib will be discontinued again until tumor progression. Patients with RECIST 1.1 stable disease continue the combination of avelumab and axitinib until progression of disease. The primary endpoint is to evaluate the rate of patients free of progression after 8 weeks from axitinib discontinuation. The study is currently ongoing in twenty centres in Italy.

Real-World Evidence Data on Metastatic Renal-Cell Carcinoma Treatment in Austria: The RELACS Study.

Treatment decisions in routine clinical practice are based on reports of clinical trials, which represent highly selected populations. Limited studies reported real-world evidences representing routine clinical practices in patients with renal-cell carcinoma (RCC) in Europe. The aim of this retrospective, noninterventional chart review was to collect data on the treatment landscape for patients with advanced/metastatic RCC in routine clinical practice in a broader patient population in Austria. Patients with advanced/metastatic RCC receiving systemic treatment between June 2010 and June 2016 across 12 centers in Austria were included. Parameters were entered into an electronic case report form from the participating sites via the application Hermesoft electronic data capture system. Progression-free survival (PFS) and overall survival (OS) were the 2 primary end points. The median PFS and OS were 12 months and 44 months, respectively (first-line PFS was 14 months for pazopanib and 13 months for sunitinib; first-line OS was 44 months for pazopanib and 48 months for sunitinib). Factors influencing the OS were sex, with female patients at a significantly higher risk than male patients (hazard ratio= 1.719), Eastern Cooperative Oncology Group performance status > 0 increased the risk twice (hazard ratio= 2.048), and number of metastases > 3 before the first line doubled the risk compared to metastases (hazard ratio= 2.064). OS in this retrospective chart review was considerably longer than the previous reports in real-world patients, underlining the benefit of current RCC treatment options in routine clinical practice.

Sequential Treatment Based on Sunitinib and Sorafenib in Patients with Metastatic Renal Cell Carcinoma.

Objectives: The aim of our study was to evaluate the outcome of alternative sequences of sunitinib followed by sorafenib versus sorafenib followed by sunitinib therapies in patients with metastatic renal cell carcinoma (mRCC).Materials and Methods: This single-center study analyzed patients with mRCC on systemic therapy between January 2005 and August 2011. Patients were treated with the recommended first-line therapy (sunitinib, sorafenib, pazopanib, or immunotherapy) until progression or intolerable toxicity and afterward switched to another guideline-recommended systemic therapy. Only patients starting first-line therapy on either sorafenib or sunitinib and switching to the other of these drugs were included in this analysis.Results: Out of 266 patients (females: 85, males: 181) with a median age of 57.1 years (30 - 76 years), 57 patients with a sequence of sunitinib and sorafenib were identified. First-line sorafenib therapy was followed by sunitinib (So-Su) in 32 patients; sunitinib was followed by sorafenib (Su-So) in 25 patients. Progression-free survival (PFS) for patients with first-line sorafenib was 11.6 months and was 8.7 months for sunitinib. Overall survival (OS) rates for Su-So was 118.8 months and 83.3 months with So-Su (p = 0.82). No new safety signals were detected.Conclusion: None of the therapeutic first-line approaches was superior to the other. Sequencing tyrosine kinase inhibitor (TKI) therapy seems to be effective in mRCC and superior to single-line therapy. Further studies should focus on the efficacy of single treatment lines rather than treatment sequences to estimate more potent drugs based on PFS rather than overall survival (OS).

Analysis of Efficacy and Toxicity Profile of First-Line Sunitinib or Pazopanib in Metastatic Clear Cell Renal Cell Carcinoma in the Brazilian Population.

PurposeSunitinib and pazopanib are multitargeted tyrosine kinase inhibitors (TKIs) that act against vascular endothelial growth factor receptors and are standard first-line treatment options for metastatic clear cell renal cell carcinoma (ccRCC). The Brazilian public health system diverges from the randomized clinical trials in the availability of first and subsequent lines of treatment and in clinical and demographic characteristics of patients. Therefore, it is essential to describe the history of advanced ccRCC during and after TKI treatment in this population.MethodsWe performed a retrospective analysis of patients with advanced ccRCC treated with a first-line TKI (either sunitinib or pazopanib) between February 2009 and March 2017 in a single academic Brazilian cancer center (Instituto do Câncer do Estado de São Paulo).ResultsOf the 222 patients, 109 were treated with sunitinib and 113 with pazopanib. The median duration of treatment and overall survival (OS) were 6.4 and 15.2 months for sunitinib and 6.7 and 14.2 months for pazopanib, respectively. Discontinuation of treatment occurred secondarily to progressive disease or death in 64.2% of patients using sunitinib and in 54.8% of patients using pazopanib. Adverse events were responsible for discontinuation of treatment in 28.4% of patients in the sunitinib group and in 22.1% in the pazopanib group. According to Memorial Sloan-Kettering Cancer Center risk categories, the OS was 32.9 months, 15.9 months, and 8.1 months for low risk, intermediate risk, and poor risk, respectively (hazard ratio, 1.72; 95% CI, 1.13 to 2.26; P < .001).ConclusionThe use of TKI inhibitors as first-line treatment of metastatic RCC is effective and feasible in the Brazilian public health. However, the median OS of our population is considerably lower compared with the prospective trials that evaluated the same drugs.

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

BackgroundRECORD-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 methodsPatients 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.ResultsAt 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.ConclusionsResults 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 numberClinicalTrials.gov identifier, NCT00903175

Maintenance Sunitinib following Initial Platinum-Based Combination Chemotherapy in Advanced-Stage IIIB/IV Non–Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study—CALGB 30607 (Alliance)

IntroductionThe aim of this study was to evaluate efficacy of maintenance sunitinib after first-line chemotherapy for stage IIIB/IV NSCLC. MethodsCancer and Leukemia Group B 30607 trial was a randomized, double-blind, placebo-controlled, phase III study that enrolled patients without progression after four cycles of first-line platinum-based doublet chemotherapy with or without bevacizumab. Bevacizumab was allowed only during the four cycles of chemotherapy. Patients were randomized to receive sunitinib, 37.5 mg/d, or placebo and were treated until unacceptable adverse event(s), progression, or death. The primary end point was progression-free survival (PFS). ResultsA total of 210 patients were enrolled, randomized, and included in the intent-to-treat analysis. Ten patients did not receive maintenance therapy (four who received placebo and six who received sunitinib). Grade 3/4 adverse events affecting more than 5% of the patients were fatigue (25%), thrombocytopenia (12%), hypertension (12%), rash (11%), mucositis (11%), neutropenia (7%), and anemia (6%) for sunitinib and none for placebo. There were three grade 5 events in patients receiving sunitinib (one pulmonary hemorrhage, one other pulmonary event, and one death not associated with a Common Terminology Criteria for Adverse Events term) and two grade 5 events in patients receiving placebo (one other pulmonary event and one thromboembolism). Median PFS was 4.3 months for sunitinib and 2.6 months for placebo (hazard ratio = 0.62, 95% confidence interval: 0.47–0.82, p = 0.0006). Median overall survival was 11.7 months for sunitinib versus 12.1 months for placebo (hazard ratio = 0.98, 95% confidence interval: 0.73–1.31, p = 0.89). ConclusionsMaintenance sunitinib was safe and improved PFS as maintenance therapy in stage IIIB/IV NSCLC but had no impact on overall survival. There is no room for future investigations of sunitinib in this setting.

Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study

In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. NCT00428597.

Pharmacoepidemiology of Clinically Relevant Hypothyroidism and Hypertension from Sunitinib and Sorafenib.

Thyroid dysfunction and hypertension (HTN) have been sporadically reported with sunitinib (SUN) and sorafenib (SOR). Determination of the side effect incidence will enhance monitoring and management recommendations. An observational cohort study was performed using deidentified pharmacy claims data from a 3-year period to evaluate patients prescribed SUN, SOR, or capecitabine (CAP; comparison group). The primary outcome was time to first prescription for thyroid replacement or HTN treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. A total of 20,061 patients were eligible for evaluation of thyroid replacement therapy, which was initiated in 11.6% of those receiving SUN (HR, 16.77; 95% CI, 13.54-20.76), 2.6% of those receiving SOR (HR, 3.47; 95% CI, 2.46-4.98), and 1% of those receiving CAP, with median time to initiation of 4 months (range, 1-35 months). A total of 14,468 patients were eligible for evaluation of HTN therapy, which was initiated in 21% of SUN recipients (HR, 4.91; 95% CI, 4.19-5.74), 14% of SOR recipients (HR, 3.25; 95% CI, 2.69-3.91), and 5% of CAP recipients, with median time to initiation of 1 month (range, 1-18 months) for SOR and 2 months (range, 1-25 months) for SUN. SUN and SOR significantly increased the risk for clinically relevant hypothyroidism; the risk was at least 4 times greater with SUN than with SOR. Patients receiving SUN and SOR had a similar elevated risk for clinically relevant HTN. These data provide robust measures of the incidence and time to onset of these clinically actionable adverse events. The Oncologist 2017;22:208-212Implications for Practice: The side effect profiles for novel therapies are typically used to create monitoring and management recommendations using clinical trial data from patient populations that may not represent those seen in standard clinical practice. This analysis using a large pharmacy claims database better reflects typical patients treated with sorafenib or sunitinib outside of a clinical trial. The findings of increased need for thyroid replacement in patients receiving sunitinib compared with sorafenib and a similar increase in need for hypertension therapy with both agents can be used to form clinically relevant monitoring recommendations for these agents.

Sunitinib, Pazopanib or Sorafenib for the Treatment of Patients with Late Relapsing Metastatic Renal Cell Carcinoma

Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first-line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment.

Sunitinib Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer: A Phase III Trial

Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC. Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm. In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.

Updated overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) of sunitinib (SU) versus placebo (PBO) for patients (Pts) with advanced unresectable pancreatic neuroendocrine tumors (NET).

4008 Background: In a double-blind phase 3 trial, SU improved PFS vs PBO (11.4 vs 5.5 months; HR 0.418, 95% CI 0.263, 0.662; p=0.0001) and was well tolerated in pts with advanced well-differentiated, unresectable NET that had progressed in ≤12 months (NEJM, Feb 2011). Initial OS showed a benefit for SU over PBO, but median OS was not reached (NR). Here we report updated results of median OS and also PFS assessed by BICR to correct for potential unblinding due to identifiable adverse events (AE). Methods: Pts were randomized 1:1 to SU 37.5 mg as a continuous daily dose or PBO, each with best supportive care. Primary endpoint was PFS; secondary endpoint was OS. Median OS and HR were estimated using Kaplan-Meier (K-M) methods and Cox proportional hazards models. Baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from 6/2007 to 4/2009. The trial ended early when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure, and pts were offered open-label SU. At study end, there were 9 and 21 deaths in SU and PBO arms, respectively; HR of 0.409 (95% CI 0.187, 0.894; p=0.0204) favoring SU. By 6/2010, there were 34 and 39 deaths, respectively; median OS was 30.5 (95% CI 20.6, NR) and 24.4 (95% CI: 16.3, NR) months, respectively. The HR of 0.737 (95% CI 0.465, 1.168; p=0.1926) continued to favor SU; a K-M plot showed early/persistent separation of curves. For BICR analysis, scans were collected for 170 (99.4%) pts, with 160 (93.6%) having complete scan sets/time points. Median PFS by BICR was 12.6 vs 5.8 months for SU and PBO (HR 0.315 [95% CI 0.181, 0.546; p=0.000015]). Conclusions: SU led to a 6.1-month improvement in median OS vs PBO, and BICR analysis confirmed the investigator-assessed PFS benefit of SU. These updated results support the robustness of the initial findings and the clinical benefit of treatment with sunitinib.

Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.

249 Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. In a phase III, double-blind, placebo-controlled, randomized trial in patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET), sunitinib 37.5 mg continuous daily dosing significantly improved investigator-assessed progression-free survival (PFS) compared with placebo (median, 11.4 months vs. 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P=0.0001). To evaluate the possibility that recognizable treatment- associated adverse events (AEs) might have impacted the efficacy results by unblinding the investigators, we conducted a retrospective blinded independent central review (BICR) of the tumor imaging scans. Methods: PFS was defined as the time from randomization to the first objective progression of disease or death due to any cause, whichever occurred first. Baseline and on-study CT/MRI scans were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists. Reading radiologists were blinded to investigator tumor assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist. Results: Overall, 171 patients were randomized to treatment (sunitinib, n=86, placebo, n=85). Scans were collected retrospectively for 170 (99.4%) patients. Complete scan sets/time points were available for 160 patients (93.6%). Median PFS based on BICR of scans was 12.6 months for sunitinib and 5.8 months for placebo with an HR of 0.315 (95% CI: 0.181, 0.546; p=0.000015), consistent with the investigator- assessed PFS results. Conclusions: This BICR of tumor scans confirms the investigator-assessed, clinically meaningful PFS benefit of sunitinib in patients with pancreatic NET, and provides evidence against the presence of any systematic bias favoring sunitinib. [Table: see text]

Cox proportional hazard analysis of sunitinib (SU) efficacy across subgroups of patients (pts) with progressive pancreatic neuroendocrine tumors (NET).

4031 Background: Sunitinib (SU) improved median progression-free survival (PFS) vs. placebo in pts with pancreatic NET (11.4 vs 5.5 months for SU [n = 86] vs placebo [n = 85], hazard ratio [HR] 0.418; 95% CI 0.263, 0.662; p = 0.0001) in a phase III, randomized, double-blind trial (NCT00428597). We report exploratory subgroup analyses evaluating the impact of baseline characteristics on the efficacy of SU treatment, which may aid future study design. Methods: Pts with advanced, well-differentiated pancreatic endocrine tumors and disease progression in the past 12 months were randomized (1:1) to SU 37.5 mg daily or placebo, each with best supportive care (primary endpoint: PFS). The influence of baseline characteristics on treatment effect was assessed using Cox proportional hazards analysis. Results: The treatment effect was statistically significant regardless of age (< 65 vs. ≥ 65 yrs), race (White vs. non-White), gender, ECOG status (0 vs. 1 or 2), number of metastatic sites (≤ 2 vs. ≥ 3) or time from diagnosis to study enrolment (< 3 vs. ≥ 3 yrs). SU showed benefit over placebo in nonfunctioning tumors, with a trend for benefit in functioning pancreatic NET. Somatostatin analogs (SSAs) were allowed before and/or during the study; HR favored SU both in pts with no SSA treatment and those who received SSAs before and/or during the study. Similarly, SU improved PFS in chemo-naïve pts as well as those previously treated with chemotherapy. Baseline characteristics were also evaluated as potential prognostic factors. Multivariate analysis (Cox model) found only time from diagnosis (≥ 3 vs. < 3 yrs; HR 0.603; 95% CI 0.382, 0.952; p = 0.0299) was a potential independent prognostic variable. The PFS advantage with SU was greater when adjusting for time from diagnosis (HR 0.374; 95% CI 0.234, 0.599; p < 0.0001). Exploratory analysis of the 72 pts with available Ki-67 data showed a statistically significant improvement in PFS for the subset of pts with tumor Ki-67 index ≤ 5% (n = 43; HR 0.378; p = 0.0259). Conclusions: Sunitinib resulted in a clinically meaningful improvement in PFS vs placebo across all subgroups studied, supporting its use in pancreatic NET pts independent of baseline characteristics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer