Olga Valota

Randomized Phase II Trial of Sunitinib on an Intermittent Versus Continuous Dosing Schedule As First-Line Therapy for Advanced Renal Cell Carcinoma

PURPOSE Sunitinib has shown antitumor activity with a manageable safety profile as metastatic renal cell carcinoma (RCC) treatment, when given by the standard intermittent schedule as well as a continuous daily dosing (CDD) schedule. A trial was conducted to compare the schedules. PATIENTS AND METHODS Patients with treatment-naive, clear cell advanced RCC were randomly assigned 1:1 to receive sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2; n = 146) or 37.5 mg/d on the CDD schedule (n = 146) for up to 2 years. The primary end point was time to tumor progression. RESULTS Median time to tumor progression was 9.9 months for schedule 4/2 and 7.1 months for the CDD schedule (hazard ratio, 0.77; 95% CI, 0.57 to 1.04; P = .090). No significant difference was observed in overall survival (23.1 v 23.5 months; P = .615), commonly reported adverse events, or patient-reported kidney cancer symptoms. Schedule 4/2 was statistically superior to CDD in time to deterioration, a composite end point of death, progression, and disease-related symptoms (P = .034). CONCLUSION; There was no benefit in efficacy or safety for continuous dosing of sunitinib compared with the approved 50 mg/d dose on schedule 4/2. Given the numerically longer time to tumor progression with the approved 50 mg/d dose on schedule 4/2, adherence to this dose and schedule remains the treatment goal for patients with advanced RCC.

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma

BACKGROUND The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). RESULTS The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. CONCLUSIONS Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. TRIAL REGISTRATION ClinicalTrials.gov, NCT01210495.

Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer.

Purpose This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination. Materials and Methods Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data. Results Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months. Conclusion In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group

Micro‐Abstract A retrospective analysis of patient outcome according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model from a phase III trial of sunitinib versus interferon‐&agr; as treatment for metastatic renal cell carcinoma was performed; IMDC benchmarks from this analysis for objective response rate, progression‐free survival, and overall survival for sunitinib‐treated patients are reported. Background: Sunitinib malate, a targeted tyrosine kinase inhibitor, is standard of care for metastatic renal cell carcinoma (mRCC) and serves as the active comparator in several ongoing mRCC clinical trials. In this analysis we report benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first‐line setting. Materials and Methods: A retrospective analysis was performed on data from sunitinib‐treated patients (n = 375) in the pivotal phase III trial of sunitinib versus interferon‐&agr; as first‐line treatment for mRCC. Objective response rates (ORRs) were determined from independently reviewed radiologic assessments. The Kaplan–Meier method was used to estimate median progression‐free survival (PFS) and median overall survival (OS) according to patient risk group. Results: Median PFS (95% confidence interval [CI]) was 14.1 (13.4‐17.1), 10.7 (10.5‐12.5), 2.4 (1.1‐4.7), and 10.6 (8.1‐10.9) months in sunitinib‐treated patients in the IMDC favorable (n = 134), intermediate (n = 205), poor (n = 34), and intermediate + poor (n = 239) risk groups, respectively. Median OS (95% CI) was 23.0 (19.8‐27.8), 5.1 (4.3‐9.9), and 20.3 (16.8‐23.0) months in sunitinib‐treated patients in IMDC intermediate, poor, and intermediate + poor risk groups, respectively, and was not reached in the favorable risk group (>50% of patients were alive at data cutoff). ORRs (95% CI) was 53.0% (44.2%‐61.7%), 33.7% (27.2%‐40.6%), 11.8% (3.3%‐27.5%), and 30.5% (24.8%‐36.8%) in sunitinib‐treated patients in IMDC favorable, intermediate, poor, and intermediate + poor risk groups, respectively. Conclusion: Results of this retrospective analysis show differences in patient outcomes for PFS, OS, and ORR on the basis of IMDC prognostic risk group assignment for patients with mRCC.

Validation of the 16-Gene Recurrence Score in patients with locoregional, high-risk renal cell carcinoma from a phase 3 trial of adjuvant sunitinib

Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit. Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer–specific survival (RCSS) were analyzed using Cox proportional hazards regression. Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15–39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant. Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407–15. ©2018 AACR.

Axitinib Versus Placebo as an Adjuvant Treatment for Renal Cell Carcinoma: Results From the Phase III, Randomized ATLAS Trial

Abstract Background The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy. Patients and methods In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted. Results A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660–1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468–0.879; P = 0.0051), and by IRC (0.735; 0.525–1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo. Conclusions ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported. Trial registration number NCT01599754

Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study

Background: An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. Methods: The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. Results: Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. Conclusions: Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.

A case for the use of receiver operating characteristic analysis of potential clinical efficacy biomarkers in advanced renal cell carcinoma.

Aim: Assess patient-level utility of suggested pretreatment biomarkers of sunitinib in advanced renal cell carcinoma. Patients & methods: Kaplan–Meier analysis of data from a randomized, Phase II study (n = 292) suggested baseline predictive value for circulating soluble Ang-2 and MMP-2 and HIF-1α percentage of tumor expression. Using this dataset, the sensitivity, specificity and area under the curve (AUC) were calculated, using receiver operating characteristic (ROC) curves. Results: Based on a ROC (sensitivity vs 1 - specificity) threshold AUC value of >0.8, neither Ang-2 (0.67) nor MMP-2 (0.65), nor HIF-1α percentage of tumor expression (0.65), performed appropriately from a patient-selection standpoint. Conclusion: To properly assess potential biomarkers, sensitivity and specificity characteristics should be obtained by ROC analysis.

Abstract CT120: Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Hepatobiliary excretion is the major elimination pathway for axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, approved for second-line treatment of advanced renal cell carcinoma. A formal hepatic impairment (HI) study was previously conducted in subjects with Child-Pugh A (CPA) and Child-Pugh B (CPB) disease but who were otherwise healthy to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of axitinib following a single 5 mg oral dose. The safety and PK of axitinib were further evaluated in CPA and CPB patients (pts) with advanced hepatocellular carcinoma (HCC) following continuous multiple axitinib dosing. Methods: Two study portions (randomized double-blind portion of axitinib versus placebo, and non-randomized portion) were conducted in parallel in pts with advanced HCC after failure of one prior antiangiogenic therapy. In the non-randomized portion, the effect of HI on safety and PK were evaluated in HCC CPA (starting dose: 5 mg twice a day [BID]) and CPB (Score 7, starting dose: 2 mg BID) pts. This was also intended to identify the recommended starting dose of axitinib in HCC CPB pts. Serial PK samples up to 8 hour postdose were collected at steady state (Cycle 1 Day 15). Results: Data from 15 CPA and 7 CPB pts were available for safety analysis. Most pts were male (n = 17) and Asian (n = 21). Overall, the most frequently reported all-causality treatment emergent adverse events (TEAE) in all, CPA and CPB pts were fatigue (63.6%, 80% and 28.6%), decreased appetite (54.5%, 46.7% and 71.4%), diarrhea (45.5%, 60% and 14.3%), hypertension (45.5%, 46.7% and 42.9%), and palmar-plantar erythrodysesthesia syndrome (45.5%, 53.3% and 28.6%). Overall, the most frequently reported Grade ≥3 TEAEs in all, CPA and CPB pts were hypertension (27.3%, 26.7% and 28.6%), fatigue (18.2%, 20% and 14.3%) and hyponatraemia (18.2%, 6.7% and 42.9%). One out of 6 evaluable CPB pts treated with 2 mg BID experienced Cycle 1 dose limiting toxicity (proteinuria; >3.5 g/24 hours). PK samples were collected from 12 CPA and 7 CPB pts (AUC0-24 and CL/F reported for 8 CPA and 6 CPB pts, respectively). In CPA and CPB pts, the geometric mean (geometric% coefficient of variance [CV]) values for axitinib AUC0-24 were 311 (63) and 316 (118) ng.hr/mL, respectively. The geometric mean (geometric% CV) values for axitinib CL/F were 32.2 (63) and 12.7 (118) L/hour, respectively, indicating that axitinib CL/F is decreased with increasing HI. Conclusions: The safety profile of axitinib in HCC CPA and CPB pts in this study was consistent with the known safety profile of axitinib. Axitinib plasma exposures were comparable in CPB pts receiving 2 mg BID axitinib and CPA pts receiving 5 mg BID axitinib. These data are in agreement with the previous single-dose HI study and further support that 2 mg BID is an appropriate axitinib starting dose for CPB pts with HCC. Citation Format: Yoon-Koo Kang, Tara E. Seery, Mina Kato, Debasis Chakrabarti, Olga Valota, Ying Chen, Jie Tang, Yazdi K. Pithavala, Masatoshi Kudo. Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT120. doi:10.1158/1538-7445.AM2015-CT120