Prior Vascular Endothelial Growth Factor Research Articles

INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer.

Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. Regorafenib improves survival compared with placebo in refractory AGOC.

A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer

BackgroundAlthough different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers. ObjectiveTo evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer. Design, setting, and participantsWe conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy. InterventionPatients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results and limitationsCohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3–4 and no grade 5 events. ConclusionsThe first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC. Patient summaryWe conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.

CASSIOPE: A prospective noninterventional study of cabozantinib treatment following prior vascular endothelial growth factor (VEGF) -targeted therapy in patients with advanced renal cell carcinoma (aRCC).

4529 Background: Cabozantinib is a tyrosine kinase inhibitor approved as monotherapy for aRCC in the USA, and as first-line therapy for patients with intermediate or poor risk aRCC, or after previous VEGF-targeted therapy in Europe. In the METEOR trial, a substantial proportion of patients required cabozantinib dose modifications. We report a real-world study of cabozantinib use for aRCC. Methods: CASSIOPE was a non-interventional prospective cohort study (conducted Apr 2018–May 2022; NCT03419572). Enrollment spanned 11 European countries (91 sites) where cabozantinib is marketed for aRCC. Patients had aRCC and had received ≥ 1 prior VEGF-targeted therapy (excluding cabozantinib). Decision to initiate cabozantinib was made prior to enrolment. The primary endpoint was cabozantinib usage (dose interruptions, reductions or discontinuations due to AEs) in the second- (2L) or later- (≥ 3L) line settings. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and tolerability. Data were analyzed descriptively for patients with safety follow-up after ≥ 1 cabozantinib dose. Results: In total, 679 patients were included (73.0% male; median [range] age 67.0 [29–93] yrs; 85.7% clear-cell aRCC; 80.3% prior nephrectomy). Median (range) observation period was similar for 2L (n = 335; 8.51 [0.2–15.4] mo) and ≥ 3L cabozantinib (n = 343; 9.26 [0.0–15.0] mo). Usage data are shown. For the overall population, ORR (95% CI) and median (95% CI) PFS according to local assessment were 21.9% (17.5%–26.9%) and 7.8 (6.3–8.7) mo for 2L cabozantinib, and 38.0% (32.7%–43.5%) and 8.7 (7.6–9.6) mo for ≥ 3L cabozantinib. Median OS (95% CI) was 13.0 (12.6–not calculated [NC]) mo for 2L, and 17.1 (13.8–NC) mo for ≥ 3L cabozantinib. Most patients (90.4%) reported treatment-related AEs (Grade 1, 71.1%; Grade 2, 70.3% of patients), most commonly any grade diarrhea (52.4%), palmar-plantar erythrodysesthesia syndrome (27.2%), decreased appetite (25.5%), hypertension (21.9%), asthenia (21.6%), fatigue (20.5%) and nausea (20.3%). Conclusions: In this real-world study, tolerability of ≥ 2L cabozantinib was consistent with the METEOR trial safety profile: cabozantinib dose modifications due to AEs were common, but discontinuation rates due to AEs were substantially less frequent. Cabozantinib activity was maintained across lines. Clinical trial information: NCT03419572 . [Table: see text]

Population Pharmacokinetics and Exposure-Response Analysis for the Phase 3 COSMIC-311 Trial of Cabozantinib for Radioiodine-Refractory Differentiated Thyroid Cancer.

In the USA, cabozantinib was approved for the treatment of patients aged ≥12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor(VEGFR)-targeted therapy based on the Phase 3 COSMIC-311 trial, which evaluated cabozantinib 60 mg/day versus placebo. Approved dosing is 60 mg/day for adults and for pediatric patients aged ≥12 years with body surface area (BSA) ≥1.2 m2, and 40 mg/day for pediatric patients aged ≥12 years with BSA <1.2 m2. This report describes a population pharmacokinetic (PopPK) and exposure-response analysis of COSMIC-311. A PopPK model was developed using concentration-time data from COSMIC-311 and 6 other cabozantinib studies. The final (full) PopPK model was used to simulate the effect of sex, body weight, race, and patient population. For exposure-response analysis, derived datasets from COSMIC-311 were constructed for time-to-event analyses of progression-free survival (PFS) and safety endpoints. The PopPK analysis included 4746 cabozantinib PK samples from 1745 patients and healthy volunteers. Body weight had minimal impact on cabozantinib exposure but increasing body weight was associated with increased apparent volume of distribution. Based on model-based simulation, adolescents <40 kg had higher maximum plasma concentration at steady state of cabozantinib 60 mg/day compared to adults. Allometric scaling simulation in adolescents <40 kg demonstrated higher exposure with 60 mg/day relative to adults receiving the same dose, while exposure with 40 mg/day in adolescents <40 kg was similar to 60 mg/day in adults. The exposure-response analysis included 115 patients. There was no clear relationship between PFS or dose modification and cabozantinib exposure. A statistically significant relationship was demonstrated for cabozantinib exposure and hypertension (Grade ≥3) and fatigue/asthenia (Grade ≥3). These results support the dosing strategy implemented in COSMIC-311 and the BSA-based label recommendationsfor adolescents. The cabozantinib dose should be reduced to manage adverse events as indicated.

Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial

BackgroundLenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. ObjectiveTo assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. Design, setting, and participantsA randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor–targeted therapy (prior anti–programmed death-1/programmed death ligand-1 therapy permitted). InterventionPatients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. Outcome measurements and statistical analysisThe primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. Results and limitationsThe ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25–39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27–42]; odds ratio: 0.88; 90% CI 0.59–1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. ConclusionsThe study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. Patient summaryIn this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.

Management of metastatic renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy: A real-world retrospective study from Taiwan.

There are limited real-world data to guide the sequencing of targeted therapies in patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to characterize real-world treatment patterns (primarily second line [2L]) after prior vascular endothelial growth factor (VEGF) targeted therapy in an unselected mRCC population from Taiwan between 2013 and 2017. Treatment-related adverse events (TRAEs) and their management were also evaluated (NCT03633579). This retrospective cohort study included patients who had received prior VEGF-targeted therapy and were treated at the National Taiwan University Hospital or the Taipei Veterans General Hospital between June 2013 and December 2017. Outcomes were characterized using descriptive statistics. Overall, 27 patients were included: 22 (81.5%) male; mean standard deviation (SD) age, 63.1 (11.1) years; 18 (66.7%) initiated targeted therapy during the year immediately following mRCC diagnosis. All patients received sunitinib as their first-line (1L) targeted therapy, with a median (range) treatment duration of 10 (1.8-65.8) months. The most common reason for discontinuing 1L sunitinib was disease progression (88.9% of patients). Everolimus was the most common 2L targeted therapy, in 23 patients (85.2%); 4 patients (14.8%) received 2L axitinib. Median (range) duration of 2L therapy was 4.0 (0.1-30.5) months for everolimus and 4.2 (0.5-9.2) months for axitinib. Ten TRAEs were reported among seven patients receiving 2L everolimus: hypertension (n = 5), hand-foot syndrome (n = 2), hyperglycemia (n = 1), renal failure (n = 1), and interstitial pneumonitis (n = 1). The majority (80%) of TRAEs were managed in the outpatient setting. No TRAEs were reported in the axitinib group. Real-world management of patients with mRCC in Taiwan broadly aligned with clinical guidelines and national reimbursement policy at the time of the study. These findings may be a useful reference for assessing the implications of evolving mRCC management approaches in Taiwan.

New Indication for Cabozantinib.

Cabozantinib (Cabometyx) is now approved to treat locally advanced or metastatic differentiated thyroid cancer that has progressed following prior vascular endothelial growth factor receptor-targeted therapy.

Health-related quality-of-life outcomes from a phase II open-label trial of two different starting doses of lenvatinib in combination with everolimus for treatment of renal cell carcinoma following one prior VEGF-targeted treatment.

314 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer, constituting 80% to 85% of primary renal neoplasms. Preserving health-related quality of life (HRQOL) is an important goal during RCC treatment, but HRQOL analyses in prospective clinical trials in RCC are limited. We report changes in HRQOL, a secondary endpoint of this phase II trial. Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of two different starting doses of lenvatinib (18 mg vs. 14 mg daily [QD]) in combination with everolimus (5 mg QD), following one prior vascular endothelial growth factor–targeted treatment (NCT03173560). HRQOL was measured using three different instruments, including the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L. Change from baseline HRQOL was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale (i.e., 10 points for EORTC, 3 points for FKSI-DRS, 0.08 points for EQ-5D index, and 10 points for EQ-VAS). The distribution of TTD and median TTD for each treatment arm were estimated using the Kaplan-Meier method. Results: Baseline characteristics, including baseline scores of the 343 participants randomly assigned to 14 mg QD lenvatinib (n = 172) and 18 mg QD lenvatinib (n = 171), were well balanced. The average scores for the 18 mg QD group were generally higher, with lower symptom severity than the 14 mg QD group. The least squares mean estimates for change from baseline were favorable for the 18 mg QD group over the 14 mg QD group for the FKSI-DRS and most EORTC QLQ-C30 scales; however, the differences between treatments did not exceed the minimally important difference for clinical significance. Both study arms showed an increase diarrhea severity. Median TTD was longer among participants in the 18 mg QD group than those in the 14 mg QD group for most scales. Conclusions: In most scales, participants who received an 18 mg QD lenvatinib starting dose had better HRQOL and longer time to deterioration than those who received a 14 mg QD starting dose. These findings suggest that the approved treatment regimen of an 18 mg starting dose of lenvatinib in combination with everolimus remains favorable for RCC treatment, following one prior vascular endothelial growth factor–targeted treatment. Clinical trial information: NCT03173560 .

Nivolumab for the Treatment of Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma (nccRCC): A Single-Institutional Experience and Literature Meta-Analysis.

Nivolumab alone and in combination with ipilimumab is approved for the treatment of patients with metastatic renal cell carcinoma (RCC) who received prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) and those who are treatment naive, respectively. However, the clinical activity of nivolumab in non-clear cell RCC (nccRCC) is unknown, as these patients were excluded from the trials. We reviewed the records of patients who received nivolumab for nccRCC and ccRCC with >20% rhabdoid with the primary endpoint to assess the objective response rate (ORR). We assessed radiographic response using RECIST, v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also reviewed the literature to identify studies reporting on the clinical activity of immune checkpoint inhibitors in nccRCC, and performed a meta-analysis of proportions for ORR and disease control rate (DCR). Twelve patients (30%) had papillary histology, 11 (27.5%) had unclassified, 8 (20%) had ccRCC with rhabdoid component, 5 (12.5%) had chromophobe, 3 (7.5%) had translocation, and 1 (2.5%) had mucinous tubular and spindle cell carcinoma. Overall, seven patients (21.6%, 95% confidence interval [CI], 8.7%-37.9%) had an objective response, including three patients (8.8%, 95% confidence interval [CI], 1.9%-23.7%) who achieved a complete remission. At a median follow-up of 24.5 monoths (95% CI, 17.7-32.6), median PFS was 4.9 monoths (95% CI, 3.53-10.27) and median OS was 21.7 monoths (95% CI, 7.83 mo to not reached). There were no treatment-related deaths. We also identified two retrospective studies reporting best ORR in patients with nccRCC receiving PD-1/PD-L1 checkpoint blockade. The ORR and DCR for the total cohort were, respectively, 18.6% (95% CI, 11.9%-26.4%) and 53.4% (95% CI, 44.2%-62.5%). Nivolumab demonstrated activity in unclassified nccRCC and ccRCC with >20% rhabdoid; further randomized clinical trials are warranted. This article reports on the clinical activity and safety of immune checkpoint inhibitors in non-clear cell kidney cancer. The retrospective data with the meta-analysis provides a summary that will help guide the treatment of this rare and heterogeneous group of kidney cancers.

Cost-effectiveness comparison of cabozantinib with everolimus, axitinib, and nivolumab in the treatment of advanced renal cell carcinoma following the failure of prior therapy in England.

PurposeThe aim of this study was to compare the cost-effectiveness of cabozantinib with the standard of care in England in adult patients with advanced renal cell carcinoma (aRCC), following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy.MethodsWe developed a partitioned-survival model with three health states to assess the cost-effectiveness of cabozantinib and its comparators. The model time horizon was 30 years. Efficacy and safety data were derived from pivotal clinical trials (METEOR: NCT01865747, CheckMate025: NCT01668784, and AXIS: NCT00678392). METEOR data were used for a direct comparison of cabozantinib and everolimus. Cabozantinib and nivolumab were compared indirectly, whereas equal efficacy for axitinib and everolimus was assumed based on a previously published expert opinion. For all efficacy endpoints, the best-fitting log-logistic or fractional polynomial curves were used to estimate outcomes. Utilities were converted from the 5-level EQ-5D version instrument applied during the METEOR study for specific health states. Reductions in utility scores due to adverse events were applied. English costs (eg, drug prices) and resource use (eg, visit to consultant) data were used.ResultsThe total treatment cost was estimated to be 84,136 Great British Pounds (GBP) per patient treated with cabozantinib. The health gains were 2.26 life-years (LYs) and 1.78 quality-adjusted LYs (QALYs). The incremental cost-effectiveness ratios (ICERs) versus axitinib and everolimus were 98,967 GBP/QALY and 137,450 GBP/QALY, respectively. Cabozantinib was less costly and more effective than nivolumab; the incremental cost was −6,742 GBP and the QALY difference was 0.18.ConclusionTreatment with cabozantinib was more effective than treatment with axitinib or everolimus but was associated with higher total costs. When compared with nivolumab, cabozantinib represents an efficient option with nominally better efficacy and lower costs.

Cabozantinib in the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor targeted therapy: clinical trial evidence and experience.

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits MET and AXL, both associated with poor prognosis in renal cell carcinoma (RCC), next to vascular endothelial growth factor receptor 2, KIT, FLT3 and RET. Chronic treatment with vascular endothelial growth factor receptor (VEGFR)-targeting sunitinib upregulates MET and AXL in RCC, indicating that cabozantinib may be particularly effective in patients with advanced RCC whose disease progressed on prior VEGFR-targeted treatment. Cabozantinib (60 mg once daily) has been investigated in comparison to everolimus (10 mg once daily) in a phase III randomized controlled trial (RCT) in 658 patients with advanced RCC of whom 71% had received one prior and 29% had received at least two prior lines of VEGR-targeted therapy. This study demonstrated highly significant improved progression-free survival of 7.4 months versus 3.9 months with a hazard ratio (HR) of 0.51 [95% confidence interval (CI) 0.41–0.62] in favour of cabozantinib. Cabozantinib also showed a superior overall survival of 21.4 months versus 16.5 months (HR 0.66; 95% CI 0.53–0.83). Objective response rate was higher in cabozantinib-treated patients, 17% versus 3%. Clinical benefit was shown in all subgroups of patients, including in patients with bone or visceral metastases. The safety profile was acceptable with manageable side effects. Based on this study, cabozantinib is a highly effective approved second-line treatment option for patients with advanced RCC with a manageable toxicity profile. Other recently approved second-line agents include checkpoint inhibitor nivolumab and VEGF-targeting agent lenvatinib combined with everolimus. In the absence of predictive markers as well as head-to-head comparisons of these three recently approved treatments, the choice between these drugs in second-line treatment will probably be made based on comorbidities, tolerability of previous treatment and presence of high tumour burden with rapidly progressive disease. Future pretreatment assessment of MET and AXL tumour aberration may aid clinicians to make a rational choice between currently approved second-line treatment options.

Cabozantinib for the treatment of renal cell carcinoma patients

Anti-angiogenesis is a key target of the first-line systemic therapy in renal cell carcinoma. Resistance to this therapy ultimately occurs in almost every patient who requires subsequent treatment to manage disease progression. Cabozantinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and additionally blocking MET and AXL kinases, which are associated with tumour growth, proliferation, invasion, and resistance. Cabozantinib has been shown to improve overall survival, progression-free survival, and objective response rate in comparison to everolimus in patients with advanced renal cell carcinoma in the phase 3 METEOR study. It resulted in the approval for use in the treatment of advanced renal cell carcinoma following prior vascular endothelial growth factor (VEGF)-targeted therapy and contributed to a change of treatment guidelines, placing cabozantinib among second-line therapy options. Herein we discuss the biological and clinical rationale behind cabozantinib use in renal cell carcinoma therapy and its position in the rapidly developing renal cell carcinoma treatment landscape. We outline current research and future directions for renal cell carcinoma therapy.

Cabozantinib: A Review in Advanced Renal Cell Carcinoma.

The multiple tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx™) is approved in the USA for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy. In the EU, cabozantinib is indicated for the treatment of advanced RCC in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. In adults with advanced or metastatic clear-cell RCC who had previously received VEGF receptor (VEGFR) TKIs, progression-free survival (PFS) and overall survival (OS) were significantly prolonged in patients who received oral cabozantinib versus oral everolimus in the pivotal METEOR trial. Objective response was achieved in a significantly higher proportion of patients receiving cabozantinib than those receiving everolimus. Cabozantinib had a manageable adverse events profile in patients with advanced RCC. Thus, cabozantinib is an important new option for use in patients with advanced RCC who have previously received antiangiogenic therapy.

818P - Analysis of regional differences in the phase 3 METEOR study of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC)

In the METEOR study (NCT01865747), patients (pts) with advanced RCC and prior treatment with an antiangiogenic therapy were randomized to receive cabo or eve. Improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were demonstrated in the cabo arm vs the eve arm (Choueiri 2016 JCO suppl abstr 4506). Baseline characteristics and clinical outcomes were evaluated in pts enrolled in three regions: Europe (EU; 19 countries), North America (NA; US, Canada) and Asia Pacific (AP; Australia, South Korea, Taiwan). 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Of pts enrolled in METEOR, 320, 240 and 86 came from EU, NA and AP, respectively. Baseline demographic characteristics other than race were similar between regions. Pts with 2 or more prior TKIs were more frequent in EU and NA (31% and 33%) than AP (17%). Prior use of axitinib was rare in AP (1%) compared to EU and NA (17% and 22%). PFS and OS in the cabo arm were prolonged vs eve in all regions, with PFS hazard ratios (HR) of 0.54, 0.50 and 0.43 and OS HRs of 0.67, 0.79 and 0.49 for EU, NA and AP, respectively. The cabo arm ORRs (% [95% CI]) for EU, NA and AP regions were 15% (10–21), 16% (10–24) and 28% (15–45). Adverse event (AE) rates were generally similar across regions. Subsequent treatment with VEGFR-TKI and anti-PD-1/L1 agents was most frequent in NA and least frequent in AP, and at higher frequency in the eve arm versus the cabo arm. Posttrial use of eve in the cabo arm was similar across regions (Table).Tabled 1Subsequent TherapiesEuropeEuropeNorth AmericaNorth AmericaAsia PacificAsia Pacificcabo (n = 167)eve (n = 153)cabo (n = 118)eve (n = 122)cabo (n = 39)eve (n = 47)Any VEGFR TKI, %25502957521Axitinib, %1728223832Sorafenib, %4143606Sunitinib, %41189311Pazopanib, %282704Cabo, %010600Anti-PD-1/PD-L1, %2291330Eve, %304284339 Open table in a new tab Improvements in PFS, OS and ORR for cabo vs eve were measured across all regions in the METEOR trial despite differences in subsequent treatment. No differences in safety were reported.

P0125 A phase 1/2 trial of BNC105P with everolimus in metastatic renal cell carcinoma

Background In patients with metastatic renal cell carcinoma (mRCC), everolimus represents a standard of care option for patients who have had prior vascular endothelial growth factor (VEGF)-directed therapy. BNC105P is an inhibitor of tubulin polymerisation and preclinical studies suggest possible synergy with everolimus. In this phase 1/2 study, the efficacy and safety of the combination was explored. Methods A phase 1 study in patients with clear-cell mRCC and any number of different prior treatments was done using a classical 3+3 design to evaluate standard doses of everolimus with increasing doses of BNC105P (4.2, 8.4, 12.6, and 16 mg/m2). At the recommended phase 2 dose, patients with clear-cell mRCC and one to two prior treatments (including ⩾1 VEGF-TKI) were randomised to BNC105P with everolimus (group A) or everolimus alone (group B). Patients were stratified by MSKCC risk factors and number of prior VEGF-TKIs. The primary endpoint of the study was 6-month progression-free survival. Findings 15 patients were included in the phase 1 component, and a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the recommended phase 2 dose. In the phase 2 study, 139 patients were randomised across 77 treatment centres (United States of America (USA): 63; non-USA: 14), with 69 and 67 evaluable patients in groups A and B, respectively. Six-month progression-free survival was similar in the treatment groups (group A: 33.82% versus group B: 30.30%, p = 0.66) and no difference in median progression-free survival was observed (group A: 4.7 months versus group B: 4.1 months; p = 0.49). Most adverse events were consistent with everolimus-related toxic effects. Changes in several biomarkers (matrix metalloproteinase-9, stem-cell factor, sex hormone binding globulin, and serum amyloid A protein) were associated with clinical outcome with BNC105P. Conclusions Although the primary endpoint was not met in an unselected population, intriguing correlative studies suggest several potentially predictive biomarkers. Further prospective assessment of BNC105P in relevant biomarker-based subsets is warranted.

A phase I study of buparlisib (BKM120) with bevacizumab (BEV) in patients (pts) with metastatic renal cell carcinoma (mRCC) progressing on prior vascular endothelial growth factor (VEGF) therapies.

4559 Background: BKM120 is a pan-PI3K inhibitor with demonstrated activity in advanced solid tumors. The primary aim of this study was to determine the maximum tolerated dose (MTD) and dose limitin...

DART Study: A phase II randomized trial of dalantercept plus axitinib versus placebo plus axitinib in advanced clear cell renal cell carcinoma (RCC): Results from Part 1.

407 Background: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis involved in blood vessel maturation and stabilization. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in dual angiogenic blockade and augmented inhibition of tumor growth in RCC xenograft models. Dalantercept (Dal) is an ALK1 receptor-fusion protein that acts as a ligand trap and has demonstrated monotherapy activity with an acceptable safety profile in a completed phase I study. Methods: Part 1 of this study evaluated the safety, tolerability, and preliminary activity of escalating dose levels of Dal plus fixed dose axitinib in pts with advanced RCC. 3-6 pts each received Dal (0.6, 0.9, or 1.2 mg/kg) SC Q3W and axitinib 5 mg PO BID. Key eligibility: predominantly clear cell RCC, 1 prior VEGFR TKI, ≤3 prior tx. Results: As of September 12, 2014, 29 pts were enrolled in three cohorts (n=6, 9, 14) at dose levels of 0.6, 0.9 and 1.2 mg/kg, respectively. At the 1.2 mg/kg dose level, 1 DLT of grade 3 abdominal and back pain occurred (n=1) in addition to more Dal associated edema events including peripheral edema (n=6), fluid overload (n=1), ascites (n=1), and pleural effusion (n=1). The 0.9 mg/kg dose level was well tolerated (3 pts with low grade edema; no pleural effusions or ascites) and selected for Part 2. Frequent AEs regardless of attribution: fatigue, diarrhea, dysphonia, nausea, peripheral edema, creatinine rise, epistaxis, hypertension, arthralgia, hand-foot rash, and cough. 28 pts were evaluable for response by RECIST 1.1. The ORR was 25% (n=7) and 31.3% (n=5) among pts who received ≥ 2 prior txs (n=16), including VEGF targeted tx, mTOR inhibitors, and immune tx. Of those evaluable for disease control at 6 mos. (n=25, 3 active pts have not reached 6 mos.), 52% (n=13) remained progression free. PFS data are maturing and will be presented. Conclusions: The combination of dalantercept and axitinib is well tolerated and associated with encouraging activity in pts with prior VEGF, mTOR, and immune therapies. Part 2 of this study randomizes pts to dalantercept + axitinib vs. placebo + axitinib and is actively accruing patients. Clinical trial information: NCT01727336.

Bevacizumab monotherapy as salvage therapy for patients with advanced clear cell renal cell carcinoma pretreated with targeted drugs.

468 Background: Bevacizumab targets vascular endothelial growth factor (VEGF) and has showed benefit in first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α (Lancet 370: 2103). This retrospective analysis assessed the efficacy of bevacizumab monotherapy after progression on targeted drugs such as VEGFr tyrosine kinase inhibitors (TKI), and/or mTOR inhibitors. Methods: A retrospective analysis was performed on patients with metastatic ccRCC who received bevacizumab monotherapy at MSKCC after progression on prior targeted therapies. Primary end point is overall survival and secondary endpoints include progression free survival, time on therapy, and toxicity analysis. Results: 71 patients were treated with bevacizumab monotherapy in the salvage setting. Patients were heavily pretreated with 36 (51%) patients receiving bevacizumab as a fourth-line agent or later and 33 (46%) patients received at least 2 prior VEGF targeted agents. Seventeen (24%) patients had a KPS &lt;80% and 20 (28%) patients were in the poor prognosis MSKCC risk group. Overall median OS was 11.5 months (95% CI, 6.4-17.4 months) and overall median PFS was 1.9 months (95% CI, 1.7-4.1). Nine (13%) patients had a prolonged time on therapy of &gt;12 months. At last analysis, 8 (11%) patients remained on therapy. Therapy was discontinued for progression of disease (n=56, 89%), adverse events (n=4, 6%), or unknown/unrelated reasons (n=3, 5%). Univariate analysis showed KPS (&lt;80% vs. ≥80%) and MSKCC Risk Factor Classification (poor vs. favorable) as prognostic for poor outcome with hazard ratios of 3.97 (95% CI, 2.09-7.52, p&lt;0.001) and 2.84 (95% CI, 1.17-6.89, p=0.021), respectively. No significant differences in OS were seen when comparing number of lines of prior therapy or lines of prior VEGF targeted therapy. Conclusions: Bevacizumab monotherapy resulted in prolonged disease control in a subset of patients with few discontinuations for adverse events in patients after progression on other targeted therapies, including those who were heavily pretreated. The number of prior VEGF targeted TKI therapies did not correlate with response to bevacizumab, which may reflect a difference in targeting the receptor vs. ligand.

Efficacy of Everolimus in Patients with Advanced Renal Cell Carcinoma Refractory or Intolerant to VEGFR-TKIs and Safety Compared with Prior VEGFR-TKI Treatment

Everolimus is positioned as second-line treatment for metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated retrospectively the efficacy and safety of everolimus in Japanese patients with advanced renal cell carcinoma in the clinical setting. Nineteen patients who discontinued treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors because of disease progression or adverse events were administered everolimus. We evaluated progression-free survival, overall survival and tumor response rate of everolimus treatment. We also compared laboratory abnormalities and adverse events of everolimus treatment with those of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors therapy. In all patients, median progression-free survival was 8.4 months and median overall survival was not reached at 25 months. The best objective response was complete response in 1 patient and stable disease in 15 patients. Eleven patients (58%) were intolerant and 8 (42%) were refractory to prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors treatment. Median overall survival was significantly longer (P < 0.01) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (>25 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (4.3 months), and median progression-free survival tended to be better (P= 0.06) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (10.0 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (2.5 months). Two patients discontinued everolimus treatment because of adverse events. In this study, the overall survival and progression-free survival were better in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects. The adverse event profiles of everolimus and vascular endothelial growth factor receptor-tyrosine kinase inhibitors were different. Patients intolerant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors may tolerate everolimus well and have greater survival benefit from switching to everolimus than those refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitors.

A Phase II Study of Bevacizumab and Everolimus as Treatment for Refractory Metastatic Renal Cell Carcinoma

BackgroundAgents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade. MethodsIn this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. ResultsThe median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity. ConclusionsIn our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.