Axitinib In Patients Research Articles

796P Neoadjuvant toripalimab plus axitinib in patients (pts) with resectable mucosal melanoma (MuM): Updated findings of a single-arm, phase II trial

Initial results of the single-arm, phase II trial (NCT04180995) showed neoadjuvant toripalimab (T) plus axitinib (A) in resectable MuM had pathologic responses rate (RR) of 28.6% (4/14, 2 pCR, 2pPR) with good tolerance. We presented the updated data of pathologic RR, RFS at 1.5-years and the multiplex immunohistochemistry (mIHC) analysis before and after surgery.

LBA01-08 INTERIM ANALYSIS OF PADRES (PRIOR AXITINIB AS A DETERMINANT OF OUTCOME OF RENAL SURGERY NCT03438708) CLINICAL TRIAL

You have accessJournal of UrologyCME1 May 2022LBA01-08 INTERIM ANALYSIS OF PADRES (PRIOR AXITINIB AS A DETERMINANT OF OUTCOME OF RENAL SURGERY NCT03438708) CLINICAL TRIAL Kevin Hakimi, Steven Campbell, Mimi Nguyen, Nityam Rathi, Luke Wang, Brian Rini, Moshe Ornstein, Rana McKay, and Ithaar Derweesh Kevin HakimiKevin Hakimi More articles by this author , Steven CampbellSteven Campbell More articles by this author , Mimi NguyenMimi Nguyen More articles by this author , Nityam RathiNityam Rathi More articles by this author , Luke WangLuke Wang More articles by this author , Brian RiniBrian Rini More articles by this author , Moshe OrnsteinMoshe Ornstein More articles by this author , Rana McKayRana McKay More articles by this author , and Ithaar DerweeshIthaar Derweesh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002669.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In renal cell carcinoma (RCC), partial nephrectomy (PN) is imperatively indicated for individuals with solitary kidney, chronic kidney disease, or bilateral tumors. Neoadjuvant Tyrosine Kinase Inhibitor therapy can potentially cytoreduce renal tumors and may therefore permit PN in circumstances not otherwise feasible. We report interim analysis of the PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery NCT03438708). METHODS: This was a single arm phase II clinical trial of neoadjuvant axitinib in patients with complex renal mass (RENAL nephrometry score 10-12 and cT1b-cT3M0) biopsy-proven clear cell RCC with strong indications for partial nephrectomy (PN), and in whom radical nephrectomy may result in dialysis dependence. Axitinib 5 mg was administered orally twice daily for 8 weeks prior to surgery. Primary outcome was reduction in longest tumor diameter based on imaging criteria; secondary outcomes included tumor response (RECIST), change in RENAL score, feasibility of PN, change in estimated glomerular filtration rate (∆eGFR), post-surgical complications, and survival outcomes. RESULTS: 27 patients consented for study of which 26 proceeded with protocol (median age 69 years; median follow-up 12 months). Prior to therapy, 19 (73.1%) patients had ≥ clinical T3a staged tumors. Post therapy, 17 (65.4%) patients had ≥T3a staged tumors, and 8/26 (31%) of patients were downstaged on imaging. Axitinib resulted in reductions in median tumor size (19%, 7.7 vs. 6.3 cm, p <0.001 and RENAL score (11 vs. 10, p <0.001); 21/26 (80.9%) had partial response, and 5/26 (19.2%) had stable disease by RECIST criteria. PN was performed in 20/26 (76.9%) with median ischemia time of 34 minutes and with 25/26 (96.8%) achieving negative margins. All radical nephrectomy patients had at ≥T3a tumors on final pathology. Five (19.2%) had Clavien III-IV post-surgical complications. At last follow up, median ∆eGFR was 4.5 mL/min/1.73m2, 1/26 (3.8%) died due to progression, and 2/26 (7.7%) had recurrence. CONCLUSIONS: In this interim analysis, neoadjuvant Axitnib resulted in significant reductions in tumor size and complexity, enabling partial nephrectomy in a cohort of highly complex renal masses, and with acceptable safety and functional preservation. Accrual is ongoing to reach a target of 50. Source of Funding: Pfizer © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1038 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kevin Hakimi More articles by this author Steven Campbell More articles by this author Mimi Nguyen More articles by this author Nityam Rathi More articles by this author Luke Wang More articles by this author Brian Rini More articles by this author Moshe Ornstein More articles by this author Rana McKay More articles by this author Ithaar Derweesh More articles by this author Expand All Advertisement PDF DownloadLoading ...

A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.

291 Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]

Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis

BackgroundMucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising...

1097O The AXINET trial (GETNE1107): Axitinib plus octreotide LAR improves PFS by blinded central radiological assessment vs placebo plus octreotide LAR in G1-2 extrapancreatic NETs

Angiogenesis plays an important role in NET development and progression. Axitinib is a potent and selective VEGFR-1,2,3 inhibitor with proven activity against other vascular-dependent solid tumors. The aim of this double-blind phase II/III randomized study was to assess the efficacy of axitinib in patients (pts) with advanced G1-2 extra-pancreatic NETs.

Abstract 1364: Exposure-response (E-R) analysis of efficacy for avelumab in combination with axitinib in patients with advanced renal cell carcinoma (aRCC) in JAVELIN Renal 101

Abstract BACKGROUND: Avelumab, a monoclonal antibody targeting PD-L1, is currently approved in the USA in combination with axitinib for the first-line treatment of patients with aRCC. This analysis evaluated the relationship between potential covariates, including avelumab exposure, and the efficacy endpoints progression-free survival (PFS; by blinded independent central review per Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and objective response (OR; per RECIST) in patients with aRCC. METHODS: Exposure metrics for all patients in JAVELIN Renal 101 who received avelumab 10 mg/kg every 2 weeks (Q2W) in combination with axitinib were derived from a population pharmacokinetic model (N=434). E-R analysis for PFS was conducted using parametric time-to-event (TTE) methodology. The hazard distribution was tested using exponential, Weibull, log-normal, and log-logistic distributions. E-R analysis for OR was performed using generalized binomial logistic regression. For OR, the full model included the influence of all potential covariates, while the final model retained statistically significant covariates after stepwise backwards elimination (α=0.15). For PFS, covariates were included in the full model based on forward addition (α=0.05), and the final model was determined using backward elimination (α=0.01). Model evaluation included TTE-visual predictive checks, the likelihood ratio test, the Hosmer-Lemeshow test, and receiver operating characteristic curves. RESULTS: The best fit to the PFS data was the log-normal distribution. Avelumab exposure (cycle 1 day 15 trough concentration) was associated with probability of longer PFS in both univariate and multivariate regression models. In addition, the favorable-risk group, according to baseline Heng criteria, was associated with probability of longer PFS relative to patients with intermediate prognosis using Heng criteria. Similarly, increasing avelumab exposure was associated with a higher probability of achieving OR. However, several factors have confounded the interpretation of the causal relationship between exposure and PFS or OR, including the imbalance of Heng prognostic criteria across exposure quartiles, correlation among covariates, and that data were from a single-dose regimen. No relationship was found between incidence of ADA or baseline PD-L1 status and the efficacy endpoints PFS or OR. CONCLUSION: The E-R analyses were considered exploratory and no definite conclusions could be made on the impact of exposure on PFS or OR, as other variables confounded interpretation of the relationship. Overall, the exposure from avelumab 10 mg/kg IV Q2W in combination with axitinib was associated with a manageable and tolerable safety profile and demonstrated superior efficacy compared with sunitinib in terms of PFS in treatment-naive patients with aRCC. Citation Format: Carlo Bello, Satjit Brar, Joanna C. Masters, Akash Khandelwal, Ana M. Novakovic, Ana Ruiz-Garcia, Jennifer Hibma. Exposure-response (E-R) analysis of efficacy for avelumab in combination with axitinib in patients with advanced renal cell carcinoma (aRCC) in JAVELIN Renal 101 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1364.

The use of a new combination of avelumab + axitinib in patients with metastatic kidney cancer in the first line of treatment

The use of a new combination of avelumab + axitinib in patients with metastatic kidney cancer in the first line of treatment

A phase 2, two-stage study of avelumab and axitinib in patients with mismatch repair proficient (MMR-P) recurrent or persistent endometrial cancer (EC).

TPS5609 Background: Despite significant strides in understanding the molecular pathogenesis of EC, there remain few effective therapies for recurrent disease. Deeper insight into the roles of disordered tumor vasculature and HIF1α- and VEGF-mediated immunosuppressive effects on myeloid-derived suppressor cells, T-cells, and PD-L1 expression contributed to the development of new targeted regimens. Activity of pembrolizumab and lenvatinib was demonstrated in a phase 2 trial in MMR-P EC (NCT02501096). By inhibiting VEGF receptor (VEGFR) and PD-L1 signaling, immunologically “cold” tumors may become inflamed. However, there are concerns regarding the toxicity of pembrolizumab/lenvatinib and alternatives are sought. The combination of the anti-PD-L1 antibody avelumab with axitinib, an inhibitor of VEGFR 1-3 and PDGFR with more potent IC50 inhibitory activity than lenvatinib, has also shown synergistic activity and is FDA approved as first line treatment for patients with renal cell cancer. We therefore hypothesized that this combination would be well tolerated and efficacious in recurrent MMR-P EC. Methods: This is an investigator-initiated, phase 2, two-stage single cohort trial evaluating avelumab with axitinib in recurrent or persistent EC. Participants must have MMR-P EC of any histology and have received at least one chemotherapeutic regimen, with no upper limit on the number of prior lines received. Prior use of immune checkpoint (IC) inhibitors is excluded. Treatment consists of avelumab 800mg IV every 2 weeks and axitinib 5mg orally twice daily. Co-primary endpoints are progression-free survival at 6 months (PFS6) and objective response rate by RECIST 1.1. Translational objectives include characterization of tumor-infiltrating lymphocytes, infiltrating myeloid cells, expression of IC markers, and whole exome sequencing to evaluate mutations in genes related to DNA repair and immunologic response. This is a two-stage design in the method of Sill et al, with 16 participants anticipated in stage 1 and 19 participants in stage 2, for a total of 35 participants. Accrual is ongoing. Clinical trial information: NCT02912572.

Efficacy outcomes of nivolumab + cabozantinib versus pembrolizumab + axitinib in patients with advanced renal cell carcinoma (aRCC): Matching-adjusted indirect comparison (MAIC).

4578 Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.[Table: see text]

FDA threatens to fine first drug firm for failing to post results to ClinicalTrials.gov

In an unprecedented action, the US Food and Drug Administration is threatening to fine a clinical trial sponsor for failing to publish study results on ClinicalTrials.gov . Federal law requires clinical trial investigators to register their studies on the website within 21 days of enrolling the first participant. Sponsors must also submit a summary of the trial results within 1 year of the study’s completion date. In a statement issued April 28 , the FDA says Acceleron Pharma hasn’t complied. The company ended a trial for dalantercept in combination with axitinib in patients with advanced renal cell carcinoma in 2017, making its results 3 years overdue. Last year, the agency sent Acceleron a letter warning that it could be fined . The company now has 30 days to comply or will be fined up to $12,316 for each day the violation is not corrected, an FDA spokesperson says. ClinicalTrials.gov was

ATLAS trial of adjuvant axitinib in patients with renal cell carcinoma: subgroup analyses with focus on axitinib dosing and racial groups

BackgroundThe ATLAS trial, investigating adjuvant axitinib versus placebo in renal cell carcinoma (RCC), was stopped for futility at a preplanned interim analysis. We report subgroup outcome analyses by ethnicity, time on treatment, dose modification and toxicity.Patients and methodsPatient demographics, baseline characteristics, treatment duration and exposure and safety were analysed for Asian versus non-Asian patients treated with axitinib versus placebo. Disease-free survival (DFS) was analysed by ethnicity, treatment duration (≥1 versus <1 year), dose modification and adverse event (AE) grade.ResultsNo DFS benefit was observed for Asian {hazard ratio (HR) 0.883 [95% confidence interval (CI) 0.638-1.220]} or non-Asian [HR 0.828 (95% CI 0.490-1.400)] patients treated with axitinib or placebo. Fewer Asian versus non-Asian patients were in the highest-risk group in axitinib (51.9% versus 72.3%) or placebo (51.5% versus 66.0%) arm. Highest-risk patients in both subgroups had no DFS benefit with either treatment. More axitinib-treated Asian versus non-Asian patients had dose reductions due to AEs (58.8% versus 46.0%; P = 0.028). Asian patients experienced more nasopharyngitis but less fatigue or asthenia than non-Asians. Among Asian patients, proteinuria, hypothyroidism, nasopharyngitis, and hypertension were more common in Japanese patients than Korean patients and more common in Korean patients than Chinese patients. Patients receiving axitinib >1 year versus ≤1 year did not have different DFS: HR 0.572 (95% CI 0.247-1.327); P = 0.1874. Compared with patients on stable axitinib dose, DFS was longer in patients with dose reduction [HR 0.458 (95% CI 0.305-0.687); P = 0.0001], whereas DFS was not different in those with dose escalation [HR 1.936 (95% CI 0.937-3.997); P = 0.0685]. DFS was not different in patients experiencing grade ≥2 versus <2 AEs within 6 months of initiating axitinib: HR 0.885 (95% CI 0.419-1.869); P = 0.7488.ConclusionsAsian versus non-Asian subgroup analysis revealed differences in AE experience and drug exposure. There were no DFS differences based on ethnicity or treatment duration, but axitinib dose reduction led to longer DFS.

NAXIVA: A phase II neoadjuvant study of axitinib for reducing extent of venous tumor thrombus in clear cell renal cell cancer (RCC) with venous invasion.

275 Background: Venous tumor thrombus (VTT) extension occurs in 4-15% cases of renal cell cancer (RCC). The Mayo classification distinguishes 4 levels of VTT extension between the renal vein and supradiaphragmatic inferior vena cava (IVC). Although surgery is performed with curative intent, mortality is high (5-15%) with complications increasing with the level of the VTT. 5-year survival rates are poor; ~40-65% in non-metastatic RCC. It is hypothesised that neoadjuvant targeted therapy could downstage the VTT reducing the extent of surgery, leading to reduced surgical morbidity and mortality, and increased survival. However, level I or II evidence is lacking. NAXIVA provides the first level II evidence in this patient group, assessing the response of VTT to axitinib. Extensive translational sampling will provide in depth interrogation of VTT (using genomics, proteomics, immunophenotyping and metabolomics) to examine the role of the tumor microenvironment of VTT and response to axitinib. Methods: NAXIVA was a single arm, single agent, multi-center phase 2 feasibility study of axitinib in patients with both metastatic and non-metastatic clear cell RCC prior to nephrectomy and thrombectomy. A Simon two stage minimax design was adopted and the trial designed for adequate power to distinguish a &lt;5% from a &gt;25% improvement in the Mayo VTT level. 21 patients were recruited over a 24 month period between 15/Dec/2017 and 06/Jan/2020 at 5 sites across the UK. Patients were treated with 8 weeks of axitinib (starting dose 5mg bd, increasing to 10mg bd as tolerated) prior to planned surgery. The primary endpoint was the percentage of evaluable patients with an improvement in VTT according to the Mayo classification (assessed using MRI abdomen scans at screening and week 9, prior to surgery. Secondary endpoints were percentage change in surgical approach, percentage change in VTT height, response rate (by RECIST) and evaluation of surgical morbidity assessed by Clavien-Dindo classification. Results: The percentage of evaluable patients with an improvement in VTT according to the Mayo classification was 26.58% [80% CI: 15.76%, 39.74%] (6 of 21 evaluable patients). 35.29% (6 of 17 patients who progressed to surgery) had a change in surgical approach to a less invasive option. There was a median percentage reduction in VTT height of 21.49% (SD=27.60%). The response rate (by RECIST) in the evaluable population was 61.90% SD, 14.29% PR, 9.52% PD. In terms of surgical morbidity 11.76% (2 of 17 patients who progressed to surgery) experienced a Clavien-Dindo 3 or greater complication (0 CD3, 1 CD4, 1 CD5). Conclusions: NAXIVA provides unique prospective data on the feasibility of neoadjuvant axitinib administration to down stage IVC VTT and reduce the extent of surgery. Work is ongoing to establish predictors of response. Clinical trial information: NCT03494816 .

Phase I with expansion clinical trial of seleno-l-methionine (SLM) in combination with axitinib in patients with relapsed clear cell renal cell carcinoma (ccRCC): Bench to bedside.

322 Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533 .

A phase II/III randomized double-blind study of octreotide acetate LAR with axitinib versus octreotide acetate LAR with placebo in patients with advanced G1-G2 NETs of non-pancreatic origin (AXINET trial-GETNE-1107).

360 Background: Angiogenesis plays an important role in NET development and progression. Axitinib is a potent and selective VEGFR-1,2,3 inhibitor, with proven activity against several vascular-dependent solid tumors. The aim of this randomized, double-blind phase II/III study was to assess the efficacy of axitinib in patients with advanced G1-2 extra-pancreatic NETs. Methods: Eligible pts were randomized (1:1) to receive octreotide LAR (30 mg IM q4w) with axitinib (5 mg BID) or placebo BID until disease progression or unacceptable toxicity. Pteswere stratified by time from diagnosis to study entry ( &gt; or &lt; 12m), primary tumor site (GI tract vs non-GI) and Ki-67 index (&lt; 5% vs &gt; 5%). Prior therapy with SSA, IFN and up to 2 lines of systemic treatment was allowed, but not prior VEGF- or VEGFR-targeted drugs. Clinical and/or radiological disease progression within 12 months prior to study entry was required. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), time to progression, overall response rate (ORR), duration of response, biochemical response and safety. Results: 256 pts were randomized (106 in the Phase II part, and 150 additional pts in the Phase III part), 126 to axitinib and 130 to placebo. The main characteristics of the study population were: median age 61 years (range: 21-85), 52% male, PS 0-1 (64-35%), G1-2 (29%-71%), primary tumor site GI (40%)-Lung (17%)-Other (32%). Prior therapies included: SSA (46%), everolimus (13%), chemotherapy (13%), TACE (5%) and PRRT (2%). ORR was significantly higher in axitinib- vs placebo-treated patients (17.5% vs 3.8%, p = 0.0004). PFS per investigator assessment also favored axitinib vs placebo-treated patients, although the difference did not reach statistical significance (median PFS 17.2 vs 12.3 months, respectively, HR 0.816, p = 0.169). Grade 3-4 treatment-related AEs occurred more frequently in the axitinib vs placebo arm (52% vs 13.8%), and included hypertension (21% vs 6 %), cardiac disorders (3.2% vs 0.7%), diarrhoea (13% vs 1.5 %), asthenia (9% vs 3%) and nausea&amp;vomiting (2% vs 0.7%). There were 3 treatment-related deaths, 1 in the axitinib arm (cardiac failure) and 2 in the placebo arm (myocardial infarction and hepatorenal syndrome). Conclusions: Although the study failed to demonstrate a significant PFS benefit per investigator assessment, axitinib in combination with octreotide LAR demonstrated activity and had a tolerable safety profile in patients with advanced G1-2 extra-pancreatic NETs. Data base cleaning and central blinded radiological PFS assessment are currently ongoing. Clinical trial information: NCT01744249.

1667TiP A phase II, single arm study of avelumab in combination with axitinib in patients with unresectable/metastatic gastrointestinal stromal tumor after failure of standard therapy - AXAGIST

1667TiP A phase II, single arm study of avelumab in combination with axitinib in patients with unresectable/metastatic gastrointestinal stromal tumor after failure of standard therapy - AXAGIST

Oncological outcomes of a multicenter cohort treated with axitinib for metastatic renal cell carcinoma

The present study aimed to evaluate the efficacy of the real‐world use of axitinib and to develop a prognostic model for stratifying patients who could derive long‐term benefit from axitinib. This was a retrospective, descriptive study evaluating the efficacy of axitinib in patients with metastatic renal cell carcinoma that had been treated with 1 or 2 systemic antiangiogenic therapy regimens at 1 of 36 hospitals belonging to the Japan Urologic Oncology Group between January 2012 and February 2019. The primary outcome was overall survival (OS). Using a split‐sample method, candidate variables that exhibited significant relationships with OS were chosen to create a model. The new model was validated using the rest of the cohort. In total, 485 patients were enrolled. The median OS was 34 months in the entire study population, whereas it was not reached, 27 months, and 14 months in the favorable, intermediate, and poor risk groups, respectively, according to the new risk classification model. The following 4 variables were included in the final risk model: the disease stage at diagnosis, number of metastatic sites at the start of axitinib therapy, serum albumin level, and neutrophil : lymphocyte ratio. The adjusted area under the curve values of the new model at 12, 36, and 60 months were 0.77, 0.82, and 0.82, respectively. The efficacy of axitinib in routine practice is comparable or even superior to that reported previously. The patients in the new model’s favorable risk group might derive a long‐term survival benefit from axitinib treatment.

Overall survival and biomarker analysis of a phase Ib combination study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) with axitinib in patients with metastatic mucosal melanoma.

10007 Background: Metastatic mucosal melanoma responds poorly to PD-1 blockade therapy in comparison with cutaneous melanoma. Vascular endothelial growth factor (VEGF) is indicated to play an important immunosuppressive role in mucosal melanoma. Combination of VEGF inhibition with PD-1 blockade might provide therapeutic opportunities. Toripalimab was approved as a second-line treatment for metastasis melanoma in Dec 2018. This study is to evaluate the safety and clinical efficacy of toripalimab combined with axitinib for the treatment of metastatic mucosal melanoma. (Clinical trial ID: NCT03086174). Methods: Patients with metastatic melanoma receive 1 or 3 mg/kg toripalimab Q2W in combination with 5 mg axitinib BID until disease progression, unacceptable toxicity, or voluntary withdrawal. Clinical response is assessed every 8 weeks according to RECISTv1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and gene expression profile (GEP) will be evaluated for correlation with clinical response. Results: From April 2017 to April 2018, 33 patients were enrolled in the study. No DLT or treatment related death was observed. 97% patients experienced treatment related AE (TRAE) and 39.4% patients experienced Grade 3-4 TRAEs. Most common TRAEs include diarrhea, proteinuria, hand and foot syndrome and hypothyroidism. Only one patient discontinued treatment due to TRAE. Among 29 treatment naïve mucosal melanoma patients, 14 PR and 11 SD were observed for an ORR of 48.3% and a DCR of 86.2%. The median DOR was 13.7 months. The median PFS was 7.5 months and the median OS was 20.7 months. PD-L1 expression or TMB had no significant differences in responders versus non-responders. In contrast, GEP scores of eight selected immune-related and four angiogenesis-related genes showed strong correlation with clinical response, whereas previous published immune related signature or angiogenesis signature alone had no correlation. Conclusions: Toripalimab combined with axitinib is a promising treatment option for metastatic mucosal melanoma. GEP scores of selected immune-related and angiogenesis-related genes might predict the response to the combination. A randomized 3-arm Phase 2 trial has been initiated to compare toripalimab plus axitinib with toripalimab or axitinib alone. Clinical trial information: NCT03086174.

Toripalimab in Combination With Axitinib in Patients With Localized Mucosal Melanoma

Toripalimab in Combination With Axitinib in Patients With Localized Mucosal Melanoma

912PD - Results of the phase II TRAXAR study: A randomized phase II trial of axitinib and TRC105 (TRAX) versus axitinib (AX) alone in patients with advanced or metastatic renal cell carcinoma (mRCC)

912PD - Results of the phase II TRAXAR study: A randomized phase II trial of axitinib and TRC105 (TRAX) versus axitinib (AX) alone in patients with advanced or metastatic renal cell carcinoma (mRCC)

First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]