Phase Ib study (COSMIC-021) of cabozantinib in combination with atezolizumab: Results of the dose escalation stage in patients (pts) with treatment-naïve advanced renal cell carcinoma (RCC)

TPS2614 Background: Standard treatments for metastatic renal cell carcinoma (mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib, pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus, everolimus). However, most patients (pts) develop resistance and complete responses are rare. Upregulation of programmed death-1 (PD-1) in tumor infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for mRCC. In preliminary results of a phase I trial, the anti-PD-1 monoclonal antibody BMS-936558 had antitumor activity in pts with advanced tumors, including objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a phase I study planned to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of BMS-936558, when combined with sunitinib or pazopanib in pts with mRCC. Methods: This open-label study will have two parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558 plus pazopanib) conducted in two parts (dose escalation and dose expansion). Pts must have received ≥1 prior systemic therapy to be eligible for dose escalation. Only treatment-naïve pts will be eligible for dose expansion. Up to 36 pts (18 per arm) will be treated in the dose-escalation phase. After determining the MTD of BMS-936558, treatment-naïve pts will be enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed on Days 1 and 22 and sunitinib or pazopanib given according to product label. Adverse events will be graded according to NCI CTCAE v4.0. Disease will be assessed every 6 weeks for the first four assessments and then every 12 weeks until disease progression. Pts will be treated until unacceptable toxicity, disease progression, or withdrawal of consent. The safety profile in pts treated at the MTD will be used to determine the recommended phase II study dose of BMS-936558 in each combination arm. Secondary objectives will include OR rate and duration of response based on RECIST 1.1. Exploratory analyses will investigate predictive biomarkers of BMS-936558.

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Phase Ib Study of Atezolizumab Plus Interferon-α with or without Bevacizumab in Patients with Metastatic Renal Cell Carcinoma and Other Solid Tumors

Current Oncology ◽

10.3390/curroncol28060455 ◽

2021 ◽

Vol 28 (6) ◽

pp. 5466-5479

Author(s):

Christian U. Blank ◽

Deborah J. Wong ◽

Thai H. Ho ◽

Todd M. Bauer ◽

Carrie B. Lee ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Solid Tumors ◽

Renal Cell ◽

Checkpoint Inhibitor ◽

Interferon Α ◽

Clinical Activity ◽

Phase Ib ◽

Treatment Naïve ◽

Previously Treated

This Phase Ib study combined programmed death-ligand 1 inhibitor, atezolizumab, with other immunomodulatory agents in locally advanced and metastatic solid tumors. Arms B-D evaluated atezolizumab plus interferon-α, with/without vascular endothelial growth factor inhibitor, bevacizumab, in renal cell carcinoma (RCC) and other solid tumors. Arm B predominantly recruited patients with previously treated RCC or melanoma to receive atezolizumab plus interferon α-2b. Arm C investigated atezolizumab plus polyethylene glycol (PEG)-interferon α-2a in previously treated RCC. Arm D evaluated atezolizumab plus PEG-interferon α-2a and bevacizumab. Primary objectives were safety and tolerability; secondary objectives included clinical activity. Combination therapy was well tolerated, with safety profiles consistent with known risks of individual agents. The most frequent treatment-related toxicities were fatigue, chills, and pyrexia. The objective response rate (ORR) in arm B was 20.0% overall and 17.8% in patients with previously treated checkpoint inhibitor–naive RCC (n = 45). No responses were reported in arm C. The highest ORR in arm D was 46.7% in patients with treatment-naive RCC (n = 15). Data showed preliminary clinical activity and acceptable tolerability of atezolizumab plus interferon α-2b in patients with previously treated checkpoint inhibitor–naive RCC and of atezolizumab plus PEG-interferon α-2a and bevacizumab in patients with treatment-naive RCC.

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Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.4644 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 4644-4644 ◽

Cited By ~ 9

Author(s):

J. A. Thompson ◽

T. Kuzel ◽

R. Bukowski ◽

F. Masciari ◽

T. Schmalbach

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Advanced Renal Cell Carcinoma ◽

Phase Ib

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Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4501 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4501-4501 ◽

Cited By ~ 13

Author(s):

Robert John Motzer ◽

Dmitry Nosov ◽

Tim Eisen ◽

Igor N. Bondarenko ◽

Vladmir Lesovoy ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Type I ◽

Patient Reported ◽

Hand Foot Syndrome ◽

Treatment Naïve

4501 Background: Tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors, showed activity and tolerability in a Phase II trial (JCO 2011;29[18S]:4550). Methods: Patients (pts) with clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, RECIST-defined measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib (T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib (S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment naïve or received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. The primary endpoint was progression-free survival (PFS) per blinded, independent radiological review. 500 pts were to be enrolled to observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 months (m) with 5% type I error (2-sided). Results: A total of 517 pts were randomized to T (n=260) or S (n=257). Demographics were well balanced between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p=0.035). Median PFS was 11.9 m for T vs 9.1 m for S (HR=0.797, 95% CI 0.639–0.993; p=0.042). In the treatment-naïve stratum (70% of pts enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 0.756, 95% CI 0.580–0.985; p=0.037). In all pts, objective response rate (ORR) for T was 33% vs 23% for S (p=0.014). The most common adverse event (AE; all grades/≥grade 3) for T was hypertension (T: 46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. Overall survival data are not mature. Conclusions: Tivozanib demonstrated significant improvement in PFS and ORR compared with sorafenib as initial targeted treatment for advanced RCC. The safety profile of tivozanib is favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, and hand-foot syndrome.

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Avelumab plus axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma: Phase 3 study (JAVELIN Renal 101).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps4594 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS4594-TPS4594 ◽

Cited By ~ 13

Author(s):

Toni K. Choueiri ◽

Brian I. Rini ◽

James M. G. Larkin ◽

Georg A. Bjarnason ◽

Gwenaelle Gravis ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Advanced Renal Cell Carcinoma ◽

Clinical Activity ◽

Line Treatment ◽

First Line ◽

Phase 3 ◽

Treatment Naïve ◽

Ecog Ps

TPS4594 Background: The combination of a checkpoint inhibitor with an anti-VEGF agent is a promising treatment strategy for advanced renal cell carcinoma (aRCC). Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in aRCC and other tumor types (eg, Apolo et al. ASCO 2016; Gulley et al. ECC 2015). Axitinib is an anti-VEGF receptor tyrosine kinase inhibitor approved for second-line treatment of aRCC (Rini et al. Lancet 2011) that has also shown clinical activity as a first-line (1L) therapy (Hutson et al. Lancet Oncol 2013). In an ongoing phase 1b study in treatment-naïve patients (pts) with aRCC, avelumab + axitinib administered at standard monotherapy doses showed a tolerable safety profile and encouraging antitumor activity (Larkin et al. ESMO 2016). JAVELIN Renal 101 is a randomized, multicenter, phase 3 study (NCT02684006) comparing avelumab + axitinib vs sunitinib in pts with treatment-naïve aRCC. Methods: The primary objective is to demonstrate superiority of avelumab + axitinib vs sunitinib in prolonging progression-free survival (PFS) in the 1L treatment of pts with aRCC. Eligibility criteria include: aRCC with a clear cell component, ECOG PS ≤1, no prior systemic therapy for advanced disease, and measurable disease per RECIST v1.1. Approximately 583 pts will be randomized 1:1 and stratified based on ECOG PS (0 vs 1) and region (US vs Canada/Europe vs rest of the world). Pts receive either avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID continuously (cycle length 6 weeks) or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. Treatment is discontinued for unacceptable toxicity or if any other criteria for withdrawal are met. Pts may continue treatment beyond progression (RECIST v1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated. PFS is assessed by blinded central review. Secondary efficacy assessments include overall survival, objective response, disease control, duration of response, and time to response. Safety, PK, and biomarker analyses will also be performed. The trial is currently active at 103 sites across 12 countries and as of Feb 2017, more than 40% of patients have been enrolled. Clinical trial information: NCT02684006.

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