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Highlighting Key Developments in Clinical and Strategic Thinking From
Web-Based Sources.
 
Updated April 2017.

Cabozantinib Recommended as Option for Previously Treated
Advanced RCC Regardless of Prior Systemic Therapy
AMSTERDAM, THE NETHERLANDS—A study of clinical outcomes according to prior therapies in the phase 3 METEOR trial of cabozantinib vs everolimus in advanced renal cell carcinoma (RCC) has demonstrated that cabozantinib should be considered a treatment option for previously treated patients regardless of prior systemic therapy.

This finding was reported at the 2017 European Cancer Congress, from January 27 -30.

Toni Choueiri, MD, of Dana-Farber Cancer Institute, Boston, explained that determining the optimal sequence of systemic therapy in patients with advanced renal cell carcinoma remains a clinical challenge. METEOR evaluated cabozantinib, a tyrosine kinase inhibitor, vs everolimus in patients with advanced renal cell carcinoma who had been treated with at least one vascular endothelial factor receptor tyrosine kinase inhibitor (VEGFR TKI). Overall survival was significantly prolonged with cabozantinib vs everolimus (median 21 vs 16.5 months [hazard ratio 0.66, 95% confidence interval 0.53 – 0.83, P = .0003]). Progression-free survival and objective response rate were also significantly improved with cabozantinib vs everolimus.  In METEOR, 658 patients were randomized 1:1 to cabozantinib (60 mg qd) or everolimus (10 mg qd), with stratification by Memorial Sloan Kettering Cancer Center risk groups and the number of prior VEGFR TKIs. Clinical outcome measures included progression-free survival (primary endpoint), objective response rate, overall survival, and safety.

The hazard ratio for overall survival for patients who had been treated with only one prior TKI was 0.65 (95% confidence interval 0.50 – 0.85) vs 0 (95% confidence interval 0.48 – 1.10) for patients who had received at least two prior TKIs.

Median overall survival was 21.4 months with cabozantinib vs 16.5 months with everolimus (hazard ratio 0.66, 95% confidence interval 0.47 – 0.93) in patients who had taken sunitinib as their only prior VEGFR TKI and 22.0 vs 17.5 months with everolimus (hazard ratio 0.66, 95% confidence interval 0.42 – 1.04) in patients who had received pazopanib as their only prior VEGFR TKI.

Dr Choueiri concluded that progression-free and overall survival, as well as the objective response rate were consistently improved with cabozantinib vs everolimus in subgroups based on prior systemic therapy of sunitinib or pazopanib as prior VEGFR TKI therapy and prior anti-PD1/PD-L1 therapy. He added that cabozantinib should be considered a treatment option for previously treated patients with advanced renal cell carcinoma regardless of prior systemic therapy.

 

Tivozanib Revisited: New Trials Seek to Improve on Earlier Results 
CAMBRIDGE, MA—AVEO Oncology announced that its pivotal, Phase 3 TIVO­3 trial, a randomized, controlled, multi­center, open­label study to compare tivozanib to sorafenib in refractory advanced renal cell carcinoma (RCC), has successfully completed the first safety review by the study’s Safety Monitoring Committee (SMC). The SMC concluded that no safety concern was observed for tivozanib and recommended that the study replace the small number of patients who dropped out prior to starting treatment.

The TIVO­3 trial is enrolling substantially ahead of schedule, with topline data expected in the first quarter of 2018. The TIVO­3 trial, together with the previously completed TIVO­1 trial of tivozanib in the first line treatment of RCC, is designed to support regulatory approval of tivozanib in the US as first and third line treatment for RCC.

Tivozanib has high selectivity for VEGF and is designed to reduce off target toxicity, thereby increasing tolerability. Earlier results with tivozanib encountered problems with FDA approval.

In a related development, AVEO Oncology also announced that the first patient has been dosed in the Phase 1/2 AVEO-sponsored TiNivo trial evaluating tivozanib in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, Opdivo® (nivolumab), in advanced RCC. The study, which will be led by the Institut Gustave Roussy in Paris, is under the direction of Bernard Escudier, MD, Chairman of the Genitourinary Oncology Committee. The Phase 1 trial will evaluate the safety of tivozanib in combination with nivolumab at escalating doses of tivozanib and, assuming favorable results, is expected to be followed by an expansion Phase 2 cohort at the established combination dose.

“There is compelling scientific rationale for combining the antiangiogenic activity of VEGF inhibition with the immunologic activity of PD-1 inhibitors. Yet, to date, the tolerability of these combinations have been a challenge with currently approved VEGF TKIs and PD-1s,” said Dr Escudier. “Tivozanib has been demonstrated to be the most selective VEGF inhibitor, delivering a uniquely favorable tolerability profile in past single agent and combination studies, and has the potential for minimal overlapping toxicities with immunotherapies. I look forward to understanding the clinical potential of combining tivozanib and nivolumab in the TiNivo study, and to the prospect of further improving outcomes in this very dynamic treatment area.”

“VEGF-PD-1 combinations have yielded promising tumor response outcomes in renal cell cancer, yet the data presented to date point to challenging or prohibitive toxicity,” said Michael Bailey, president and chief executive officer of AVEO. “We believe tivozanib offers a unique opportunity to potentially overcome this barrier, and look forward to initial results from the Phase 1 portion of the TiNivo trial in the first half of 2017.”

 

Discontinuation Recommended of ADAPT Phase 3 Trial of
Rocapuldencel-T in MetastaticRCC After Interim Data Review
DURHAM, NC—Feb. 22, 2017, Argos Therapeutics Inc. has announced that the Independent Data Monitoring Committee (IDMC) for the company’s pivotal Phase 3 ADAPT clinical trial of rocapuldencel-T in combination with sunitinib/standard-of-care for the treatment of metastatic renal cell carcinoma (mRCC) has recommended that the study be discontinued for futility based on its planned interim data analysis. The IDMC concluded that the study was unlikely to demonstrate a statistically significant improvement in overall survival in the combination treatment arm, utilizing the intent-to-treat population, the primary endpoint of the study. The IDMC noted that rocapuldencel-T was generally well-tolerated in the trial.

Rocapuldencel-T is an individualized immunotherapy designed to capture mutated and variant antigens specific to each patient’s tumor and induce an immune response targeting that patient’s tumor antigens. The randomized Phase 3 ADAPT trial evaluating rocapuldencel-T plus sunitinib/standard-of-care therapy versus standard-of-care therapy completed enrollment in July 2015. A total of 462 mRCC patients were randomized to the trial. The primary endpoint of the trial is a statistically significant improvement in overall survival.

 

CB-839 Drug Promising for Clear Cell, Papillary RCC
MUNICH — An experimental drug, CB-839, shows promise in treating kidney cancer, according to research presented at an international oncology conference in Munich. The conference is sponsored by the American Association for Cancer Research, the European Organisation for Research and Treatment of Cancer (EORTC), and the US National Cancer Institute. CB-839 targets glutaminase, an enzyme involved in the conversion of glutamine to glutamate, a nutrient that cancer cells need to survive, the researchers explained. This Phase 1 clinical trial found that the drug was effective in most patients with advanced kidney cancer when used in combination with everolimus.

In the 15 patients in the study, the dual treatment controlled tumors in 93% of the patients, who had either clear cell or papillary renal cell cancer. Tumors shrank by more than 30 percent in one patient, were stable in 13 patients, and grew by more than 20% in one patient. All 12 patients with clear cell kidney cancer had their disease controlled. The researchers found the drug to be well tolerated.

“Glutaminase is a very interesting target and previous work in the lab has shown that CB-839 is effective at inhibiting it in renal cell cancers and that it enhances the anti-tumor efficacy of everolimus,” study author Funda Meric- Bernstam, MD, chair of the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center in Houston, said in an EORTC news release. “To date, tumors in 93% of patients with clear cell and papillary renal cell cancers have had tumor control from the regimen, with a median time without their cancer growing of 8.5 months.”

 

Twelfth European International Kidney Cancer Symposium
to Be Held in Munich

MUNICH—Bringing together key individuals and representatives from leading laboratories and centers working with renal cell carcinoma, the Twelfth European International Kidney Cancer Symposium seeks to provide a forum for the exchange of ideas and information that will continue to frame directions for future research and treatment. The symposium will be held at the Westin Grand Munich, April 21-22. To register, visit the Kidney Cancer Association website at https://www.starwoodmeeting.com/Book/kidney2017

 

ASCO Scientific Sessions Scheduled for June
CHICAGO—The 2017 Scientific Sessions of the American Society of Clinical Oncology will be held in Chicago, June 2-6.

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The annual meeting brings together more than 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field.  KCJ