ESMO 2016 Press Release: Cabozantinib Improves Progression-free Survival in Metastatic Renal Cell Carcinoma

LUGANO-COPENHAGEN – Cabozantinib significantly improves progression-free survival and response rate in patients with metastatic renal cell carcinoma compared to sunitinib, according to research presented today at the ESMO 2016 Congress in Copenhagen.

Cabozantinib targets a class of enzymes called tyrosine kinases but, unlike sunitinib which targets the vascular endothelial growth factor receptors (VEGFR), cabozantinib additionally inhibits the action of MET and AXL.

“Both MET and AXL seem to be associated with tumour progression but more importantly, animal models showed that the development of resistance to VEGFR inhibitors like sunitinib can be mediated through AXL and MET,” said principal investigator Dr. Toni Choueiri, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, US.

In this phase II multicenter trial, 157 patients with untreated clear-cell metastatic renal cell carcinoma of intermediate or poor risk, were randomized either to oral cabozantinib (60mg once daily) or sunitinib (50mg once daily, 4 weeks on, 2 weeks off).

Patients treated with cabozantinib showed a 31% reduction in the median rate of progression or death compared to those treated with sunitinib (8.2 months vs. 5.6 months, p = 0.012). The objective response rate was also significantly higher in the cabozantinib arm compared to the sunitinib arm (46% vs.18%).

Researchers observed a similar rate of adverse events between the two arms of the study, with the incidence of grade 3 or higher adverse events being 70.5% in the cabozantinib arm and 72.2% in the sunitinib arm. The most common adverse events for both treatments included diarrhoea, fatigue, hypertension, palmar-plantar erythrodysesthesia, hematological events, and 16 patients in each arm terminated their treatment early due to toxicity.

The study did not include good-risk patients, but Choueiri said there was no biological or clinical rationale to think that cabozantinib would not be equally effective in that population.

“Cabozantinib is currently approved for second or later lines of therapies, after patients have progressed on a VEGFR tyrosine kinase inhibitor, but this data shows that cabozantinib has the potential to become a first-line standard treatment,” Choueiri said.

Commenting on the study, Dr Bernard Escudier, chairman of the renal cancer unit at Institut Gustave-Roussy, France, said, “For many years, sunitinib has been the most commonly used standard of care for first line metastatic renal cell carcinoma, and recently, cabozantinib was proven to be active in second line, especially after sunitinib failure.”

“Obviously, this study will raise a lot of questions, such as whether these results are expandable to all metastatic renal cell carcinoma patients, including the good prognosis group; whether cabozantinib should become a new standard of care in the first line setting; and how we should interprete all the ongoing phase III first-line studies which selected sunitinib as the control arm.”

“While more mature data and additional studies using cabozantinib in the first line setting will be required, this study raises a lot of new expectations for the treatment of metastatic renal cell carcinoma,” Escudier concluded.

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Notes to Editors

References

LBA30_PR - CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial, presented by Dr Toni Choueiri during Presidential Symposium 3 on Monday, 10 October, 16:30 to 18:10 (CEST).

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Abstract for LBA30_PR

CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial

T.K. Choueiri1, S. Halabi2, B. Sanford2, O. Hahn3, M.D. Michaelson4, M. Walsh1, T. Olencki5, J. Picus6, E.J. Small7, S. Dakhil8, D. George9, M.J. Morris10

1Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA, 2Biostatistics & Bioinformatics, Duke University, Durham, NC, USA, 3Medical Oncology, The University of Chicago Medical Centre, Chicago, IL, USA, 4Medical Oncology, Massachusetts General Hospital, Boston, MA, USA, 5Medical Oncology, Ohio State Univ Medical Center, Columbus, OH, USA, 6Medical Oncology, Washington University School of Medicine, St Louis, MO, USA, 7Medical Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, 8Hematology, Cancer Center of Kansas, Wichita, KS, USA, 9Medical Oncology, Duke University, Durham, NC, USA, 10Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Background: Cabozantinib (Cabo) is an oral, potent inhibitor of MET, AXL and VEGFR2 that increases progression free-survival (PFS) and overall survival (OS) in mRCC patients (pts) after VEGF-targeted therapy. This randomized phase II multicenter trial compared the PFS of Cabo to Sunitinib (Sun) as front-line targeted therapy in pts with mRCC.

Methods: Eligible pts had untreated clear-cell mRCC, ECOG performance status 0-2, and were intermediate or poor risk, per the International mRCC Database Consortium Criteria (IMDC, Heng JCO 2009). Pts were randomized 1:1 to Cabo (60 mg QD) or Sun (50 mg QD, 4 weeks on/2 weeks off). Pts were stratified by IMDC risk groups (intermediate vs. poor risk) and bone metastasis (yes, no). With 123 events (progression or deaths), the log-rank statistic has 85% power to detect a hazard ratio of 0.67 for PFS assuming a one-sided type I error of 0.12.

Results: From July 2013 to April 2015, 157 pts were randomized (79 to Cabo and 78 to Sun). Median follow up was 20.8 months (mo). 13 (16.46%) pts remained on therapy in the Cabo arm vs. 2 (2.56%) pts in the Sun arm. 80.9% of pts were IMDC intermediate risk and 36.3% had bone metastases and were equally distributed across arms. Median PFS was significantly increased at 8.2 mo (95% CI=6.2-8.8) for Cabo vs. 5.6 mo (95% CI=3.4-8.2) for Sun, with 31% reduction in rate of progression or death (adjusted HR 0.69, 95% CI 0.48 to 0.98, one-sided P=0.012). ORR was 46% (95% CI 34-57%) for Cabo vs. 18% (95% CI 10-28%) for Sun. Median OS was 26.4 mo. for Cabo vs. 23.5 mo for Sun (adjusted HR 0.87, 95% CI 0.55-1.4). All-causality grade 3 or higher adverse events were 70.5% for Cabo and for 72.2% for Sun, and included diarrhea (Cabo 10%, Sun 11%), fatigue (Cabo 6%, Sun 15%), hypertension (Cabo 28%, Sun 22%), palmar-plantar erythrodysesthesia (Cabo 8%, Sun 4%) and hematological (Cabo 2.6%, Sun 22.2%). In each arm, 16 pts ended treatment due to toxicity.

Conclusions: Cabozantinib demonstrated a significant benefit in PFS and ORR over standard sunitinib in untreated intermediate and poor risk mRCC pts.

Clinical trial identification: NCT01835158

Legal entity responsible for the study: Alliance/CTEP 

Funding: Exelixis

Disclosure:

T. K. Choueiri: Institutional funds from Exelixis and Pfizer. Advisory board compensation from Pfizer.
All other authors have declared no conflicts of interest.

Keywords: metastatic renal cell carcinoma, VEGF, sunitinib, resistance to treatment