ESMO @ ECC 2013: Similar Phase III Results Reported for Dovitinib vs. Sorafenib Treatment in Patients with Metastatic Renal Cell Carcinoma

Activity and safety profile of tyrosine kinase inhibitors in patients who progressed on anti-VEGF and mTOR inhibitors.

Superior efficacy was not demonstrated by dovitinib in a head to head comparison with sorefinib in patients with metastatic renal cell carcinoma (mRCC) who had progressed following therapies targeting the VEGF and mTOR pathways. However, this large, phase III trial did establish a role of tyrosine kinase inhibitors in that setting. Dovitinib showed similar activity to sorafenib and generally a well tolerated safety profile. It may offer an additional treatment alternative in this group of with limited treatment options.

Findings were presented on 29 September during the Genitourinary Malignancies Proffered Papers Session (Abstract E17-7035) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress in Amsterdam, The Netherlands. The congress was held from the 27th of September through the 1st of October, 2013 and was part of a series of European Cancer Congresses that are organised in joint partnership with ESSO, EACR, EONS and SIOPE to offer multidisciplinary and multi-professional educational opportunities in oncology.

Citing the unmet need for treatments of patients with mRCC who progress on therapies that target the VEGFR and mTOR pathways, Dr. Robert Motzer of the Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA presented late breaking results from a direct comparison of dovitinib and sorafenib.

ESMO Comments bubble

This is an important randomised phase III trial that compared two TKIs in the third line setting. Patients included in the study had progressed after at least one prior VEGF targeted therapy and one prior mTOR inhibitor. For such patients novel treatment options are urgently needed. Dovitinib (TKI258), targeting not only the VEGFR, PDGFR and ckit but also the FGFR 1-3, which may play a role in the mechanisms of escape from VEGF-targeted therapies, was in fact promising and reasonable to study in this patient population. Although this study is a negative study, not showing an improvement in progression free survival with dovitinib over sorafenib, important data was generated. Very few objective responses (4%) were seen, but a disease stabilisation in about half of the patients. The benchmark of a nearly 4 months PFS and an 11 months OS in third line patients has been established. Novel therapies for metastatic renal cell cancer will have to outreach these results.

Maria De Santis*

*Maria De Santis, ESMO spokesperson who was not involved in the study

Unmet needs in patients with mRCC who progress on VEGFR and mTOR inhibitors

Dovitinib is a multi-targeted receptor tyrosine kinase inhibitor that offers broader inhibition of the fibroblast growth factor receptor (FGFR) by binding FGFRs 1, 2, and 3 plus it also targets the platelet-derived growth factor receptor (PDGFR), FLT3 and cKIT, in addition to the vascular endothelial growth factor receptor (VEGFR). Dovitinib demonstrated promising anti-tumour activity in heavily pretreated RCC patients.

The GOLD trial (Global Oncologic Leanings for Dovitinib, NCT01223027) was an open-label, randomised, multicentre phase III trial. The GOLD enrolled 570 patients with clear cell mRCC who showed disease progression within six months of their last therapy and had received one prior treatment with an agent targeting the VEGF pathway plus one prior treatment with an mTOR inhibitor. Patients were allowed to have had prior cytokine and other anticancer therapies. The majority, 92% of patients, had received an anti–VEGF pathway agent followed by an mTOR inhibitor.

The patients were stratified by region and by MSKCC risk group: 21% of patients showed favourable, 57% intermediate, and 22% of patients showed poor risk. The patients were randomised 1:1 to receive either 500 mg of dovitinib (n= 284) orally on a 5-days-on/2-days-off schedule or 400 mg of sorafenib (n=286) orally twice daily. Patient characteristics were well balanced between groups.

The trial’s primary endpoint was progression-free survival (PFS) by central review. Secondary endpoints included overall survival (OS), response rate and safety.

The trial did not meet the primary endpoint; median PFS was 3.7 and 3.6 months in the dovitinib and sorafenib arms, respectively (HR 0.86; p = 0.063). Median OS was also nearly the same at 11.1 months with dovitinib and 11.0 months in the sorafenib arm (HR 0.96; p= 0.357). The best overall response was the same in both arms; 4% of patients receiving each treatment demonstrated partial response and stable disease was achieved by 52% of patients in each arm.

Different safety profiles were seen with each treatment. The adverse events (AEs) most commonly reported by patients receiving dovitinib were diarrhoea, nausea and vomiting; 68% versus 45% of patients reported diarrhoea, 53% versus 29% of patients had nausea and 44% versus 16% of patients reported vomiting, respectively, with dovitinib compared to sorafenib. AEs more commonly reported in the sorafenib arm compared with the dovitinib arm were palmarplantar erythrodysesthesia, hypertension and alopecia; 40% of sorafenib patients reported palmarplantar erythrodysesthesia compared to 11% of dovitinib patients, 28% versus 19% reported hypertension and 21% versus 1% of patients reported alopecia, respectively in the sorafenib and dovitinib arms.

Although superior efficacy was not demonstrated by dovitinib over sorafenib in patients with mRCC who experienced disease progression after receiving prior VEGF- and mTOR-targeted therapies, the investigators noted that results from this large phase III trial established for the first time the activity and safety profile of tyrosine kinase inhibitors in these patients.

This study was sponsored by Novartis Oncology.

The authors disclosed the following conflicts of interest:

Novartis stock ownership by C. Cai

  • R. Motzer is on the advisory boards of Pfizer and AVEO Oncology
  • C. Szczylik is on the advisory boards of Astellas, Novartis, GlaxoSmithKline and Pfizer
  • C.N. Sternberg is on the advisory boards of Novartis, GlaxoSmithKline and Pfizer
  • N.J. Vogelzang is on the advisory boards of Celgene and Sanofi
  • C. Porta is on the advisory boards of Novartis, Bayer-Schering, Pfizer, Hoffman La Roche and GlaxoSmithKline
  • C. Kollmannsberger is on the advisory boards of Novartis, Pfizer and GlaxoSmithKline
  • G.A. Bjarnason is on the advisory board of Novartis
  • B. Melichar is on the advisory boards of Novartis, Roche, Astellas, Pfizer and GlaxoSmithKline
  • U. Di Giorgi is on the advisory boards of Novartis, Pfizer, GlaxoSmithKline and Bayer
  • B. Escudier is on the advisory boards of Novartis, Pfizer, Bayer, GlaxoSmithKline and Astellas

The following authors disclosed the following corporate-sponsored research:

  • R. Motzer: Novartis, Pfizer, GlaxoSmithKline, AVEO Oncology
  • N.J. Vogelzang: Algeta, Arqule, Cougar Bio-Tech, Johnson&Johnson/Centocor,
  • GlaxoSmithKline, Novartis, Pfizer, Takeda/Millennium, Tokai, Veridex, Wilex
  • C. Porta: Novartis, Bayer-Schering

Other substantive relationships were disclosed by R. Motzer from Novartis that include support for congress attendance to present research, by N.J. Vogelzang who reported employment at US Oncology and by G. Urbanowitz, C. Cai, and M. Shi who reported employment at Novartis.