Negative Results for Cediranib in Advanced Biliary Tract Cancer

Cediranib fails to improve progression-free survival in advanced biliary tract cancer patients

medwireNews: Cisplatin and gemcitabine remain the standard of care for patients with advanced biliary tract cancer after phase II trial results showed no significant survival benefit with the addition of cediranib therapy.

After a median of 12.2 months, progression-free survival was comparable in the 62 patients given the oral Vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3 inhibitor alongside cisplatin and gemcitabine and the 62 patients given placebo plus the chemotherapy regimen, at a median of 8.0 and 7.4 months, respectively.

In addition, cediranib was associated with a higher rate of grade 3 and 4 side effects, including hypertension, diarrhoea, fatigue, and reduced platelet and white blood cell counts, report Juan Valle, from the University of Manchester in the UK, and co-workers.

However, the team notes that cediranib-treated patients were significantly more likely to achieve a RECIST response than controls (44 vs 19%) and there was a trend towards a higher rate of disease control (78 vs 65%), although they also had a slightly shorter duration of response (5.1 vs 5.8 months).

Analysis indicated that cediranib plus chemotherapy may have been more effective than placebo plus chemotherapy until toxicity led to treatment discontinuation, after a median of 4.6 months, prompting the researchers to “postulate that a better-tolerated anti-VEGF treatment might potentially result in overall benefit in combination with cisplatin and gemcitabine.”

The authors of an accompanying comment in The Lancet Oncology suggest that the “vascular pruning” associated with cediranib-induced tumour regression may, in turn, have led to hypoxia-fuelled tumour growth.

“The success of antiangiogenic drugs could rest on achieving balance between therapeutic and pathological Angiogenesis in which tumour vascular normalisation rather than vascular pruning is the goal”, they write.

“In view of the negative results of several anti-VEGF agents in advanced biliary tract cancer, future efforts with randomised trials should aim to use alternative strategies (eg, anti-VEGFR antibodies), inhibit alternative targets in angiogenesis, or use a Biomarker-driven trial design to select patients likely to benefit from this strategy.”

Andrew Zhu, from Massachusetts General Hospital in Boston, USA, and co-authors also commend the investigators for including circulating biomarker analysis in their report, revealing for the first time that a poor prognosis was predicted by increased baseline levels of CK18 and VEGFR2, and the presence of one or more circulating tumour cells per 7.5 mL of blood.

References

Valle JW, Wasan H, Lopes A, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol 2015; Advance online publication 12 July. DOI: http://dx.doi.org/10.1016/S1470-2045(15)00139-4.

Goyal L, Chong DQ, Duda DG, Zhu AX. Chemotherapy and antiangiogenics in biliary tract cancer. Lancet Oncol 2015; Advance online publication 12 July. DOI: http://dx.doi.org/10.1016/S1470-2045(15)00093-5.

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