AZ’s comeback drug cediranib stumbles in phase 3 trial

AstraZeneca’s oral VEGF inhibitor cediranib has flunked an investigator-led phase 3 trial alongside Lynparza in relapsed ovarian cancer, failing to improve on platinum-based chemotherapy.

The National Cancer Institute-sponsored GY004 study compared cediranib plus AZ and Merck & Co/MSD's leading PARP inhibitor Lynparza (olaparib) against chemo in patients with platinum-sensitive ovarian cancer, but showed that the duo didn’t lead to an improvement in progression-free survival (PFS).

Last year, Lynparza plus cediranib also failed to show a statistically significant improvement over standard chemotherapy with paclitaxel in patients with platinum-resistant ovarian cancer in the BAROCCO study, which included patients with and without BRCA mutations.

Lynparza is already approved on its own to treat BRCA-positive relapsed ovarian cancer and as first-line maintenance, with positive data in hand for ‘all-comer’ patients, regardless of BRCA-status. GY004 included a Lynparza monotherapy arm, but that data won’t be reported until later, said an AZ spokesman.

Cediranib has been developed as a potential oral alternative to drugs like Roche’s big-selling injectable VEGF inhibitor Avastin (bevacizumab), which is already used to treat ovarian cancer and other tumours. VEGF drugs block the development of blood vessels supporting tumour growth.

AZ abandoned development of cediranib in 2011 after it missed the mark in lung and colorectal cancers, but picked it up again on the strength of investigator-led studies in ovarian and cervical cancer indications, particularly the ICON6 study sponsored by Cancer Research UK.

The drugmaker ended up filing the drug with the EMA in 2015 on the ICON6 data, seeking approval in combination with platinum chemotherapy – followed by maintenance as a monotherapy – in adults with platinum-sensitive relapsed ovarian cancer.

However it pulled the marketing application the following year after the regulator said it wasn’t approvable without additional data as compliance with the drug had been poor, mainly because of side effects.

A phase 2 NCI trial reported in 2014 showed that cediranib plus Lynparza was able to nearly double progression-free survival (PFS) compared to Lynparza alone in patients who had either initially responded to platinum-based therapy or whose tumours expressed the BRCA gene mutation.

That results led to speculation that the combination could become a chemo-free option for relapsed ovarian cancer patients

It is not the end for cediranib just yet, as the drug is still being tested in combination with Lynparza in advanced ovarian cancer in the phase 2, open-label CONCERTO trial – involving patients with relapsed platinum-resistant ovarian cancer and due to generate results later this year – as well as two investigator-led trials.

The NCI is carrying out the phase 2/3 GY005 trial of Lynparza plus cediranib in platinum-resistant ovarian, fallopian tube and peritoneal cancer, while University College London researchers are running a phase 3 study – called ICON9 – which is comparing maintenance therapy with the duo Lynparza alone in relapsed platinum-sensitive patients.