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Pharmawire analysis: Cyclacel's seliciclib comes under physician scrutiny due to elevated liver enzymes in non-small cell lung cancer trial – analysis
By James Avallone
Cyclacel’s seliciclib has reported elevated liver enzymes in patients, and physicians are not impressed with the drug's current results.
Seliciclib is an orally available molecule that targets cyclin dependent kinases as a third-line treatment in patients with non-small cell lung cancer (NSCLC). The major dose limiting toxicities associated with seliciclib thus far were vomiting, fatigue, hypokalemia and elevation in liver enzymes.
Dr CK Wang, oncologist and haematologist from the Cancer Institute of Dallas said the liver enzyme elevations are definitely something that needs to be monitored closely. He further explained that this could lead to limitations in how much of the drug physicians can give patients and could prohibit the drug from advancing into further studies.
Cyclacel could not be reached for comment.
A lot of targeted therapies like seliciclib have side-effects which are not traditional compared to chemotherapy treatments. “If they have some cases where it is severe [such as elevated liver enzymes], that is very concerning,” said Wang.
Dr Eric Haura, an oncologist at the H Lee Moffitt Cancer Center & Research Institute, expressed doubt that this drug would be a paradigm shifter or represent a change in standard of care.
Dr Robert Chapman, oncologist and hematologist at the Henry Ford hospital commented that Tarceva, an FDA approved orally administered drug currently on the market for non-small cell lung cancer, has a pretty clean toxicity profile and is tolerated very well by most patients who take it. Tarceva is currently manufactured by Genentech and OSI Pharmaceuticals, and is a second-line treatment for this indication.
The Phase IIa study evaluates seliciclib in combination with a gemcitibine/cisplatin backbone. These results yielded nine patients with partial response and 21 with stable disease, out of 47 patients treated with advanced NSCLC.
Dr Scott Milligan, senior researcher at IntrinsiQ, a company that provides US oncology data and analysis, also had mixed feelings on the gemcitibine/cisplatin backbone used in Phase IIa trials. He felt it did not represent the “gold standard” and would have preferred to see this paired with carboplatin/paclitaxel as in the US this accounts for 50% of US doublet treatments. Other physicians including Dr Chapman, felt that this was a fine pairing as these doublet treatment results in very similar efficacy results.
Milligan said even smaller liver problems could be an issue depending on how the therapy was going to be used. “If you have a competitor come in and it has toxicity problems, it is certainly not going to displace Tarceva in that niche situation,” said Milligan, as from his findings, most patients do not move past Tarceva once placed on it and this drug is lining itself up to be an option after Tarceva.
The data for seliciclib as potential monotherapy was not that impressive, added Milligan. He explained that improvements in survival as opposed to partial response data is what changes physician usage. He pointed to the fact that approvals in NSCLC are based on survival data, whether it is progression free survival or overall response data.
“Until that kind of data comes out it is hard pressed for this to be considered. Could it be approved on this data sure, for lung cancer, probably not,” Milligan said.
Dr Maryada Reddy, an oncologist from the Cancer Institute of Dallas said the data thus far was decent for use in second-line. Reddy also added that the response rates thus far were in an area where Cyclacel’s seliciclib could feasibly compete with Tarceva.
Advanced non-small cell lung cancer is categorized as stages IIIb and IV, out of IV possible stages. Stage III five year survival is around 5% and this drops down even lower at stage IV, according to physicians.
Cyclacel currently has a market cap of USD 37.8m.