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PD1 drugs could end 'decades of silence' in bladder cancer therapy

Merck's Keytruda and Roche antibody showing promise

TabletsMerck & Co's Keytruda and Roche's experimental antibody MPDL3280A have both achieved durable responses in patients with advanced bladder cancer, raising hopes of the first new therapy for the aggressive disease in more than 30 years.

Bladder cancer affects almost 400,000 people a year and kills around 150,000, but is proved to be remarkably resistant to new drug therapy. The standard of care remains cisplatin, but around half of all patients are not eligible for treatment with that form of chemotherapy. Meanwhile, cisplatin remains only modestly effective in patients who can take the drug.

Data from early stage trials reported at the European Society of Medical Oncology (ESMO) conference in Madrid this week reveal that Keytruda (pembrolizumab) and MPDL3280A - both of which act on the programmed death-1 (PD1/PDL1) pathway - have encouraging activity in advanced urothelial cancer.

A phase Ib trial of Keytruda revealed that as a monotherapy the drug achieved a 24% overall response rate in patients with PDL1-positive tumours, with three of the 29 patients in the small study achieved a complete response. At the time of analysis, patients had shown responses of between 16 and 40-plus weeks.

Meanwhile, Roche's antibody was tested in 68 heavily pre-treated bladder cancer patients and revealed an overall response rate of 25%, rising to 52% in a subset of patients with PDL1-positive tumours. Once again, the responses seemed to be long and durable, extending beyond 30 weeks in some cases.

If the results of the early-stage trials are confirmed in larger studies, it could bring "decades of silence" in the treatment of the cancer to an end, according to Dr Maria De Santis of the Kaiser Franz Josef Hospital in Vienna, Austria, who was the official discussant for both trials at the ESMO meeting.

Merck has already indicated that a phase III study of Keytruda is due to get underway in bladder cancer later this year, while Roche is conducting a phase II trial of MPDL3280A in this indication. Keytruda has already been approved in the US for melanoma, while Roche's drug has reached the phase III trial stage in non-small cell lung cancer (NSCLC), its lead indication.

"For the first time in many years exciting news has emerged for patients with bladder cancer," commented De Santis, who said that the mechanism of action of the new drugs - mobilising the patient's own immune system to fight the disease - ties in with the treatment of non-muscle invasive bladder cancer with the BCG vaccine.

"The immune system is also active in muscle invasive urothelial bladder cancer," she said. "Inhibition of PD-L1 interactions can restore anti-tumour T-cell activity and enhance the cellular immune attack on antigens."

Earlier this week, Bristol-Myers Squibb reported the first phase III data for a PD1-targeting drug at ESMO, revealing an objective response rate of 32% with its Opdivo (nivolumab) product in melanoma.

Opdivo is already on the market in Japan as a melanoma therapy and has just been validated for review by the European Medicines Agency (EMA) in NSCLC.

Article by
Phil Taylor

30th September 2014

From: Research

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