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AZ's selumetinib stumbles at last fence in lung cancer

Phase III trial shows failure to improve patient survival rates

AstraZeneca global R and D corporate headquarters 

AstraZeneca's selumetinib has failed a phase III trial, dashing the company's hopes of extending its portfolio of lung cancer therapies.

Despite promising results in earlier studies, the MEK 1/2 inhibitor was unable to improve progression-free survival (PFS) or overall survival in patients with non-small cell lung cancer (NSCLC) whose tumours tested positive for the KRAS mutation in the SELECT-1 trial.

The drug was being tested in combination with docetaxel in the study, which is thought to be the first to examine whether a MEK inhibitor in combination with chemotherapy is superior to chemotherapy alone.

The result is a disappointment for AZ - which has long been highlighting the drug as one of its growth drivers for the coming years - as well as for cancer patients and their doctors, as KRAS-positive NSCLC is considered a pressing clinical need. 

KRAS is one of the most common mutations seen in NSCLC - occurring in around a third of patients - and typically causes adenocarcinoma tumours that are associated with a poor prognosis and limited treatment options. At the moment there is no approved therapy for KRAS-positive NSCLC.

Moreover, it is not the first time that selumetinib has failed to pass muster in a late-stage trial. Last year AZ abandoned development of the drug in uveal melanoma, a rare form of eye cancer, based on the results of the SUMIT study.

The list of potential indications for selumetinib is now growing short, although AZ is still developing the MEK inhibitor as a treatment for differentiated thyroid cancer - claiming orphan status for this indication in the US in May - as well as neurofibromatosis type 1, a rare genetic disorder that causes tumours to grow along nerves.

While a setback, selumetinib is not among the biggest prospects in AZ's oncology pipeline, with initial prospects in NSCLC somewhat dampened by the performance of immuno-oncology drugs in that setting. 

It has been anticipated that checkpoint inhibitors such as Bristol-Myers Squib's Opdivo (nivolumab) and Merck & Co's Keytruda (pembrolizumab) - which have been remarkable successful as second-line therapies in NSCLC - would move first-line with targeted therapies such as selumetinib used later. (Opdivo's prospects as a first-line therapy have however been dented by the results of the CheckMate-026 trial this week).

Nevertheless, AZ's portfolio of new cancer drugs includes recently-approved third-generation EGFR inhibitor Tagrisso (osimertinib) for NSCLC, PARP inhibitor Lynparza (olaparib) for ovarian cancer and PD-L1-targeting immuno-oncology drug durvalumab, which has also shown promise in NSCLC in combination with CTLA-4 inhibitor tremelimumab.

"We remain committed to further developing treatments in the lung cancer setting, such as our immunotherapy combinations and targeted EGFR treatments," said AZ's chief medical officer Sean Bohen.

The SELECT-1 failure is also a blow to Array BioPharma, which originally discovered selumetinib and licensed it to AZ in 2003.

Article by
Phil Taylor

9th August 2016

From: Research, Regulatory



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