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AZ to address Imfinzi setback, but sees potential with Tagrisso

Pharma giant to deliver oncology pipeline update at AACR


AstraZeneca is expected to share some oncology pipeline developments towards the end of the month, providing updates on two of its biggest selling cancer assets Tagrisso and Imfinzi.

At the American Association for Cancer Research (AACR) Meeting in Atlanta, US, AZ intends to address Imfinzi’s latest setback as a first-line therapy in metastatic non-small cell lung cancer (NSCLC).

During the MYSTIC trial, Imfinzi failed to hit the mark on progression-free survival and overall survival endpoints, but AstraZeneca said it would try the drug’s luck as a monotherapy in those with a high tumour mutation burden (TMB).

Those who express a high TMB could carry more markers on the cancer cell surface that could make them vulnerable to cancer immunotherapy.

Bristol-Myers Squibb also followed a similar pattern with its PD-1 inhibitor Opdivo, after it failed in first-line NSCLC, but paired that drug up with its CTLA4 inhibitor Yervoy.

BMS ran into a hurdle with this combo earlier this year however, and pulled the marketing application in the US after the FDA requested for more information on TMB, PD-L1 expression and overall survival rates, casting a cloud over PD-L1 checkpoint inhibitor Imfinzi in this setting.

However, AZ has confirmed that Imfinzi did demonstrate clinical activity within the primary analysis, and claims MYSTIC is the only phase 3 randomised, controlled trial to demonstrate an association between high TMB and overall survival benefit.

Meanwhile, AZ has plans to expand the use of its biggest selling oncology asset Tagrisso, after it announced that is being tested with potential new medicines savolitinib or selumetinib in NSCLC patients who have progressed on prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment.

The TATTON trial supports SAVANNAH, an ongoing Phase 2 trial exploring the combination of Tagrisso and savolitinib to overcome MET-driven EGFR-TKI resistance following treatment with Tagrisso in EGFR-mutated (EGFRm) NSCLC.

Results from the TATTON trial will also inform the trial design of ORCHARD, a phase 2 platform trial which will explore potential new treatment options to address resistance mechanisms in patients with EGFRm NSCLC who have experienced disease progression following first-line treatment with Tagrisso.

“AstraZeneca is continuing to strengthen its portfolio of innovative cancer medicines by exploring new indications and developing a pioneering next-generation pipeline,” said José Baselga, Executive Vice President, Research & Development, Oncology.

“We will be sharing some of our latest research at the 2019 AACR Annual Meeting, including 28 new molecular entities and six combinations."

Baselga also confirmed that it will "highlight an exciting new phase of scientific discovery", in the form of a new wave of DNA Damage Response (DDR) targets.

Moving its DDR pipeline beyond PARP inhibition, AZ will share data on a potent and selective DNA-PK inhibitor, which is critical in repairing DNA double strand breaks through the non-homologous end joining (NHEJ) pathway.

“There are opportunities to combine a DNA-PK inhibitor with DNA double strand break inducing agents, and additional data will be shared on reversing PARP inhibitor resistance by targeting alternative DDR dependencies”, said AZ.

The drugmaker will also present some key data from small molecules and antisense oligonucleotides (ASOs) targeting immunosuppressive mechanisms in cancer, and the company’s exploration of the adenosine pathway, which “represents a new frontier within IO”.

Article by
Gemma Jones

14th March 2019

From: Research



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