AZ's ATR inhibitor ceralasertib flunks lung cancer test

AstraZeneca has had a setback in its late-stage oncology pipeline, after AKT inhibitor ceralasertib, given in combination with cancer immunotherapy Imfinzi, failed to extend survival in a lung cancer study.

The phase 3 LATIFY trial is investigating the dual regimen as a second-line option, after frontline immunotherapy plus chemotherapy, in a broad population of non-small cell lung cancer (NSCLC) without alterations that would make them eligible for targeted therapies.

Patients were randomised to either ceralasertib plus PD-L1 inhibitor Imfinzi (durvalumab) or docetaxel, a standard second-line treatment option. According to an AZ statement issued this morning, there was no statistically significant difference between the groups on overall survival, although the dual treatment was well-tolerated.

ATR is a kinase involved in the cellular response to DNA damage and has been a major target for pharma companies hoping to develop new cancer therapies based on the concept of 'synthetic lethality.' That is a targeted strategy based on closing off a survival escape route for malignant cells with a particular mutation, which came to the fore with PARP inhibitor drugs, including AZ's pioneering Lynparza (olaparib), for BRCA-mutated tumours.

The disappointing result with ceralasertib isn't the first for the drug, coming after AZ abandoned a study of the drug in skin cancer melanoma, and follows setbacks with other ATR inhibitors, including Bayer's elimusertib, which was discontinued in 2023, and Merck KGaA's berzosertib, which started clinical trials in 2020 and has also been shelved.

Last year, Roche handed back rights to Repare Therapeutics candidate camonsertib, ending a deal that involved upfront fees of $125 million and up to $1.2 billion in downstream payments, although Repare pledged to continue its development.

Repare made no mention of the drug in its second quarter update and is now in the throes of a proposed acquisition by XenoTherapeutics in a deal whose objectives include the sale of camonsertib to another developer.

According to the clinicaltrials.gov registry, a further 630-patient phase 3 trial of ceralasertib and Imfinzi as adjuvant therapy for NSCLC is recruiting patients and is due to generate results in 2028. AZ has not provided an update on that trial, or a phase 2 programme in solid tumours that is also listed in its pipeline.

"Our goal in the LATIFY trial was to reinvigorate the immune response of patients with lung cancer whose tumours stopped responding to available therapies by combining ATR inhibition with immunotherapy," commented the company's head of oncology and haematology R&D, Susan Galbraith.

"While we are disappointed by this result, we remain committed to pioneering new medicines to address the urgent need to improve outcomes for patients with lung cancer through our industry-leading portfolio," she added.

Photo by Everett Bartels on Unsplash