This study will assess the efficacy and safety of the combination of ceralasertib and durvalumab versus standard of care docetaxel in patients with locally advanced and metastatic NSCLC after progression on prior anti-PD-(L)1 therapy and platinum-based chemotherapy.

This study will consist of two treatment arms (Groups A and B).

Participants will be randomised in a 1:1 ratio to one of the two treatment groups:

• Group A: Ceralasertib plus durvalumab combination therapy Each 28-day cycle will begin with ceralasertib administered orally followed by durvalumab administered intravenously.
• Group B: Docetaxel monotherapy Each 21-day cycle will begin with the administration of docetaxel.

Inclusion Criteria:

• Histologically or cytologically documented NSCLC that is locally advanced or metastatic according to Version 8 of the IASLC Staging Manual in Thoracic Oncology.
• Documented epidermal growth receptor factor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type status as determined at a local laboratory.
• Documented radiological PD whilst on or after receiving the most recent treatment regimen.
• Eligible for second- or third-line therapy and must have received an anti-PD-(L)1 therapy and a platinum doublet containing therapy for locally advanced or metastatic NSCLC either separately or in combination.
• Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0 or 1.
• Adequate organ function and marrow reserve
• Minimum life expectancy of 12 weeks.
• Body weight > 30 kg and no cancer-associated cachexia.
• Negative pregnancy test (serum test) for women of childbearing potential (WOCBP).

Exclusion Criteria:

• Participant with mixed SCLC and NSCLC histology.

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention.

• Persistent toxicities (CTCAE Grade > 2) caused by previous anticancer therapy.

• Active or prior documented autoimmune or inflammatory disorders.

• Participants who have received more than one line of prior anti-PD-(L)1, either alone or in any combination.

• Participants:

  1. Must not have experienced a toxicity that led to permanent discontinuation of the prior anti-PD(L)1 therapy.
  2. All AEs while receiving prior anti-PD(L)1 therapy must have completely resolved.
  3. Must not have experienced a Grade ≥ 3 immune-mediated adverse event (imAE) or an immune-related neurologic or ocular AE of any grade while receiving prior anti-PD(L)1 therapy.
  4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.

• Participants who have received more than one prior line of platinum-based chemotherapy in metastatic setting.

• Participants who have received a prior ataxia telangiectasia and Rad3-related protein (ATR) inhibitor.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.