A Global Study to Assess the Effects of Durvalumab With Oleclumab or Durvalumab With Monalizumab Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer

• Durvalumab (Drug): Durvalumab IV (intravenous infusion)
• Oleclumab (Drug): Oleclumab IV (intravenous infusion)
• Monalizumab (Drug): Monalizumab IV (intravenous infusion)
• Placebo (Other): Placebo IV (intravenous infusion)

Primary outcomes

• Progression Free Surival (PFS) [Up to 5 years after first patient randomized.]: Progression Free Survival (PFS) as assessed by BICR, per RECIST 1.1.

Secondary outcomes

• Overall Survival (OS) [Up to 9 years after first patient randomized]: Overall survival (OS)
• Objective response rate (ORR) [Up to 5 years after first patient randomized]: Objective response rate (ORR) per RECIST 1.1 as assessed by BICR
• Overall survival (OS) at 24 months [Up to 9 years after first patient randomized]: Overall survival (OS) at 24 months
• Duration of response (DoR) [Up to 5 years after first patient randomized]: Duration of response (DoR) per RECIST 1.1 as assessed by BICR
• Progression free survival (PFS) at 6, 12, 18, and 24 months [From date of randomization until 24 months]: Progression free survival (PFS) at 6, 12, 18, and 24 months respectively, per RECIST 1.1 as assessed by BICR
• Time from randomization to second progression (PFS2) [Up to 5 years after first patient randomized]: Time from randomization to second progression (PFS2)
• Time from randomization to first date of distant metastasis or death (TTDM) [Up to 5 years after first patient randomized]: Time from randomization to first date of distant metastasis or death (TTDM)
• Time from randomization to start date of first subsequent therapy (TFST) [Up to 9 years after first patient randomized]: Time from randomization to start date of first subsequent therapy (TFST)
• Progression free survival (PFS) as assessed by Investigator [Up to 5 years after first patient randomized]: Progression free survival (PFS) as assessed by Investigator
• IHC analysis of PD-L1 TC expression [Up to 5 years after first patient randomized]: IHC analysis of PD-L1 TC expression relative to efficacy outcomes
• Concentration of Durvalumab [From date of randomization until 3 months after date of last IP dose]: To assess the Pharmacokinetics of Durvalumab when in combination with Monalizumab or Oleclumab - serum peak and trough concentrations
• Anti-drug antibodies (ADAs) [From date of randomization until 3 months after date of last IP dose]: The immunogenicity of durvalumab, oleclumab, and monalizumab as assessed by presence of anti-drug antibodies (ADAs)
• Time to deterioration in pulmonary symptoms (TTFCD) [Up to 5 years after last patient randomized]: Time to deterioration in pulmonary symptoms (TTFCD)
• Concentration of Oleclumab [From date of randomization until 3 months after last dose of IP]: To assess the Pharmacokinetics of Oleclumab when in combination with Durvulumab - serum peak and trough concentrations
• Concentration of Monalizumab [From date of randomization until 3 months after last dose of IP]: To assess the Pharmacokinetics of Monalizumab when in combination with Durvalumab - serum peak and trough concentrations

Sex: All, ages: 18 Years to any

INCLUSION CRITERIA:

* Participant must be ≥ 18 years at the time of screening.
* Histologically- or cytologically-documented NSCLC and have been treated with concurrent CRT for locally advanced, unresectable (Stage III) disease
* Provision of a tumour tissue sample obtained prior to CRT
* Documented tumour PD-L1 status by central lab
* Documented EGFR and ALK wild-type status (local or central).
* Patients must not have progressed following definitive, platinum based, concurrent chemoradiotherapy
* Participants must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy
* Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique.
* WHO performance status of 0 or 1 at randomization
* Adequate organ and marrow function

EXCLUSION CRITERIA:

* 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 and of low potential risk for recurrence, adequately resected non-melanoma skin cancer and curatively treated in situ disease, or adequately treated carcinoma in situ or Ta tumours without evidence of disease.
* Mixed small cell and non-small cell lung cancer histology.
* Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced (Stage III) unresectable NSCLC.
* Participants with locally advanced (Stage III) unresectable NSCLC who have progressed during platinum-based cCRT.
* Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy (excluding alopecia).
* Participants with ≥grade 2 pneumonitis from prior chemoradiation therapy.
* History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or idiopathic pneumonitis - regardless of time of onset prior to randomisation. Evidence of active non-CRT induced pneumonitis (≥ Grade 2), active pneumonia, active ILD, active or recently treated pleural effusion, or current pulmonary fibrosis - diagnosed in the past 6 months prior to randomization.
* Active or prior documented autoimmune or inflammatory disorders (with exceptions)
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.

102 more sites not listed.

• Results publication: Barlesi F, Cho BC, Goldberg SB, Yoh K, Zimmer Gelatti AC, Mann H, Gopinathan A, Bielecka ZF, Newton M, Aggarwal C. PACIFIC-9: Phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer. Future Oncol. 2024;20(29):2137-2147. doi: 10.1080/14796694.2024.2354160. Epub 2024 Jul 18. PMID 39023287

• Fabrice Barlesi, MD, Principal investigator, Gustave Roussy, Cancer Campus, Grand Paris

NIH grants: 2023