This is a randomized trial evaluating the efficacy and safety of sequential dual-agent immunotherapy and risk-adapted radiotherapy for patients with locally advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score of at least 50%. Participants will be randomized between two dual-agent immunotherapy regimens: durvalumab + monalizumab versus durvalumab + oleclumab.
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
Patient is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations, including follow-up.
Age > 18 years at time of study entry
Body weight ≥35 kg
Participation in another clinical study with an investigational product during the last 3 months
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment on this study may be included after consultation with the Study Physician.
Parallel
Durvalumab
DrugDurvalumab is a human mAb of the immunoglobulin G 1 kappa subclass that blocks the interaction of PD-L1 (but not PD-L2) with PD 1 on T cells and CD80 (B7.1) on immune cells.
Monalizumab
DrugMonalizumab is a humanized mAb of the IgG4 subtype that specifically binds and inhibits Cluster of Differentiation 94 (CD94)/NK cell protein group 2 A(NKG2A).
Oleclumab
DrugOleclumab is a human IgG1λ mAb that selectively binds to and inhibits the ectonucleotidase activity of CD73.
Radiotherapy
RadiationPET based dose painted radiotherapy. If these treatment techniques are not available for some reason treatment may be delivered using a sequential boost technique (2.75 Gy x 17 to the low-risk PTV followed by 2.75 Gy x 3 to the high-risk planning target volume).
Response rate observed using FDG-PET imaging
Response rate will be assessed using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria prior to radiotherapy initiation. Response rate will be defined as a ≥ 30% decline in maximum standardized uptake value (SUV) without development of new disease sites. Response rates, which include partial metabolic responses and complete metabolic responses, will be presented as a count and percentage for each study arm. Participants who do not undergo FDG-PET after completion of induction immunotherapy (e.g., due to clinical disease progression, toxicity, or death) will be counted as non-responders.
Response rates observed using Computed Tomography (CT)
Response rates will also be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria prior to radiotherapy initiation. Response rates, which include partial responses and complete responses, will be presented as a count and percentage for each study arm, along with a 95% Clopper-Pearson exact confidence interval. Participants who do not undergo imaging after completion of induction immunotherapy (e.g., due to clinical disease progression, toxicity, or death) will be counted as non-responders.
Progression free survival (PFS)
PFS duration will be defined for each participant as the interval from the date of randomization to the first date of documented disease progression or death due to any cause, whichever occurs first. Subjects who die without reported progression will be considered to have the PFS event on the date of their death. Subjects who do not progress or die will be censored on the date of their last evaluable tumor assessment or clinic visit. PFS duration will be summarized for each study arm and estimated using the Kaplan-Meier product-limit method.
Overall survival (OS) rates
OS duration will be defined for each participant as the interval from the date of randomization to the date of death due to any cause. Subjects who do not die will be censored on the date of their last evaluable tumor assessment or clinic visit. OS duration will be summarized for each study arm and estimated using the Kaplan-Meier method.
Rates of disease progression during treatment
Rates of disease progression during induction dual-agent immunotherapy and before initiation of thoracic radiotherapy will be assessed using a binary ("Yes" or "No") outcome. PET/CT and/or biopsy to confirm disease progression may be performed, at the discretion of the treating physicians. In some cases, disease progression may be detected by other means (e.g., thoracentesis demonstrating malignant effusion). Rates of disease progression will be summarized and reported for each arm as counts and percentages.
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Montefiore Medical Center
Lead sponsor
AstraZeneca
Collaborator
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