Immune Profiling of Stage III Non-small Cell Lung Cancer Patients Treated With Concurrent Chemoradiation and Adjuvant Durvalumab: A Prospective Observational Phase II Trial

Study Overview
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Brief Summary
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Currently, there is only limited data available on the functional immune changes after concurrent chemoradiation in NSCLC (non-small cell lung cancer) patients. Identifying the effect of the treatment on immune cells and what their functional consequences are is an essential first step to come to prognostic and predictive biomarkers. Many studies investigating the role of immunomodulatory effects of treatment are carried out in either in vitro or in vivo animal models. However, identified factors frequently hamper clinical validation. In addition, as mentioned earlier, although several immunogenic factors have been shown to be released by irradiated tumor cells, so far, only a limited number of studies searched for potential predictive and prognostic immunological biomarkers. This will be the first time that the immune effects of both treatment modalities will be studied, with, in addition, the immune changes during durvalumab treatment, which are also unknown at present. By getting more insight in the treatment-induced immunomodulatory effects, ultimately, in subsequent projects, this will allow to determine optimal immune stimulation and hence improved outcomes of subsequent durvalumab immune therapy.

Detailed Description
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Even with the addition of durvalumab to concurrent chemoradiation, approximately only half of the patients are alive at 3 years, and more have progressed already, either locally or distant. Not much is known regarding to identification of patients that will benefit from adjuvant durvalumab, or regarding resistance to adjuvant durvalumab after chemoradiation. Most data on immunotherapy resistance come from metastatic patients treated with monotherapy PD-(L)1 antagonists. Depending on PD-L1 expression level, 10-44% of patients respond well to PD-(L)1 antagonists. The majority of patients are either unresponsive, or experience a tumor recurrence after achieving an initial response. The development of individual immunological treatment strategies (e.g. selection of best treatment: mono- or combination ICI, ICI combined with chemotherapy, or the addition of radiotherapy) is hampered by the lack of knowledge in the best timing, sequencing, and dosing of all modalities and the lack of optimal biomarkers for monitoring the treatment response. This highlights the need of clear biomarkers that can be used to select the best treatment for each individual patient and predict whether patients will benefit from adjuvant immunotherapy. Currently, there is only limited data available on the functional immune changes after concurrent chemoradiation in NSCLC patients. Identifying the effect of the treatment on immune cells (e.g. T-, B-, NK-cells, dendritic cells, macrophages) and what their functional consequences are is an essential first step to come to prognostic and predictive biomarkers. Many studies investigating the role of immunomodulatory effects of treatment are carried out in either in vitro or in vivo animal models. However, identified factors frequently hamper clinical validation. In addition, as mentioned earlier, although several immunogenic factors have been shown to be released by irradiated tumor cells, so far, only a limited number of studies searched for potential predictive and prognostic immunological biomarkers. This will be the first time that the immune effects of both treatment modalities will be studied, with, in addition, the immune changes during durvalumab treatment, which are also unknown at present. By getting more insight in the treatment-induced immunomodulatory effects, ultimately, in subsequent projects, this will allow to determine optimal immune stimulation and hence improved outcomes of subsequent durvalumab immune therapy.

Official Title
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Immune Profiling of Stage III Non-small Cell Lung Cancer Patients Treated With Concurrent Chemoradiation and Adjuvant Durvalumab: A Prospective Observational Phase II Trial

Conditions
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Carcinoma, Non-Small-Cell Lung

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathological diagnosis of adequately staged (according to standard practice using chest-CT, FDG-PET, brain imaging MRI/CT) NSCLC Participant is willing and able to give informed consent for participation in the trial Male or female, aged 18 years or above Scheduled to receive one of the following two therapeutic strategies: Concurrent chemotherapy and radiotherapy with photons (60 Gy in 30 fractions of 2 Gy) in patients with stage III NSCLC Concurrent chemotherapy and radiotherapy with protons (60 Gy in 30 fractions of 2 Gy) in patients with stage III NSCLC Is able and willing to comply with all trial requirement Exclusion Criteria: Mixed non-small cell lung cancer with other histologies such as small cell lung cancer Not able to comply with the study protocol Less than 18 years' old Pregnancy or not able to comply with adequate contraception in women with child baring potential Previous radiotherapy to the chest for benign or malignant conditions, including radiation for breast cancer Previous malignancy treated with chemotherapy, immune therapy or radiotherapy (irrespective of when this happened) Previous malignancies treated with surgery only are allowed if 2 years or more before inclusion in the present study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Proton<br>Patients receiving proton therapy | |
| Photon<br>Patients receiving photon therapy in 4 fractions or less | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune changes | Number of patients with immune changes in stage III NSCLC patients receiving concurrent chemoradiation with protons or photons followed by durvalumab. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression Free Survival | 12 months | 
| OS | Overall survival | 12 months | 
| Toxicity chemoradition | - Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during and after concurrent chemoradiation, also in relation to the irradiated bone marrow volume | until 3 months after chemo/radiotherapy | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during courses of Durvalumab | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 of durvalumab and chemoradiation treatment | Until 12 months after chemo/radiotherapy | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Incidence and severity of adverse events (Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 and patient reported outcome (PRO)-CTCAE) | Until 12 months after chemoradiation | 
| Immune changes compared | Number of patients with immune changes that are distinct for proton therapy compared with photon therapy | Until 12 months after chemoradiation | 
| Cardiac function | Troponins | Until 12 months after chemoradiation | 
| Cardiac function | ECG QT Interval | Until 12 months after chemoradiation | 
| Cardiac function | blood pressure | Until 12 months after chemoradiation | 
| Cardiac function | BNP | Until 12 months after chemoradiation | 
| Neurocognitive function test | MOS | Until 12 months after chemoradiation | 
| Neurocognitive function test | Controlled oral word association | Until 12 months after chemoradiation | 
| Neurocognitive function test | Trail making test | Until 12 months after chemoradiation | 
| Neurocognitive function test | HVALT-R test | Until 12 months after chemoradiation | 
| Tumor material | Obtaining tumor material from standard diagnostic material for translational purposes | Until 12 months after chemoradiation |