Durvalumab After chemoRadioTherapy for NSCLC patients Background

Approximately one third of patients with non–small-cell lung cancer (NSCLC) have stage III, locally advanced disease at diagnosis [1]. The standard of care for patients with a good performance status and unresectable stage III NSCLC is platinum-based doublet chemotherapy concurrent with radiotherapy (chemoradiation). If the tumour is PD-L1 positive, the patient is eligible for adjuvantimmunotherapy for one year.

Clinical studies have demonstrated increased overall survival for stage III lung cancer patients treated with the PDL1-inhibitor durvalumab after chemoradiation. This treatment is now available in Norway for PD-L1 positive patients. As not all patients benefit, there is an urgent need for better and more standardized biomarkers predicting which patients are most likely to benefit. In this clinical study, patients will be treated with durvalumab after chemoradiation (PD-L1 positive and negative). We will collect biological material and imaging data, aiming at identifying robust biomarkers predictive of response.

Hypothesis, aims and objectives

Our main aim is to identify prognostic and predictive biomarkers for effect of chemoradiation followed by durvalumab treatment for stage III patients with NSCLC eligible for curatively intended chemoradiation. In order to identify biomarkers, we need to elucidate the biology responsible for the response to durvalumab in the adjuvant setting, or the lack thereof. Our hypothesis is that the immunological microenvironment in the tumour influences responses, and that more lung cancer patients are cured.

• Primary objectives:

1. To investigate the immunological response, tumour development (if present) and dynamics in the tumour micro-environment and in circulation. This includes the following:
   - Evaluation of immune cell infiltration in the primary tumour and in the relapse tumour (if present)
   - Evaluation of circulating biomarkers related to tumour (ctDNA) and host response (immune cells / CYTOF analyses)
   - Evaluations of genomic (gene expression and genetic alterations) characteristics of the primary tumour and the relapse (if present)
2. To investigate tumour mutational burden in tumour tissue and blood samples, as predictors for clinical response
3. To evaluate imaging protocols for response prediction. PET-CT will be part of screening prior to durvalumab treatment. All patients have PET prior to chemoradiation. PET will be included after chemoradiation and after 12 months
4. To investigate potential changes in gut microbiota in serial samples from patients treated with durvalumab and investigate whether microbiota profile prior to, or dynamic changes during treatment can predict clinical outcome and treatment response

• Secondary objectives:

1. To evaluate toxicity in lung cancer patients receiving PDL1-inhibitor after chemoradiotherapy
2. To evaluate progression-free survival and overall survival