Immune profiling of stage III non-small cell lung cancer patients treated with concurrent chemoradiation and adjuvant durvalumab: A prospective observational phase II trial

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
(53-56).

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

Hypothesis: Our hypothesis is that we can identify immune changes in stage III
NSCLC patients receiving concurrent chemoradiation with protons or photons
followed by durvalumab, as is done in standard clinical practice in The
Netherlands.

Primary Objective:
To identify immune changes between baseline, one week of radiotherapy, end of
radiotherapy and three months of durvalumab
- Identification of differentially expressed proteins at all time points
- Identification of differentially expressed genes at all time points
- Investigate the functional immunological activity of serum samples at all
time points
- Investigate the immune cell composition in blood samples from all time points

Secondary Objectives:
- To investigate the progression-free survival (PFS)
- To investigate the overall survival (OS)
- To evaluate toxicity during and after concurrent chemoradiation, also in
relation to the irradiated bone marrow volume:
o Lymphopenia and subtypes
o Neutropenia
o Anemia
o Other toxicity
o Dose and intensity of chemotherapy (i.e. dose delays/reductions)
- To evaluate toxicity of durvalumab and chemoradiation treatment:
o Pneumonitis
o Cardiac side effects
o Cognitive side effects
- Incidence and severity of adverse events (Common Terminology Criteria for
Adverse Events (CTCAE) v 5.0 and patient reported outcome (PRO)-CTCAE)
- To investigate immune changes that are distinct for proton therapy compared
to photon therapy
- To evaluate the effects of protons versus photons on the occurrence of cancer
cachexia/sarcopenia
- To evaluate whether a higher percentage of patients treated with protons will
be able to receive adjuvant durvalumab, compared with photon treated patients
- Obtaining routine imaging (chest-CTs, 18FDG-PET, brain MRI/CTs) for
qualitative and quantitative image analyses.
- To evaluate the effect of durvalumab and chemoradiation on the cardiac
function: BNP, Troponins, ECG, blood pressure
- To evaluate the effect of durvalumab and chemoradiation on neurocognitive
function: HVALT-R, trail making test, controlled oral word association, and MOS
- Obtaining tumor material from standard diagnostic material for translational
purposes
- To investigate the genetic and phenotypic tumor heterogeneity of the tumor
biopsy
- Biobanking blood samples for later translational research
- To detect circulating tumor DNA (ctDNA) to determine minimal residual disease
- To evaluate the effect of durvalumab after photon and proton therapy on
LC3/GABARAPL protein family in the blood

This is a prospective, non-randomized observational phase II non-interventional
clinical trial.

Patients with stage III NSCLC who are eligible for curative intent concurrent
chemotherapy and radiotherapy will be enrolled in the study. They receive
standard radiotherapy (60 Gy in 30 fractions of 2 Gy) with protons or photons
according to the standard of care. Eligible patients will thereafter receive
standard durvalumab immune therapy for 12 months. Eligibility criteria for this
study are therefore similar to those for standard of care treatment.

The risk of the investigations in this trial (ECG's, blood pressure and blood
withdrawals) are minimal. The biggest burden for participants may be the time
needed for these investigations.