Immune Profiling of Stage III Non-small Cell Lung Cancer Patients Treated With Concurrent Chemoradiation and Adjuvant Durvalumab: A Prospective Observational Phase II Trial (IPON-1)

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.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

• Study Contact: Name: Chantal Overhof; Phone Number: +31 88 44 55 686; Email: chantal.overhof@maastro.nl
• Study Contact Backup: Name: Sylvie Canisius; Phone Number: +31 88 44 55 686; Email: sylvie.canisius@maastro.nl

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6229 ET
    • Recruiting
    • Maastricht Radiation Oncology (MAASTRO clinic)
    • Contact: Dirk De Ruysscher, Dr.; Phone Number: 31-88-445-5666; Email: dirk.deruysscher@maastro.nl
    • Principal Investigator: Dirk De Ruysscher, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Proton; Patients receiving proton therapy
Photon; Patients receiving photon therapy in 4 fractions or less

What is the study measuring?

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
OS	Overall survival	12 months
PFS	Progression Free 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

Collaborators and Investigators

• Sponsor: Maastricht Radiation Oncology
• Investigators: Principal Investigator: Dirk De Ruysscher, MD, PhD, Maastro

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: June 9, 2020
• First Submitted That Met QC Criteria: June 11, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): August 23, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: IPON-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No