Immunotherapy, Chemotherapy, Radiotherapy and Surgery for Synchronous Oligo-metastatic NSCLC

Non-small Cell Lung Cancer Clinical Trial

— CHESS  

Official title:

A Multicentre Single Arm Phase II Trial Assessing the Efficacy of Immunotherapy, Chemotherapy and Stereotactic Radiotherapy to Metastases Followed by Definitive Surgery or Radiotherapy to the Primary Tumour, in Patients With Synchronous Oligo-metastatic Non-small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03965468
• Other study ID #: ETOP 14-18
• Secondary ID: 2018-003011-22ES
• Status: Recruiting
• Phase: Phase 2
• Start date: November 19, 2019
• Est. completion date: December 2026

Study information

• Verified date: May 2024
• Source: ETOP IBCSG Partners Foundation
• Contact: Barbara Ruepp, PharmD
• Phone: +41315119400
• Email: barbara.ruepp[@]etop.ibcsg.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A multicentre single arm phase II trial assessing the efficacy of immunotherapy, chemotherapy plus stereotactic radiotherapy to metastases followed by definitive surgery or radiotherapy to the locoregional primary tumour, in patients with histologically-confirmed synchronous oligo-metastatic non-small cell lung cancer (NSCLC).

Description:

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer-related mortality worldwide. Even with adjustment for age NSCLC is responsible for almost 20% of cancer-related deaths. Recent years have brought tremendous progress in the understanding of the disease, its underlying biology and the development of effective therapies. Traditionally, NSCLC has been treated with surgery, platinum-based chemotherapy or radiotherapy alone or in combination, depending on tumour stage, tolerability of expected side effects and prognosis. Various strategies are currently being pursued in order to increase the patient population that may benefit from immunotherapy and to further improve the outcome of patients with NSCLC.

The CHESS clinical trial is for patients with NSCLC that has progressed to a small number of other parts of the body (oligo-metastatic) and has not been previously treated, or after surgical resection of a single metastasis (central nervous system or adrenal). The trial aims to reduce the risk of systemic progression and thereby improve progression free survival. Participants will receive induction treatment consisting of immunotherapy combined with platinum-based doublet chemotherapy and stereotactic body radiotherapy (SBRT) that will be given to all oligo-metastatic locations. SBRT started early and concurrently with immunotherapy aims at enhancing a postulated immune effect and simultaneously effectively control the macro-metastases.

Preclinical data have shown a strong immune-enhancing effect of radiotherapy, especially when delivered to small volumes, in high-single fraction doses and over a short period of time. Consequently, stereotactic body radiotherapy (SBRT) is currently being intensively investigated as a partner for systemic immunotherapy. Earlier clinical studies generated proof-of-principle data for the synergistic effects of combined radiotherapy and immunotherapy. Chemotherapy and high-dose radiotherapy are well known triggers of immunogenic cell death and are therefore highly promising partners for combination with immunotherapy.

The sub-group of patients with "oligometastatic" disease was originally described by Hellman and Weichselbaum in 1995. In line with this concept, the current NCCN and ESMO guidelines describe that Stage IV NSCLC patients presenting with solitary metastases can be treated with curative intent using local surgery and/or radiotherapy. Local treatment for oligo-metastatic NSCLC has been adopted rapidly in the oncological community and one reason is the progress made in the fields of surgery and radiotherapy, both becoming less toxic (minimally invasive surgery) and simultaneously less toxic and more effective (precision radiotherapy), respectively. SBRT allows treatment of small peripheral primaries and metastases at virtually all anatomical locations with a favourable therapeutic ratio of local tumour control rates >90% and low rates of toxicity. Simultaneously, minimally invasive surgery for early and locally advanced NSCLC today achieves excellent local tumour control with low rates of toxicity.

Patients with a limited number of metastases - oligometastatic disease - are currently treated with combined radical local treatment for all active lesions (locoregional primary and metastases) and their prognosis is better as compared to patients who receive systemic treatment only for widespread metastatic disease. However, the majority of patients still develop systemic disease progression indicating the urgent clinical need for more effective systemic treatment to control subclinical disease.

All CHESS trial participants will receive induction treatment with the immunotherapy drug durvalumab, standard platinum-chemotherapy and radiation therapy of the lung cancer metastases (SBRT). Durvalumab is a human monoclonal antibody carefully engineered to attach to immune cells to stimulate their activity against cancer cells. There are now several approved antibodies for the treatment of cancer or other diseases. Standard platinum-chemotherapy includes treatment with carboplatin and paclitaxel.

After three months of induction treatment the status of the lung cancer will be restaged. If the primary lung cancer is stable or has not increased in size it will be surgically removed if possible or, alternatively, treated with radiation therapy. Treatment with durvalumab will continue until the disease relapses or for a maximum of one year from the start of induction treatment. If the lung cancer has increased in size at the time of the three month restaging all trial treatment will stop and the study doctor will discuss other treatment options that are available.

The efficacy, safety and tolerability of combining immunotherapy with standard platinum-chemotherapy and SBRT will be evaluated in the CHESS clinical trial.

Encouraged by the positive results of the POSEIDON trial, we amended the CHESS protocol to include a second cohort of additional 47 patients who will receive tremelimumab, in addition to the protocol treatment of the original CHESS protocol (e.g., durvalumab, platinum-based doublet chemotherapy, and SRBT to the oligo-metastatic lesions, followed by definitive local treatment for patients that have not progressed at the time of restaging).

Objectives and endpoints, patient selection and statistical assumption remain the same as for cohort 1 in the original protocol.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 96
• Est. completion date: December 2026
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed non-small cell lung cancer

• Synchronous oligo-metastatic stage IV disease: maximum of three distant metastases, one of which must be extra-cerebral for stereotactic body radiotherapy (SBRT); Initial mediastinal staging is recommended (except for lymph nodes <1 cm on CT and PET-negative) preferentially by endobronchial ultrasound (EBUS); Neurosurgical resection of one single central nervous system (CNS) metastasis or laparoscopic resection of one adrenal metastasis before study inclusion is allowed (one extra-cerebral metastasis must be available for SBRT)

• Able to understand and give written informed consent and comply with study procedures

• Age =18 years

• ECOG Performance Status 0-1

• Availability of tumour tissue for translational research

• Adequate haematological, renal and liver function

Exclusion Criteria:

• Prior chemotherapy, radiotherapy or therapeutic surgery for NSCLC (an exception is the resection of one single CNS or adrenal metastasis, as above)

• Activating driver mutation: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), proto-oncogene receptor tyrosine kinase (ROS1)

• More than three distant metastases

• Brain metastases not amendable for radiosurgery or neurosurgery

• Extracranial metastatic locations such as malignant ascites, pleural or pericardial effusion, diffuse lymphangiomatosis of skin or lung, diffuse bone marrow metastasis, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques.

• Primary lung cancer not suitable for radical therapy (pneumonectomy excluded)

• History of leptomeningeal carcinomatosis

• Major surgery or significant traumatic injury from which the patient has not recovered at least 28 days before enrolment

• Any uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease or serious chronic gastrointestinal conditions associated with diarrhea, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol

• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc) at screening.

• Known positivity for human immunodeficiency virus (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)

• Active autoimmune disease requiring systemic treatment

• Severe or uncontrolled cardiac disease requiring treatment

• History of active primary immunodeficiency

• History of allogeneic organ transplant

• Receipt of live attenuated vaccines within 30 days prior to enrolment

• Known allergies or hypersensitivity to trial drugs or to any excipient.

• Women who are pregnant or in the period of lactation.

• Sexually active men and women of childbearing potential who are not willing to use a highly effective contraceptive method during the trial and up to 90 days after last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer
• Oligometastasis
• Stage IV

Intervention

Drug:
• Durvalumab
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1. Durvalumab is expected to stimulate the patient's antitumour immune response by binding to PD L1 and shifting the balance toward an antitumour response.
• Carboplatin
Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.
• Paclitaxel
A compound extracted from the Pacific yew tree Taxus brevifolia with antineoplastic activity. Paclitaxel binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2).

Radiation:
• Stereotactic body radiation therapy (SBRT)
SBRT of all oligo-metastatic lesions

Procedure:
• Surgical resection - definitive local treatment.
Surgical resection of primary tumour for patients with single station, non-bulky tumours.

Radiation:
• Radical radiotherapy - definitive local treatment.
Conventional or moderately hypo-fractionated radiotherapy to the primary tumour for other tumour stages, or in case of medical inoperability.

Drug:
• Tremelimumab
Tremelimumab is a human mAb of the IgG 2 subclass that is directed against CTLA-4 (CD152), a cell surface receptor that is expressed primarily on activated T-cells and acts to inhibit their activation. Tremelimumab completely blocks the interaction of human CTLA-4 with CD80 and CD86, resulting in increased release of cytokines (interleukin-2 and IFN-?) from human T-cells, peripheral blood mononuclear cells and whole blood.

Locations

Country	Name	City	State
Italy	European Institute of Oncology	Milano
Italy	Istituto Oncologico Veneto - Irccs	Padova
Italy	IRCCS Istituto Nazionale Tumori Regina Elena	Roma
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Erasmus Medical Centre	Rotterdam
Spain	Hosp. De la Santa Creu i Sant Pau	Barcelona
Spain	Hosp. Uni. Virgen de las Nieves	Granada
Spain	Hosp. Sanchinarro- Centro Integral Oncología Clara Campal	Madrid
Spain	Vall d'Hebron University Hospital	Madrid
Spain	Hosp. Uni. Politécnico La Fe	Valencia
Switzerland	Inselspital Bern	Bern
Switzerland	Geneva University Hospital	Geneva
Switzerland	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne
Switzerland	University Hospital Zurich	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation	AstraZeneca

Countries where clinical trial is conducted

Italy,  Netherlands,  Spain,  Switzerland, 

References & Publications (10)

Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016 Aug;13(8):516-24. doi: 10.1038/nrclinonc.2016.30. Epub 2016 Mar 8. — View Citation

Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017 Feb;17(2):97-111. doi: 10.1038/nri.2016.107. Epub 2016 Oct 17. — View Citation

Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, Demaria S, Formenti SC. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 2015 Jul;16(7):795-803. doi: 10.1016/S1470-2045(15)00054-6. Epub 2015 Jun 18. — View Citation

Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10. doi: 10.1200/JCO.1995.13.1.8. No abstract available. — View Citation

Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer. 2016 Sep 20;4:51. doi: 10.1186/s40425-016-0156-7. eCollection 2016. — View Citation

Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10. — View Citation

Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8. — View Citation

Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, Chow LQ, Gerber DE, Laurie SA, Goldman JW, Shepherd FA, Chen AC, Shen Y, Nathan FE, Harbison CT, Antonia S. Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Sep 1;34(25):2969-79. doi: 10.1200/JCO.2016.66.9861. Epub 2016 Jun 27. — View Citation

Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9. — View Citation

Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011 Jun;8(6):378-82. doi: 10.1038/nrclinonc.2011.44. Epub 2011 Mar 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival at 12 months	The PFS rate at 1-year is the primary endpoint of this trial and it is defined as the rate of patients without a PFS event at 1-year after enrolment. The rate will be estimated as the percentage of patients without a PFS event over the total number of patients who have completed a 1-year follow-up period after the enrolment. PFS is defined as the time from the date of enrolment until documented progression or death, if progression is not documented. Progression is defined as the development of new metastatic lesions or local progression of resected or irradiated metastases or primary tumour, assessed according to RECIST criteria version 1.1	Assessed from the date of enrolment to completion of treatment at 12 months.
Secondary	Overall survival	Overall survival (OS) is defined as the time from the date of enrolment until death from any cause. Censoring for OS (patients without reported death) will occur at the last follow-up date.	Time from date of enrolment until death from any cause. Assessed for up to 30 months.
Secondary	Pattern of disease progression	Defined as the site of first progression. None, locoregional, distant, or both locoregional and distant.	Assessed from the date of enrolment until progression, from enrolment up to 12 months.
Secondary	Response to induction therapy	Defined as the best overall response [complete response (CR) or partial response (PR)] according to RECIST 1.1 criteria.	Assessed from the start of protocol treatment until the 3-month restaging
Secondary	Distant progression-free survival	Defined as the date of development of new metastases, excluding oligometastasis diagnosed at enrolment.	Assessed from the date of enrolment for up to 12 months.
Secondary	Overall response	Defined as best overall response [complete response (CR) or partial response (PR) according to RECIST 1.1 criteria.	Assessed from the start of protocol treatment across all time points until the end of follow-up, assessed for up to 30 months.
Secondary	Duration of response	Defined as the interval from the date of first documentation of objective response (CR or PR), according to RECIST 1.1 criteria to the date of first documented progression, relapse or death from any cause.	Assessed from the date of enrolment for up to 12 months.
Secondary	Symptom-specific and global quality of life: The Lung Cancer Symptom Scale	The Lung Cancer Symptom Scale, a 9-item one page questionnaire will be used to assess change in total score (average of all 9 items).	Assessed at trial entry, until 6 months after treatment start and at 12 months from enrolment.
Secondary	Toxicity before and after surgery/radiotherapy	Safety parameters will be assessed in terms of adverse events graded by CTCAE v5.0 including events leading to dose interruptions, withdrawals of protocol treatment and death; severe, serious and selected adverse events; deaths; clinically significant laboratory parameters and abnormalities, and vital signs.	Adverse events will be collected from the date of consent until 90 days after the completion of treatment.