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

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

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).

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.

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