This will be a phase II trial testing if the combination of stereotactic ablative body
radiotherapy (SABR) and L19-IL2 improve the progression-free survival in patients with
limited metastatic non-small cell lung cancer (NSCLC). The trial consists of one cohort with
two arms; C-arm and an E-arm.
Patients with oligometastatic disease will receive SABR to minimal 1 and max all metastatic
sites (max 5 sites irradiated) and patients with diffuse metastatic lesions (6 to max 10)
will receive radiotherapy to max 5 sites. In the experimental arm, immunotherapy will be
given after irradiation.
IMMUNOSABR will include 126 patients. In this single-stage controlled randomised open-label
phase II trial, we aim to demonstrate an absolute increase in progression-free survival
(primary endpoint). PFS will be determined as the time between randomisation and disease
progression, according to RECIST 1.1, death due to any cause or last patient contact alive
and progression-free. Patients will be randomized between control (no immunocytokine) and
experimental arms (with immunocytokine L19-IL2) in a 1:1 ratio. The accrual period will be 29
months (or 2.41 years), and the minimum follow-up will be 18 months (or 1.5 years), making
the total study duration 47 months. Comparison between control and experimental arms will be
made using the Log-Rank statistic. This test for superiority will be one-sided with the
desired type I error of 0.10 and power of 0.90.
Patients enrolled in the trial will be randomised into the control arm (C-arm) or
experimental arm (E-arm).
- C-arm: Standard of Care (SOC) according to the local and national guidelines: (wait and
see or surgery and/or chemotherapy and/or standard (symptomatic) radiotherapy and/or
SABR, oligometastatic disease.
- E-arm: SABR (oligometastatic disease) or radiotherapy (diffuse disease) + L19-IL2 up to
6 cycles (+ aPD(L)1 if SOC)
The expected 1.5-year PFS is 15% in the C-arm and 35% in the E-arm. A sample size of 116
patients (58 patients per treatment arm) is needed to show this difference of 20% in PFS,
using a logrank test with a two-sided alpha of 0.05 and power of 85%. Patients will be evenly
divided over the two arms. Assuming a drop-out rate of 10%, a total of 126 patients (63 per
arm) need to be included.
Primary objective The main objective of the trial is to test if the activity of the
combination of (SAB)R and L19-IL2 in patients with metastatic NSCLC will result in improved
progression-free survival (PFS) compared to the SOC.
Secondary Objectives
- Assessment of the PFS of the patient cohort, at 5 years after randomisation.
- Assessment of the overall survival of the patient cohort, at 5 years after
randomisation.
- To assess the toxicity of this treatment schedule;
- To assess Quality of Life (QoL);
- To assess the occurrence of an Out of Field Radio-Immune (OFRI) response / abscopal
effect using imaging;
- To assess the occurrence of an In Field Radio-Immune (IFRI) response using imaging;
- To perform correlative biomarker studies related to treatment response.
Exploratory endpoints:
- Correlative biomarker studies:
- Tumour tissue: e.g EDB expression, non-synonymous mutations, immune monitoring;
- Blood: e.g. EDB expression, cfDNA, and immune monitoring;
- Radiomics on CT and if available MRI;
- Faeces: diversity in microbiota.
- iRECIST
- Tumour grow kinetics
Inclusion criteria
Oligometastatic disease (≤5 metastases)
- Histological confirmed limited metastatic adult NSCLC patients, regardless of the
PD-L1 status.
- Maximum of 5 metastatic lesions, maximum two brain lesion with a total cumulative
diameter of 5cm is allowed.
SOC baseline imaging e.g MRI and/or PET-CT and CT-brain or MRI brain and/or CT-scan with at
least covering thorax-upper abdomen-brain, within 6 weeks prior to randomisation.
If a patient has unclear lesions in the liver or brain an MRI would be advised following
the ESMO guidelines.
o In patients with 2 lung tumours, it can be unclear if the patient has 2 concurrent
primary tumours or a primary lung tumour with 1 metastasis. In this case, the local
multidisciplinary tumour board will decide whether the patient has an M1 disease or not.
• Previous treatment: Prior cancer treatments are allowed but must be discontinued for at
least 4 weeks before randomisation. In case of maintenance chemotherapy, this therapy will
only be started after the end of the L19-IL2 treatment or only in case of Anti-PD(L)1
treatment, during L19-IL2 therapy.
- Age of 18 years or older.
- WHO performance status 0-1;
- Adequate bone marrow function, evaluated in the local laboratory (Lab): Absolute
Neutrophil Count (ANC) of ≥ 1.0 x 109 /L, platelet count ≥ 100 x 109/L, Haemoglobin
(Hb) ≥ 6.0 mmol/L (or 9.67 g/dL) (it is allowed to give a blood transfusion if Hb is
initially too low);
- Adequate hepatic function (evaluated in the local lab): total bilirubin ≤ 1.5 x upper
limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase ≤ 2.5 x
ULN for the institution or ≤ 5 in case of liver metastasis);
- Adequate renal function (evaluated in the local lab): creatinine clearance of at least
40 ml/min;
- Adequate endocrine (TSH, FT4) function, local guidelines
- The patient is capable of complying with study procedures;
- Life expectancy of at least 12 weeks;
- Negative serum pregnancy test for females of childbearing potential.
- Signed and dated written informed consent.
- Ability to comply with contraception requirements:
Non-sterilised, sexually active male patient with a female partner who is of child-bearing
age, must use two acceptable birth control methods like a condom combined with spermicidal
cream or gel from the first dose of study medicine, during the study and at least up to 12
weeks after the last administration of the study medicine and up to 5 months after the last
dose of the medicine with anti-PDL)1 as an action mechanism (if you get this product
besides the study medicine), as an addition to the use, by the female partner, of as
described in the following section:
Women of childbearing potential (WOCBP) and WOCBP partners of male patients must be using,
from the screening to three months following the last study drug administration and 4 5
months after last dose of anti-PD(L)1 maintenance treatment, effective contraception
methods ((a) IUD (IUD) or intrauterine hormone delivery system (IUS), b) combined (with
estrogen and progesterone) hormonal contraception associated with ovulation inhibition
(oral, intravaginal, transdermal), c) hormonal contraception with progesterone only
associated with ovulation inhibition (oral, injectable, implantable), as defined by the
"Recommendations for contraception and pregnancy testing in clinical trials" issued by the
Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html).
Poly-metastatic disease (6 to 10 metastases)
• Histological confirmed limited metastatic adult NSCLC patients, regardless of the PD-L1
status.
A minimum of 6 and maximum of 10 metastatic lesions, maximum two brain lesion with a total
cumulative diameter of 5cm is allowed.
At least one measurable lesion (according to RECIST 1.1) that has no overlap with the PTV
of the lesion subjected to radiotherapy.
• Previous treatment: The time between the last administration of chemotherapy and the
randomisation must be at least 4 weeks. In case of maintenance chemotherapy, this therapy
will only be started after the study if e-arm, allowed during c-arm. In case of Anti-PD(L)1
treatment, this is allowed in both arms, so also during L19-IL2 therapy.
- Age of 18 years or older;
- WHO performance status 0-1;
- Adequate bone marrow function (evaluated in the local lab): Absolute Neutrophil Count
(ANC) of ≥ 1.0 x 109 /L, platelet count ≥ 100 x 109/L, Hb ≥ 6.0 mmol/L (or 9.67 g/dL)
(it is allowed to give a blood transfusion if Hb is initially too low);
- Adequate hepatic function (evaluated in the local lab): total bilirubin ≤ 1.5 x upper
limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase ≤ 2.5 x
ULN for the institution or ≤ 5 in case of liver metastasis);
- Adequate renal function (evaluated in the local lab): creatinine clearance of at least
40 ml/min;
- Adequate endocrine (TSH, FT4) function, local guidelines;
- The patient is capable of complying with study procedures;
- Life expectancy of at least 12 weeks;
- Negative serum pregnancy test for females of childbearing potential;
- Ability to comply with contraception requirements (see oligo)
- Signed and dated written informed consent.
Exclusion criteria
- More than 10 metastatic lesions.
- More than 2 brain metastatic lesions.
- 2 brain metastases with a cumulative diameter larger than 5 cm.
- Patients with non-infectious pneumonitis, uncontrolled thyroid disease, pleuritis,
pericarditis and peritonitis carcinomatosis.
- Patients who received live vaccines 30 days or fewer prior to enrolment.
- Patients who are already actively participating in another study.
- Patients who need simultaneous radiation on the primary tumour and metastatic
lesion(s). For these patients it might be an option to treat the primary tumour first
although this is not mandatory for this study. There must be minimal four weeks
between last treatment and randomisation.
- Whole brain radiotherapy (WBRT) is not allowed, although it is accepted when given at
least 4 weeks prior to randomisation or after the treatment period. Patients with
stable brain metastases are not excluded.
- Previous radiotherapy to an area that would be re-treated by (SAB)R, resulting in
overlap of the high dose areas.
- Maintenance therapy with Anti-PD(L)1 treatment combined with chemotherapy is not
allowed during treatment ((SAB)R and L19-IL2 cycles).
- Other active malignancy or malignancy within the last 2 years (except localised skin
basal/squamous cell carcinoma, non-muscle invasive carcinoma of the bladder or in situ
carcinoma from any site).
- Concomitantly administered glucocorticoids may decrease the activity of IL2 and
therefore should be avoided. However, patients who develop life-threatening signs or
symptoms may be treated with dexamethasone until toxicity resolves or reduces to an
acceptable level (generally grade 1 and 2, however must be based at the research
physician's discretion).
- History of allergy to intravenously administered proteins/peptides/antibodies/
radiographic contrast media.
- HIV positive; active HIV infection, or active hepatitis B or C (assessed in local
lab).
- Systemic treatment with either corticosteroid (>10 mg daily prednisone equivalents) or
Interferon alpha or immunosuppressive medications within 14 days prior to
randomisation. Topical or inhalation steroids are allowed. If a patient needs to take
unexpectedly immunosuppressive medication during the trial, it will be allowed but
decreasing the dose as soon as possible is strongly advised.
- Prior history of organ transplant, including autologous stem cell transplant.
- Acute or sub-acute coronary syndromes within the last year, acute inflammatory heart
disease, heart insufficiency NYHA > 2, or irreversible cardiac arrhythmias.
- A known impaired cardiac function defined as left ventricular ejection fraction (LVEF)
< 50 % (or below the study site's lower limit of normal) as measured by MUGA or ECHO.
- Uncontrolled hypertensive disease; (systolic blood pressure (SBP) ≥160 or diastolic
blood pressure (DBP) ≥100 mm Hg during two measurements).
- History or evidence of active autoimmune disease.
- Severe diabetic retinopathy (neoangiogenesis targeted by L19 outside the tumour).
- Major trauma, including oncologic surgery, but excluding smaller procedures like the
placement of porth-à-cath or surgical biopsy, within 4 weeks prior to randomisation
(neoangiogenesis targeted by L19 outside a tumour).
- Any underlying mental, medical or psychiatric condition which in the opinion of the
investigator will make administration of study drug hazardous or hinder the
interpretation of study results. Unstable or serious concurrent uncontrolled medical
conditions.
- Pregnancy or breast feeding; it is well known that ED-B, the target of both L19IL2, is
expressed in a variety of fetal tissues. Furthermore, anti-PD(L)1 treatment may
increase the risk of immune-mediated disorders. Therefore, it will be contra-indicated
for pregnant or lactating women.
