Although it is usually described as an immunosuppressive modality and not thought of as
immunotherapy, there are new preclinical evidences suggesting that high-dose ionizing
irradiation (IR) results in direct tumour cell death and augments tumour-specific immunity,
which enhances tumour control both locally and distantly. Importantly, IR effects exceed the
classical cytocidal properties by also causing phenotypic changes in the fraction of
surviving cells, markedly enhancing their susceptibility to T cell-mediated elimination.
However, not all IR-induced modifications of the tumour and its microenvironment favor immune
rejection. The tumour microenvironment is populated by various types of inhibitory immune
cells including Tregs, alternatively activated macrophages, and myeloid-derived suppression
cells (MDSCs), which suppress T cell activation and promote tumour outgrowth. Chiang et al.
showed the accumulation of pro-tumourigenic M2 macrophages in areas of hypoxia present in
irradiated tumours. IR then may also induced responses that are inadequate to maintain
antitumuor immunity.
Close interaction between IR, T cells, and the PD-L1/PD-1 axis exsit and provide a basis for
the rational design of combination therapy with immune modulators and radiotherapy. Deng et
al. demonstrate that PD-L1 was upregulated in the tumour microenvironment after IR. Moreover,
administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent
mechanism. Concomitant with IR-mediated tumour regression, IR and anti-PD-L1 synergistically
reduced the local accumulation of tumour-infiltrating MDSCs, which suppress T cells and alter
the tumour immune microenvironment. Finally, activation of cytotoxic T cells with combination
therapy mediated the reduction of MDSCs in tumours through the cytotoxic actions of TNF.
Sagiv-Barfi et al, also demonstrated in 5 patients receiving atezolizumab and radiation
therapy, at least stabilization of systemic progression in all patients and a RECIST partial
response at systemic sites in 1 patient. Transient, grade 1-2 inflammatory adverse events
(fevers, flu-like symptoms) occurred with no serious immune-related toxicities. Abscopal
out-field effects of irradiation has also been described in addition to a reduction in
circulating MDSCs in a melanoma patient treated with the anti CTLA-4 ipilimumab and
radiotherapy.
Lastly, recent evidence demonstrates that loco-regional curative treatment with stereotactic
ablative radiotherapy (SABR) is a good alternative as compared with conventional 3D RT for
patients with solid tumour, with durable remissions and a low toxicity profile. Many
non-randomised studies have shown that SBRT for oligometastases is safe and effective, with
local control rates of about 80%. Importantly, these studies also suggest that the natural
history of the disease is changing, with 2-5 year progression-free survival of about 20%. For
colorectal, non-small cell, and renal cell cancers, 1-year metastasis control rates ranged
from 67 to 91%. Moreover, abscopal reponses in the setting of immune checkpoints inhibitors
and radiotherapy combinations have been made in the setting of metastatic disease event in
patients with extensive tumor burden. The goal of SABR is to deliver appropriate metastasis
directed radiotherapy while minimizing exposure of surrounding normal tissues. Interestingly,
the dose and fractionation employed modulate RT ability to synergize with immunotherapy.
Vanpouille-Box et al, showed that immune response genes were differentially expressed in
irradiated tumours by 8Gyx3 but not 20Gyx1. This highlight the interest of hypofractionated
SABR acting as a "in situ tumour vaccine".
As hypofractionated SABR may, in addition to its good local control, increase the
effectiveness of anti PD-L1, investigators aimed to investigate the efficacy and the
tolerability of the combination of anti-PD-L1 antibody with SABR.
Inclusion Criteria:
1. Patients must be 18 years of age or older.
2. Histologically or cytologically proven metastatic solid tumours including:
- colorectal (CRC, Microsatellite instability negative and positive) in treatment
failure as per the current standard recommendation ;
- non-small cell lung cancer (NSCLC) pretreated by at least one line of treatment
.Patients EGFR-mutant can be included only if they have been treated with, or
developed toxicity with or refused to be treated with anti-EGFR therapy; Patients
pretreated by anti-PD1, or anti-PDL1 therapeutic antibodies can be included only
if they have received at least 4 months of treatment.;
- renal cell carcinoma (RCC) pretreated by at least one line therapy by a tyrosin
kinase inhibitor.
- metastatic sarcomas of any type (soft tissue, bone, GISTs) pretreated by at least
one line of standard therapy ; at least three lines of standard TKi must be given
in patients with GISTs. No enrolment restriction to certain
sarcomasubtypes/groups was decided given the relative rarity of this disease type
and that immunotherapy efficacy in certain histological subtypes is only
preliminary.
3. Patients with at least:
- one measurable metastasis by RECIST 1.1 eligible for SABR in terms of dose
constraints at organ at risk and ≤ 4 cm, and
- one not treated measurable metastasis by RECIST 1.1. If all tumour sites are
accessible to SABR, one of them will not be treated. Metastase located within the
proximal bronchial tree as defined in RTOG 0236) or within the brain are not
eligible for SABR treatment in the present study. However, it can be considered
as a not treated evaluable metastase.
4. WHO performance status of 0-1
5. Evaluation by a radiation oncologist within 45 days prior to study registration,
including imaging workup to document metastases (cf. description in assessment
section)
6. Patients must have adequate organ function defined by the following laboratory results
obtained within 28 days prior to the first study treatment:
- Absolute neutrophil count of ≥ 1500/mm3;
- Lymphocyte count ≥ 500 mm3;
- Platelets ≥ 100,000/mm3;
- Hemoglobin > 9 gr/dL;
- Clearance Creatinine > 60 mL/min;
- Total bilirubin ≤ 1.5X ULN (unless Gilbert where 3X ULN is permitted);
- Serum ALT and AST ≤ 2.5X ULN (unless documented liver metastases where ≤ 5X ULN
is permitted),
- ALK ≤ 2.5 ULN (unless documented bone or liver metastases where ≤ 5X ULN is
permitted).
7. Life expectancy of more than 3 months
8. Patients must be aware of the investigational nature of the therapy and provide
written informed consent.
9. Sexually active women of childbearing potential must agree to use a highly effective
method of contraception supplemented with a barrier method, or to abstain from sexual
activity during the study and for at least 5 months after the last dose of
atezolizumab. Sexually active males patients must agree to use condom while on SABR
treatment and for at least 90 days after SABR treatment.Taking into account the
irradiated area, use of condom after SABR treatment can be shortened at investigator
discretion. Also, their women of childbearing potential partner should use a highly
effective method of contraception.
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or
surgically sterile must have a negative serum β-HCG pregnancy test result within 7
days prior to initiation of study drug. A list of highly effective birth control
methods and the definition of a woman of childbearing potential are provided in the
core protocol (section 4.1).
10. Patients must be free of significant comorbid conditions that would preclude safe
administration or completion of protocol therapy.
11. Patients may not have used any systemic anticancer treatment (approved or
investigational agent) within 4 weeks prior to cycle 1 day 1.
12. The irradiated and unirradiated tumour sites must be accessible to tumour biopsy
(additional written consent required).
13. Patients must be affiliated to a social security system
Exclusion Criteria:
1. Known allergy to anti-PD-L1 including :
- History of severe allergic anaphylactic reactions to chimeric, human or humanized
antibodies, or fusion proteins.
- Known hypersensitivity to CHO cell products or any component of the atezolizumab
formulation.
2. Pregnant or breastfeeding women
3. Any malignancy other than the disease under study in the past 5 years excepting skin
cancers such as BCC or SCC.
4. Uncontrolled tumour-related pain Patients requiring pain medication must be on a
stable regimen at study entry. Asymptomatic metastatic lesions whose further growth
would likely cause functional deficits or intractable pain (e.g., epidural metastasis
that is not presently associated with spinal cord compression) should be considered
for loco-regional therapy if appropriate prior to enrolment.
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently).
Patients with indwelling catheters (e.g., PleurX) are allowed.
6. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected
serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of
bisphosphonate therapy or denosumab.
Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent
skeletal events and who do not have a history of clinically significant hypercalcemia
are eligible. However, patients who are receiving denosumab prior to enrollment must
be eligible to receive bisphosphonate instead and willing to switch to bisphosphonate
therapy while on the study.
7. Severe, active co-morbidity, defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months prior to registration;
- Transmural myocardial infarction within the last 6 months prior to registration;
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration;
- Uncontrolled Chronic Obstructive Pulmonary Disease or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days prior to
registration
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or
evidence of active pneumonitis on screening chest CT scan History of radiation
pneumonitis in the radiation field (fibrosis) is permitted.
- Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic
disease.
- Known HIV positive status.
- End-stage renal disease (i.e., on dialysis or dialysis has been recommended).
- Patients with active hepatitis B (defined as having a positive hepatitis B
surface antigen [HBsAg] test at screening) or hepatitis C.
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
(defined as having a negative HBsAg test and a positive antibody to hepatitis B core
antigen [anti-HBc] antibody test) are eligible Patients positive for hepatitis C virus
(HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for
HCV RNA.
8. Active or History of autoimmune or inflammatory disease, including but not limited to
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with
anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see
Appendix 3 for a more comprehensive list of autoimmune diseases) Patients with a
history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone
are eligible Patients with controlled Type 1 diabetes mellitus on a stable insulin
regimen are eligible Patients with vitiligo or psoriasis or grave's disease, not
requiring systemic treatment within the last 2 years, are eligible
9. Metastases located to the brain and with clinical signs and/or leptomingeal
carcinomatosis, or with indistinct borders making targeting not feasible Metastases
located to the brain and without clinical signs can be included.
10. Irradiation required for cord compression and for superior veina cava syndrome.
11. Irradiation by SABR should not include metastases located within 3 cm of the
previously irradiated structures:
- Spinal cord previously irradiated to > 40 Gy
- Brachial plexus previously irradiated to > 50 Gy
- Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
- Brainstem previously irradiated to > 50 Gy
- Lung previously irradiated with prior V20Gy > 30%
12. Metastasis localized to the central part of the chest and requiring irradiation (see
"no fly zone" in Appendix 1: Rules for SABR administration according to tumour
location).
13. Any approved anticancer therapy, including chemotherapy, hormonal therapy or
radiotherapy, within 4 weeks prior to initiation of study treatment and while on study
treatment; however, the following are allowed:
- Hormone-replacement therapy or oral contraceptives
- Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1
14. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or
anticipation that such a live attenuated vaccine will be required during the study.
15. Influenza vaccination should be given during influenza season only (example:
approximately October to March in the Northern Hemisphere). Patients must not receive
live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1,
Day 1 or at any time during the study
16. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [TNF] agents)
within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic
immunosuppressive medications during the trial Patients who have received acute,
low-dose, systemic immunosuppressant medications (e.g., a one-time dose of
dexamethasone for nausea) may be enrolled in the study The use of inhaled
corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g.,
fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental
corticosteroids for adrenocortical insufficiency are allowed.
17. Patient already enrolled in another therapeutic trial involving an investigational
substance, and when such a substance has been taken during the previous 4 weeks.
18. Persons deprived of their freedom or under guardianship, or for whom it would be
impossible to undergo the medical follow-up required by the trial, for geographic,
social or psychological reasons
19. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1,
or anti-PDL1 therapeutic antibodies Only patients with non-small cell lung cancer are
allowed to have received anti-PD1, or anti-PDL1 therapeutic antibodies. Subjects who
have received prior anti-PD-1/L1 therapies must have received at least 4 months of
treatment.
Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided
at least 5 half-lives (approximately 75 days) have elapsed from the last dose of
anti-CTLA-4 to the first dose of atezolizumab and there was no history of severe
immune-mediated adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 and 4)
20. Treatment with systemic immunostimulatory agents (including but not limited to
interferon-alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of
the drug (whichever is shorter) prior to Cycle 1, Day 1
