This study is a phase II, multicenter, randomized and comparative study designed to evaluate
whether the combination of hypofractionated stereotactic radiation therapy with the
anti-PD-L1 Durvalumab in patients with brain metastases from NSCLC (Non-Small-Cell Lung
Carcinoma) improves brain tumor control compared to hypofractionated stereotactic radiation
therapy alone.
Patients will be assigned in one of the two following arms:
- Arm A (control arm): radiotherapy alone
- Arm B (Experimental arm): combined treatment radiotherapy with anti-PD-L1 durvalumab
Total duration of treatment will be 12 months (at maximum in the experimental arm).
Patients will be followed for a maximum of 2 years following the date of randomization.
Inclusion Criteria:
1. Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)
2. Stage IV metastatic disease with intra-cranial progressive disease documented by MRI
evidence
3. Patient with 1 to 4 brain metastases (< 3.5 cm on T1 post-gadolinium sequence) all
amenable to hFSRT, with at least 1 metastasis ≥ 1 cm (RANO-BM criteria evaluation)
4. Patient with no evidence of extra-cranial progressive disease on 18-FDG PET-CT
5. Patient with wild type EGFR and ALK
6. Age ≥ 18 years at time of study entry
7. ECOG performance status < 2 i.e. 0 or 1
8. Body weight >30kg
9. Life expectancy of at least 3 months
10. Previously treated patients even with immunotherapy are accepted
11. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 are accepted, if
the following conditions are completed:
- All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study
- Must not have experienced a ≥Grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably
maintained on appropriate replacement therapy and are asymptomatic Must not have
required the use of additional immunosuppression other than corticosteroids for
the management of an AE, not have experienced recurrence of an AE if
re-challenged, and not currently require maintenance doses of > 10 mg prednisone
or equivalent per day.
12. Adequate Hematology laboratory data within 6 weeks prior to start of treatment:
Absolute neutrophils> 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 9 g/dL
13. Adequate Biochemistry laboratory data within 6 weeks prior to start of treatment:
Total bilirubin ≤ 1.5 x ULN (except patient with confirmed Gilbert's syndrome or liver
metastasis: Total bilirubin ≤ 3 X ULN), Transaminases ≤ 2.5 x ULN, Alkalin
phosphatases ≤ 5 x ULN, Creatinine clearance > 40 mL/min (Cockcroft)
14. Women should be post-menopaused or willing to accept the use an effective
contraceptive regimen during the treatment period and at least 3 months after the end
of the study treatment. All nonmenopaused women should have a negative pregnancy test
within 72 hours prior to registration. Men should accept to use an effective
contraception during treatment period and at least 3 months after the end of the study
treatment
15. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up
16. Signed written informed consent
17. Patient affiliated to a Social Health Insurance in France
Exclusion Criteria:
1. Central nervous system complications for whom urgent neurosurgical intervention is
indicated (e.g., resection, shunt placement)
2. Brain metastases in the brainstem
3. Known leptomeningeal metastases
4. All other cancer histology other than NSCLC
5. Prior history of brain radiotherapy
6. Patient with associated extra-cranial progressive disease documented by 18-FDG PET-CT
7. Patient unable to have MRI for any reason (e.g., due to pacemaker, ferromagnetic
implants, claustrophobia, extreme obesity)
8. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician
2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the Study
Physician
9. Participation in another therapeutic trial within the 30 days prior to entering this
study (participation in a survival follow-up period of a clinical study is not an
exclusion criterion)
10. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
11. Current or prior use of immunosuppressive medication within 14 days before the first
fraction of RT (exception: systemic corticosteroids at physiologic doses not exceeding
10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication
for hypersensitivity reactions (eg, CT scan premedication) - Topical, inhaled, nasal
and ophthalmic steroids are not prohibited)
12. Active suspected or prior documented autoimmune disease (including inflammatory bowel
disease, celiac disease, diverticulitis with the exception of diverticulosis, systemic
lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
Note: participants with vitiligo or alopecia, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, patients with celiac disease
controlled by diet alone, psoriasis not requiring systemic treatment, or conditions
not expected to recur in the absence of an external trigger, are permitted to enroll
13. Known primary immunodeficiency or active HIV (positive HIV 1/2 antibodies)
14. Known active or chronic viral hepatitis or history of any type of hepatitis within the
last 6 months indicated by positive test for hepatitis B surface antigen (HBV sAG) or
hepatitis C virus ribonucleic acid (HCV antibody)
15. History of active tuberculosis (clinical evaluation that includes clinical history,
physical examination and radiographic findings, and TB testing in line with local
practice)
16. 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, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent
17. History of another primary malignancy except for:
1. Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of IP and of low potential risk for recurrence
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
3. Adequately treated carcinoma in situ without evidence of disease
18. History of severe allergic reactions to any unknown allergens or any components of the
study drug
19. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
20. History of allogenic organ transplantation
21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP
22. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab
23. Patient who has forfeited his/her freedom or who is under legal protection
(curatorship and guardianship, protection of justice)