Immunotherapeutic approaches targeting immune checkpoint proteins PD-1/PD-L1 have recently
demonstrated clinical efficacy in several cancer types, and have changed the therapeutic
landscape in metastatic melanoma or non-small cell lung cancer (NSCLC).
The monoclonal anti-PD-1 antibody nivolumab has been registered by both FDA (Food and Drug
Administration) and EMA (European Medicine Agency), for metastatic NSCLC patients, after
failure of a prior platinum-based chemotherapy.
The approval was based on the results of phase III clinical trials in metastatic NSCLC. But
all the trials only enrolled patients with good general condition, PS (Performance Status) 0
or 1. However, the prevalence of poor PS patients at time of diagnosis is high in lung cancer
patients.
For patients with metastatic NSCLC and PS 3, there is no standard treatment except best
supportive care, since all trials that accrued unselected PS 3 patients fail to prove any
survival advantage, and most PS >3 patients die within 2 to 4 months from diagnosis. Indeed,
these patients are currently excluded from clinical trials. Specific dedicated clinical
trials and treatment guidelines for this patient population are urgently needed, taking into
account for the high prevalence of such patients.
Inclusion Criteria:
1. Subjects must have signed and dated an IEC (Independent Ethic Committee) approved
written informed consent form in accordance with regulatory and institutional
guidelines. This must be obtained before the performance of any protocol related
procedures that are not part of normal subject care.
Subjects must be willing and able to comply with scheduled visits, treatment schedule,
and laboratory testing.
2. Histologically or cytologically-proven NSCLC (squamous or non-squamous). If the
diagnosis is cytologically-proven, sufficient material is necessary with at least 100
tumor cells evaluated for PD-L1 IHC (Immunohistochemistry).
3. PD-L1 expression ≥25% of tumor cells as assessed by the local pathology laboratory
using protocols validated.
4. Available tumor samples for centralized PD-L1 immunohistochemistry analysis.
5. No EGFR (Epidermal Growth Factor Receptor) mutation and no ALK(Anaplasic Lymphoma
Kinase) gene rearrangement.
6. Stage IV (8th classification TNM) M1a or M1b or M1c.
7. ECOG (Eastern Cooperative Oncology Group) PS = 2 (in the first step) or 3 (in the
second step) despite optimal symptomatic treatment.
8. Body weight >30kg
9. No prior systemic anticancer therapy (chemotherapy, immunotherapy including
durvalumab, or EGFR or ALK inhibitors) given as primary therapy for advanced or
metastatic disease. Neoadjuvant or adjuvant chemotherapy is not considered as
chemotherapy for advanced or metastatic disease.
10. Limited field of radiation for palliation within 2 weeks of the first dose of
durvalumab is allowed, provided the lung is not in the radiation field and irradiated
lesion(s) cannot be used as target lesions.
11. Age 18-75 years.
12. Measurable tumor disease by CT per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1.
13. Life expectancy > 8 weeks according to the investigator opinion.
14. Adequate biological functions:
neutrophils ≥ 1500/mm3 ; platelets ≥ 75 000/mm3 ; Hemoglobin ≥ 9 g/dL ; Creatinine
Clearance > 40 mL/min , AST and ALT ≤ 2,5 ULN unless liver metastases are present, AST
(aspartate aminotransferase) and ALT (alanine aminotransferase) ≤ 5 x ULN, serum
bilirubin ≤ 1.5 x ULN except for patients with proved, Gilbert syndrome (≤ 5 x ULN) or
patients with hepatic metastases (≤ 3 x ULN).
15. Other investigations detailed in Section 5 must have been performed within the
timelines indicated.
16. Protocol treatment is to begin within 7 days of patient inclusion.
17. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
18. Females of childbearing potential who are sexually active with a nonsterilized male
partner or men who are sexually active with women of childbearing potential must use a
highly effective method of contraception prior the first dose of investigational
product, and must agree to continue using such precautions for 90 days after the final
dose of investigational product. Periodic abstinence, the rhythm method, and the
withdrawal method are not acceptable methods of contraception.
Exclusion Criteria:
1. Pure or combined SCLC.
2. Known HER2 (Human Epidermal Growth Factor Receptor), B-Raf, activating tumor
mutations, or exon 14 c-MET splice mutations (mesenchymal-epithelial transition), or
known ROS1 gene rearrangement.
3. Asymptomatic or symptomatic brain metastasis.
4. Carcinomatous meningitis.
5. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The
following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with IFCT
- Patients with celiac disease controlled by diet alone
6. Immunosuppressive treatment including systemic treatment with corticosteroids with
greater dose than 10 mg prednisone equivalent daily, within 15 days before enrollment.
Inhaled, nasal or topic corticosteroids are allowed.
7. History of allogenic organ transplantation.
8. Stage 4 (very severe, FEV1 (forced expiratory volume at one second) <30% predicted)
chronic obstructive pulmonary disease (COPD) according to GOLD classification.
9. NYHA (New York Heart Association) class 4 chronic heart failure
10. Pre-existing interstitial lung.
11. History of another primary malignancy except for :
- Malignancy treated with curative intent and with no known active disease ≥2 years
before the first dose of IP (Investigational Product) and of low potential risk
for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of residual disease
Patients with a prostate adenocarcinoma history within the previous 5 years could
be included in case of localized prostate cancer.
12. Living attenuated vaccine received within the 30 previous days.
13. Received any other experimental treatment or participation to any other therapeutic
clinical trial.
14. Known allergy or hypersensitivity to any of the study drug or any of the study drug
excipients.
15. 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.
16. Major surgical procedure within 28 days prior to the first dose of IP or planned
surgical procedure during treatment.
17. 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 (Adverse Events) or compromise the ability of the patient to
give written informed consent.
18. Active infection including tuberculosis, hepatitis B (known positive HBV surface
antigen (HBsAg) result) and hepatitis C,. Patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible
only if polymerase chain reaction is negative for HCV RNA. History of active
tuberculosis or evident primo-infection for which there is no record or evidence of an
active anti-tuberculous treatment (please consult IFCT in case of doubt).
19. Patient with human immunodeficiency virus (positive HIV ½ antibodies)
20. Any condition that, in the opinion of investigator, could compromise the adherence to
treatment and follow-up.
21. Mental illness or psychological condition, which in the opinion of investigator could
compromise the expression of the informed consent.
22. No public health insurance.
