Inclusion Criteria:
1. Age≥ 18 years
2. Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration
Lung Study Group (VALG) staging system)
3. No prior treatment for ES-SCLC
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
5. Patients with a history of treated, asymptomatic CNS metastases are eligible providing
they meet the following criteria
- Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
midbrain, pons, medulla or spinal cord)
- No ongoing requirement for corticosteroids as therapy for CNS disease
- No stereotactic brain radiation within 7 days
- No evidence of interim progression between the completion of CNS-directed therapy
and the screening radiographic study
- Patients with new asymptomatic Central Nervous System (CNS) metastases detected
at the screening scan must receive radiation therapy and/or surgery for CNS
metastases. Following treatment, these patients may then be eligible without the
need for an additional brain scan prior to randomization, if all other criteria
are met.
6. At least one liver metastasis measuring 1 cm.
7. Measurable disease, as defined by RECIST v1.1, in addition to the liver lesion(s) to
which SBRT is planned.
8. Patients must submit a pre-treatment tumor tissue sample from a liver metastasis.
Tumor tissue must be obtained prior to the start of treatment.
9. Adequate hematologic and end organ function, defined by the following laboratory
results:
- Absolute neutrophil count (ANC) ≥1500 cells/μL without granulocyte
colony-stimulating factor support
- Lymphocyte count ≥500/μL
- Platelet count ≥100,000/μL without transfusion
- Hemoglobin ≥9.0 g/dL Patients may be transfused to meet this criterion.
- International Normalized Ratio (INR) or Activated Partial Thromboplastin Time
(aPTT) ≤1.5×upper limit of normal (ULN) This applies only to patients who are not
receiving therapeutic anticoagulation; patients receiving therapeutic
anticoagulation should be on a stable dose.
- Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline
phosphatase ≤5×ULN
- Serum bilirubin ≤1.25×ULN (Patients with known Gilbert disease who have serum
bilirubin level ≤3×ULN may be enrolled)
- Serum creatinine ≤1.5×ULN
10. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods as defined below:
- Women must remain abstinent or use contraceptive methods with a failure rate of <
1% per year during the treatment period and for 6 months after the final dose of
carboplatin and etoposide
- A woman is considered to be of childbearing potential if she is postmenarchal,
has not reached a postmenopausal state (≥12 continuous months of amenorrhea with
no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus). The definition of childbearing
potential may be adapted for alignment with local guidelines or requirements.
- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper
intrauterine devices.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of contraception
11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
a condom, and agreement to refrain from donating sperm, as defined below:
- With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during treatment with chemotherapy (i.e.,
carboplatin and etoposide) and for at least 6 months after the last dose of
chemotherapy to avoid exposing the embryo.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence and withdrawal are not acceptable methods of
contraception.
12. Negative HIV test at screening, with the following exception: patients with a positive
HIV test at screening are eligible, provided they are stable on anti-retroviral
therapy, have a CD4 count3 200/µL, and have an undetectable viral load
13. Ability to understand and the willingness to sign a written informed consent document.
14. Ability to comply with the study protocol, in the investigator's judgment.
Exclusion Criteria:
1. Active or untreated CNS metastases as determined by computed tomography (CT) or
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic
assessments
2. Spinal cord compression not definitively treated with surgery and/or radiation or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for ≥1 week prior to randomization
3. Leptomeningeal disease
4. Prior radiation treatment of SCLC outside of the CNS
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 or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12
mg/dL or corrected serum calcium >ULN)
7. Patients who are receiving denosumab prior to randomization must be willing and
eligible to discontinue its use and replace it with a bisphosphonate while in the
study.
8. Malignancies other than SCLC within 5 years prior to randomization, with the exception
of those with a negligible risk of metastasis or death (e.g., expected 5-year OS >90%)
treated with expected curative outcome (such as adequately treated carcinoma in situ
of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated
surgically with curative intent, ductal carcinoma in situ treated surgically with
curative intent)
a. Prior radiation for non-SCLC malignancies >5 years prior to randomization will be
permitted, with the exception of those who underwent liver-directed treatments
9. Child-Pugh class B cirrhosis or worse
10. History of liver-directed ablative therapy for any indication, including radiation,
chemoembolization, radiofrequency ablation, or other similar modalities
11. Women who are pregnant, lactating, or intending to become pregnant during the study
12. Pregnant women are excluded from this study because carboplatin and etoposide are
category D agent with the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants secondary
to treatment of the mother with atezolizumab, breastfeeding should be discontinued if
the mother is treated with atezolizumab.
13. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
14. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or any component of the atezolizumab formulation
15. History of autoimmune disease, including but not limited to myasthenia gravis,
myositis,autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis
1. Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone may be eligible for this study.
2. Patients with controlled Type I diabetes mellitus on a stable dose of insulin
regimen are eligible for this study.
16. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
excluded) are permitted provided that they meet the following conditions:
- Rash must cover less than 10% of body surface area
- Disease is well controlled at baseline and only requires low potency topical
steroids
- No acute exacerbations of underlying condition within the last 12 months (not
requiring psoralen plus ultraviolet A radiation (PUVA), methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors, high potency, or oral steroids)
17. 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).
18. Patients with active hepatitis B (chronic or acute; 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 the presence of hepatitis B core antibody (HBcAb) and absence of
HBsAg) are eligible. HBV DNA must be obtained in these patients prior to
randomization.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA.
19. Active tuberculosis
20. Severe infections at the time of enrollment, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
21. Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), myocardial infarction within 3 months prior to randomization,
unstable arrhythmias, or unstable angina (Patients with known coronary artery disease,
congestive heart failure not meeting the above criteria, or left ventricular ejection
fraction <50% must be on a stable medical regimen that is optimized in the opinion of
the treating physician, in consultation with a cardiologist if appropriate).
22. Major surgical procedure other than for diagnosis within 28 days prior to
randomization or anticipation of need for a major surgical procedure during the course
of the study
23. Prior allogeneic bone marrow transplantation or solid organ transplant
24. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk for treatment
complications
25. Previous anti-cancer therapy for ES-SCLC
26. Treatment with any other investigational agent or participation in another clinical
study with therapeutic intent within 28 days prior to enrollment
27. Administration of a live, attenuated vaccine within 4 weeks before randomization or
anticipation that such a live attenuated vaccine will be required during the study
- Influenza vaccination should be given during influenza season only (approximately
October through May in the Northern Hemisphere and approximately April through
September in the Southern Hemisphere).
- Patients must agree not to receive live, attenuated influenza vaccine
(e.g.,FluMist®) within 28 days prior to randomization, during treatment or within
90 days following the last dose of atezolizumab/placebo.
28. Prior treatment with immune checkpoint blockade therapies, anti-PD-1, and
anti-PD-L1therapeutic antibodies
29. Treatment with systemic immunosuppressive medications (including, but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor (anti-TNF) agents) within 2 weeks prior to randomization
- 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 after discussion with and approval by the Principal Investigator
- 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.
30. History of allergic reactions to carboplatin or etoposide
