This single-arm phase 2 study will enroll patients with resectable and operable stage IB -
III non-small cell lung cancer and treat them with pre-operative ipilimumab + nivolumab plus
low-dose stereotactic body radiation therapy (SBRT) delivered concurrently. Only patients who
proceed to surgery will be evaluable for the primary endpoint. The primary efficacy outcome
measurement will be pathologic response (including Major Pathologic Response (MPR), and
Complete Pathologic Response (CPR)). Secondary outcome measures include safety, and
exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A
two-stage design will stop the study if fewer than 3 of the first 9 evaluable patients do not
achieve MPR. An early stopping rule for safety will stop the study if more than 12 patients
are enrolled to find the first 9 evaluable patients.
Inclusion Criteria:
1. Pathologically confirmed NSCLC
2. Age > 18
3. ECOG Performance Status 0-1.
4. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1 at
least 2 L. If less than 2 L, the predicted postoperative forced expiratory volume in 1
second (FEV1) must be > 0.8 L or be > 35% of the predicted value. Postoperative
predicted DLCO ≥ 35% is required.
5. Resectable stage IB-IIIB (T2-3N0, T1-T3N1-2) NSCLC (per the 8th Edition American Joint
Committee on Cancer (AJCC) classification) who are candidates for surgery with intent
of R0 resection. Invasive T3 disease (eg, phrenic nerve, pericardium, chest wall other
than Pancoast superior sulcus) may be included if the surgeon and study team deem it
to be resectable.
6. N2 nodes must be discrete (ie, not invading surrounding structures). If patients have
N2 disease, as suspected by CT or PET, histologic proof of N2 status is recommended.
7. Patients must be evaluated by a Thoracic Surgeon prior to registration. Operability is
defined as having adequate pulmonary, cardiac, renal, nutritional, musculoskeletal,
neurologic, and cognitive capacity to undergo major pulmonary resection with
acceptable morbidity and mortality. Absence of major associated comorbidities that
increase the surgery risk to an unacceptable level.
8. No prior history of thoracic radiation.
9. Adequate Organ and marrow function as defined below
- leukocytes ≥2,000/mcL,
- absolute neutrophil count ≥1,000/mcL,
- platelets ≥100,000/mcL,
- Hemoglobin >8.0 g/dL
- Total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
- creatinine within normal institutional limits OR creatinine clearance ≥50
mL/min/1.73 m2 for participants with creatinine levels above institutional
normal.
10. Patients are capable of giving informed consent and/or have an acceptable surrogate
capable of giving consent on the subject's behalf.
11. Nonpregnant and non-nursing. The effect of ipilimumab and nivolumab on the fetus is
unknown.
12. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 5 months after the last dose of study medication. Patients of
childbearing potential are those who have not been surgically sterilized or have not
been free of menses >1 year.
13. Evidence of postmenopausal status or negative urinary or serum pregnancy test for
female premenopausal patients. Women will be considered postmenopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
14. Women <50 years of age would be considered postmenopausal 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
postmenopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).
15. Women ≥50 years of age would be considered postmenopausal 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).
16. 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.
17. Male patients must agree to use an adequate method of contraception starting with the
first dose of study therapy through 7 months after the last dose of study therapy.
Exclusion Criteria:
1. Pathologically confirmed NSCLC *
2. Age > 18 *
3. ECOG Performance Status 0-1.
4. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1 at
least 2 L. If less than 2 L, the predicted postoperative forced expiratory volume in 1
second (FEV1) must be > 0.8 L or be > 35% of the predicted value. Postoperative
predicted DLCO ≥ 35% is required.
5. Resectable stage IB-IIIB (T2-3N0, T1-T3N1-2) NSCLC (per the 8th Edition American Joint
Committee on Cancer (AJCC) classification) who are candidates for surgery with intent
of R0 resection. Invasive T3 disease (eg, phrenic nerve, pericardium, chest wall other
than Pancoast superior sulcus) may be included if the surgeon and study team deem it
to be resectable.
6. N2 nodes must be discrete (ie, not invading surrounding structures). If patients have
N2 disease, as suspected by CT or PET, histologic proof of N2 status is recommended.
7. Patients must be evaluated by a Thoracic Surgeon prior to registration. Operability is
defined as having adequate pulmonary, cardiac, renal, nutritional, musculoskeletal,
neurologic, and cognitive capacity to undergo major pulmonary resection with
acceptable morbidity and mortality. Absence of major associated comorbidities that
increase the surgery risk to an unacceptable level. *
8. No prior history of thoracic radiation.
9. Adequate Organ and marrow function as defined below
- leukocytes ≥2,000/mcL,
- absolute neutrophil count ≥1,000/mcL,
- platelets ≥100,000/mcL,
- Hemoglobin >8.0 g/dL
- Total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
- creatinine within normal institutional limits OR creatinine clearance ≥50
mL/min/1.73 m2 for participants with creatinine levels above institutional
normal.
10. Patients are capable of giving informed consent and/or have an acceptable surrogate
capable of giving consent on the subject's behalf.
11. Nonpregnant and non-nursing. The effect of ipilimumab and nivolumab on the fetus is
unknown.
12. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 5 months after the last dose of study medication. Patients of
childbearing potential are those who have not been surgically sterilized or have not
been free of menses >1 year.
13. Evidence of postmenopausal status or negative urinary or serum pregnancy test for
female premenopausal patients. Women will be considered postmenopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
14. Women <50 years of age would be considered postmenopausal 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
postmenopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy).
15. Women ≥50 years of age would be considered postmenopausal 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).
16. 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.
17. Male patients must agree to use an adequate method of contraception starting with the
first dose of study therapy through 7 months after the last dose of study therapy.
