Radiation Therapy, Chemotherapy, Ipilimumab, and Nivolumab in Treating Patients with Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

Inclusion Criteria

• Participants must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-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 patient care
• Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study
• Patients with NSCLC including both squamous and non-squamous subtypes documented by histology or cytology from brushing, washing, or needle aspiration of a defined lesion, but not from sputum cytology alone; patients with a known targetable EGFR or ALK mutation will be eligible
• Participants must have presented at initial diagnosis with stage III disease according to American Joint Committee on Cancer (AJCC) cancer staging manual, 8th edition
• Participants must be deemed by the treating investigator to be surgically unresectable. Ideally, each patient’s case will be discussed by the institution’s multidisciplinary board, consisting of at least 1 thoracic surgeon, radiation oncologist, and medical oncologist with expertise in the treatment of lung cancer.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Participants must initiate study treatment 60 days from the date of pathologic diagnosis
• Tumor biopsy specimen including at least formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or up to 10 unstained slides of tumor sample (archival or recent) for biomarker evaluation must be available for submission to the central lab for correlative studies
• Patient re-enrollment: This study permits the re-enrollment of a participant who has discontinued the study due to pre-treatment failure (ie, participant has not been treated). If re-enrolled, the participant must be re-consented
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 14 days prior to the start of thoracic radiation therapy
• Women must not be breastfeeding
• Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception, which have a failure rate of < 1% when used consistently and correctly. Azoospermic males are exempt from contraceptive requirements
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total of 5 months post-treatment completion
• WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of the study drug (half-life up to 25 days) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion
• Male participants must be willing to refrain from sperm donation during the entire study and for 5 half- lives of study drug plus 90 days (duration of sperm turnover)
• HIGHLY EFFECTIVE METHODS OF CONTRACEPTION At a minimum, participants must agree to the use of one highly effective method of contraception as listed below: Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. WOCBP participants and female partners of male participants who are WOCBP are expected to use one of the highly effective methods of contraception listed below. Male participants must inform their female partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner. Contraception methods are as follows: * Progestogen-only hormonal contraception associated with inhibition of ovulation * Hormonal methods of contraception, including oral contraceptive pills containing combined estrogen + progesterone, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena * Nonhormonal IUDs, such as ParaGard * Bilateral tubal occlusion *Vasectomized partner with documented azoospermia 90 days after procedure ** Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success. * Intrauterine hormone-releasing system (IUS) * Complete abstinence ** Complete abstinence is defined as the complete avoidance of heterosexual intercourse ** Complete abstinence is an acceptable form of contraception for all study drugs and must be used throughout the duration of the study treatment (plus 5 half-lives of the investigational drug plus 30 days); ** It is not necessary to use any other method of contraception when complete abstinence is elected; ** Participants who choose complete abstinence must continue to have pregnancy tests ** Acceptable alternate methods of highly effective contraception must be discussed in the event that the participant chooses to forego complete abstinence ** The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant
• UNACCEPTABLE METHODS OF CONTRACEPTION * Periodic abstinence (calendar, symptothermal, post-ovulation methods) * Withdrawal (coitus interruptus) * Spermicide only * Lactation amenorrhea method (LAM)

Exclusion Criteria

• Participants who have received no more than 1 prior cycle of induction platinum based chemotherapy may be enrolled at the discretion of the treating investigator
• Women who are pregnant or breastfeeding
• Active, known, or suspected autoimmune disease. Patients with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study initiation. Corticosteroids with minimal systemic absorption (inhaled or topical steroids) and adrenal replacement steroid doses =< 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
• Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways)
• Prior history or active pneumonitis, interstitial lung disease that required corticosteroids or that is symptomatic or may interfere with the detection or management of suspected drug and/or radiation-related pulmonary toxicity
• Any patient requiring supplemental oxygen therapy
• Previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period
• Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug(s) administration or interfere with the interpretation of safety results, including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, history of myocardial infarction or cerebrovascular accident or transient ischemic attacks within 6 months from initiation of study drug, uncontrolled seizures or psychiatric illness/social situations that would limit compliance
• Major surgery or significant traumatic injury that is not recovered at least 14 days before the initiation of thoracic radiation therapy
• Patients may not have received a live attenuated vaccination within 30 days of starting study therapy
• Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection * Individuals with a positive test for HCV antibody but no detection of HCV RNA indicating no current infection are eligible
• Known medical history of testing positive for human immunodeficiency virus (HIV) or known medical history of acquired immunodeficiency syndrome (AIDS)
• Absolute neutrophil count (ANC) < 1500/mm^3
• Platelet count < 100,000/mm^3, or
• Hemoglobin level < 9.0 g/dL
• Total bilirubin level >= 1.5 times the upper limit of normal (ULN) (except patients with Gilbert syndrome, who are excluded if total bilirubin >= 3 times ULN), or
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels >= 2.5 times the ULN or >= 5 times the ULN if liver metastases are present
• Lipase > 1.5 ULN. Participants with lipase > 1.5 ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis
• Amylase > 1.5 ULN. Participants with amylase > 1.5 ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis
• Calculated creatinine clearance (CrCl) of < 60 mL/min (Cockcroft-Gault formula)
• History of allergy or hypersensitivity to any of the study drugs or study drug components
• Prisoners or individuals who are involuntarily incarcerated
• Individuals who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness