This randomized phase III trial studies proton chemoradiotherapy to see how well it works compared to photon chemoradiotherapy in treating patients with stage II-IIIB non-small cell lung cancer that cannot be removed by surgery. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor, such as photon or proton beam radiation therapy, may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as paclitaxel, carboplatin, etoposide, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether proton chemoradiotherapy is more effective than photon chemoradiotherapy in treating non-small cell lung cancer.

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) in patients with stage II-IIIB non-small cell lung cancer (NSCLC) after image guided, motion-managed photon radiotherapy (Arm 1) or after image guided, motion-managed proton radiotherapy (Arm 2) both given with concurrent platinum- based chemotherapy.

II. To compare the cardiac toxicity and lymphocyte reduction (lymphopenia) definitely, probably, or possibly related to treatment between the 2 arms.

SECONDARY OBJECTIVES:

I. To compare 2-year progression-free survival (PFS) between the 2 arms. II. To compare the development of grade 3 or higher adverse events not included above that are definitely, probably, or possibly related to treatment.

III. To compare differences between the two arms in quality of life (QOL) based primarily on the development of shortness of breath at 6 months and secondarily on the development of sore throat at the end of chemoradiotherapy (chemoRT) (as measured by the lung cancer module of the MD Anderson Symptom Inventory [MDASI-Lung]), as well as breathing related functioning impairments as measured by the Shortness Breath Questionnaire [SOBQ].

IV. To compare cost-effectiveness outcomes between the 2 arms. V. To compare pulmonary function changes by treatment arms and response. VI. To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo photon beam radiation therapy 5 days per week for a total of 35 fractions and receive either paclitaxel* intravenously (IV) over 1 hour and carboplatin* IV weekly during radiation therapy or etoposide IV on days 1-5 and 29-33 and cisplatin IV on days 1, 8, 29, and 36. Patients with non-squamous cell cancera may receive pemetrexed IV and carboplatin IV on every 21 days.

ARM II: Patients undergo proton beam radiation therapy 5 days per week for a total of 35 fractions and receive either paclitaxel* and carboplatin*, etoposide and cisplatin, or pemetrexed and carboplatin (for non-squamous cell cancer patients only) as in Arm I.

*In both arms, patients who receive paclitaxel and carboplatin must complete 2 courses of consolidation therapy.

CONSOLIDATION THERAPY: Beginning 3-6 weeks after chemoradiotherapy, patients receive either paclitaxel IV over 3 hours and carboplatin IV on day 1 or durvalumab IV every 2 weeks. Treatment repeats every 21 days for 2 courses or every 2 weeks for up to 12 months for durvalumab in the absence of disease progression or unacceptable toxicity. Patients with non-squamous cell carcinoma may receive durvalumab or pemetrexed IV and carboplatin IV on day 1 every 21 days for up to 4 courses.

After completion of study treatment, patients are followed up at 4-8 weeks, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Inclusion Criteria:

• Histologically or cytologically proven diagnosis of non-small cell lung cancer

• Clinical American Joint Committee on Cancer (AJCC) (AJCC, 7th ed.) II, IIIA or IIIB (with non-operable disease; non-operable disease will be determined by a multi-disciplinary treatment team within 60 days prior to registration; note: for patients who are clearly nonresectable, the case can be determined by the treating radiation oncologist and/or a medical oncologist or pulmonologist

  • Patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor are eligible
  • Patients who refuse surgery are eligible
  • Patients who develop local recurrence after surgery and rendered candidate for definitive concurrent chemoradiation are also eligible
  • Patients who have received systemic treatment (up to 4 cycles of induction chemotherapy, or up to 6 months of targeted therapy) are eligible

• Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:

  • History/physical examination within 30 days prior to registration including resting heart rate;

  • Fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scan for staging within 60 days prior to registration

  • Magnetic resonance imaging (MRI) scan with contrast of the brain (preferred) or CT scan of the brain with contrast within 60 days prior to registration;

  • Forced expiratory volume in one second (FEV1) >= 0.8 liter or >= 35% predicted with or without bronchodilator within 90 days prior to registration;

    • Patients who meet the criterion above without oxygen (O2), but who need acute (started within 10 days prior to registration) supplemental oxygen due to tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2 needed has been stable

• Zubrod performance status 0-1 within 30 days prior to registration

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 obtained within 30 days prior to registration

• Platelets >= 100,000 cells/mm^3 obtained within 30 days prior to registration

• Hemoglobin >= 9.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable), obtained within 30 days prior to registration

• Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) within 30 days prior to registration

  • It is highly recommended but not required that SGOT or SGPT be =< 1.5 upper limit of normal

• Total bilirubin =< 1.5 within 30 days prior to registration

  • It is highly recommended but not required that total bilirubin be =< 1.5 upper limit of normal

• Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 mL/min within 30 days prior to registration estimated by the Cockcroft-Gault formula

• Peripheral neuropathy =< grade 1 at the time of registration

• Patients with non-malignant pleural effusion are eligible

  • If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:

    • When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative
    • Exudative pleural effusions are excluded, regardless of cytology
    • Effusions that are minimal (i.e, not visible on chest x-ray) that are too small to safely tap are eligible

• Patients must have measurable or evaluable disease

• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration

• Women of childbearing potential and male participants must practice adequate contraception

• Patient must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Prior invasive malignancy unless disease free for a minimum of 3 years; however, skin cancer and in situ carcinomas of the breast, oral cavity, cervix, and other organs and are permissible

• Patients with prior history of either small cell lung cancer or NSCLC regardless of the treatment received, other than patients who have recurrent disease following resection

• Prior systemic chemotherapy for the study cancer, if more than 4 cycles of induction chemotherapy or more than 6 months of targeted therapy; note that prior chemotherapy for a different cancer is allowable

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

• Severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
  • Transmural myocardial infarction within the last 6 months;
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness other than the diagnosed lung cancer requiring hospitalization or precluding study therapy within 30 days before registration;
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol

• Unintentional weight loss > 10% within 30 days prior to registration

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.