Local Consolidative Therapy and Durvalumab for Oligoprogressive and Polyprogressive Stage III NSCLC After Chemoradiation and Anti-PD-L1 Therapy

PRIMARY OBJECTIVES: I. To determine the efficacy of local consolidative therapy (LCT) followed by durvalumab for oligoprogressive non-small cell lung cancer (NSCLC) compared to historical standard control in terms of progression-free survival (PFS). II. To determine the efficacy of LCT followed by chemotherapy and durvalumab for polyprogressive NSCLC compared to historical standard control in terms of PFS. SECONDARY OBJECTIVES: I. To determine the efficacy of LCT followed by durvalumab for oligoprogressive NSCLC compared to historical standard control in terms of overall survival (OS)1. II. To determine the efficacy of LCT followed by chemotherapy and durvalumab for polyprogressive NSCLC compared to historical standard control in terms of OS1. III. To determine the efficacy of LCT followed by durvalumab for oligoprogressive NSCLC compared to historical standard control in terms of OS2. IV. To determine the efficacy of LCT followed by chemotherapy and durvalumab for polyprogressive NSCLC compared to historical standard control in terms of OS2. V. To assess patterns of failure after LCT followed by durvalumab for oligoprogressive NSCLC. VI. To assess patterns of failure of LCT followed by chemotherapy and durvalumab for polyprogressive NSCLC. VII. To assess quality of life of LCT followed by durvalumab for oligoprogressive NSCLC. VIII. To assess quality of life of LCT followed by chemotherapy and durvalumab for polyprogressive NSCLC. SAFETY OBJECTIVES: I. To assess the safety and tolerability profile of LCT followed by durvalumab for oligoprogressive NSCLC. II. To assess the safety and tolerability profile of LCT followed by chemotherapy and durvalumab for polyprogressive NSCLC. EXPLORATORY OBJECTIVES: I. Biomarker analyses on tumor biopsies pre-radiation, while on systemic therapy (cycle 2), and optional at progression, as well as blood collections pre-radiation, pre-durvalumab, while on systemic therapy (cycle 2), every other restaging scan, and optional at progression. II. Microbiome analyses on stool sample pre-radiation, pre-systemic therapy, and at progression. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT A (OLIGOPROGRESSIVE): Patients undergo LCT consisting of radiation therapy and/or surgery, then receive durvalumab intravenously (IV) over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT B (POLYPROGRESSIVE): Patients undergo LCT consisting of radiation therapy and/or surgery, then receive durvalumab IV over 1 hour on day 1. Patients also receive one of the following chemotherapy options: carboplatin and paclitaxel on day 1, carboplatin on day 1 and nab-paclitaxel on days 1, 8, 15, or carboplatin on day 1 and gemcitabine on days 1 and 8. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with non-squamous histology receive pemetrexed on day 1 every 21 days for cycles 1-4, pemetrexed and durvalumab IV on day 1 every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for 2 years.