The current study focuses on unresectable stage III non-small cell lung cancer (NSCLC) patients who are starting Durvalumab consolidation after concurrent chemoradiation with a goal of cure. The overall hypothesis of this study is that the addition of Copanlisib to Durvalumab will be well-tolerated at a biweekly schedule. It will test whether the addition of Copanlisib to Durvalumab can overcome resistance to Durvalumab.

Treatment will be administered in outpatient settings. Durvalumab will be administered as infusion intravenously once every two weeks on D1 and D15, every 28 days (10 mg/Kg based on body weight) or 1500mg on D1 every 28 days. Copanlisib will be given as infusion intravenously on D1, D15 in a 28-day cycle (flat dose). The starting dose of Copalisib will be 60 mg D1 and D15. It will be reduced to 45 mg for the first dose reduction and to 30 mg for the second dose reduction. The Durvalumab dose will remain constant when Copanlisib is reduced.

Once the appropriate dose is determined, e.g. Copanlisib 60 mg iv d1, 15, q4w, in the dose-finding phase, this will become the recommended dose for the dose-expansion phase. Patients will be treated at the dose-expansion phase to increase our understanding of pharmacokinetics and to confirm safety as well as initial efficacy in this population.

Inclusion Criteria:

• Histologically confirmed NSCLC (e.g., adenocarcinoma, squamous cell) deemed unresectable or inoperable who have received concurrent chemoradiation.
• Durvalumab will be started as consolidation therapy
• Have at least one measurable lesion.
• ECOG performance status ≤2.
• Adequate organ and marrow function.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Mixed Non-small cell and small cell histology; known EGFR and/or ALK driver mutations.
• Treated with sequential chemoradiation therapy.
• Autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus, requiring systemic treatment with immunosuppressant in the past two years.
• Patients who are receiving any other investigational agents orally or intravenously.
• Systemic steroid for other purpose exceeding 10 mg prednisone a day except local injection at the discretion of the investigator.
• Solid organ or bone marrow transplant recipients.
• History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function.
• Patients with uncontrolled inter-current illness.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements and patients with seizure disorder not well controlled.
• Received live vaccine in the past 4 weeks.
• Pregnant or breast-feeding/lactating women.
• Receiving medications prohibited by the study.
• New York Heart Association Class 3 or above.
• Myocardial infarction within the last 6 months.
• Unstable angina.
• Venous thromboembolism within last 3 months.
• Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks.
• Proteinuria of ≥ CTCAE Grade 3 or estimated by urine protein: creatinine ratio > 3.5
• Major surgeries within the last 28 days.
• Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study.