A multicenter, Phase II, open label, randomized trial evaluating the efficacy of Tedopi plus docetaxel or Tedopi plus nivolumab as second-line therapy in metastatic non-smallcell lung cancer progressing after first-line chemo-immunotherapy (Combi-TED)

Prior treatment

• No previous chemoimmunotherapy for metastatic disease or evidence of disease progression during the first 4 cycles of chemoimmunotherapy (primary resistance). Patients with adjuvant resistance (documented loco-regionally and/or systemic relapse of their disease occurring <6 months after the last dose of anti-PD-(L)1-based systemic adjuvant therapy) are excluded
• Patients with intervening systemic therapy following prior anti-PD-(L)1-based therapy
• Symptomatic brain metastases. Asymptomatic brain metastases are allowed if not requiring corticosteroids use at a dose >10mg daily prednisone (or equivalent)
• Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease

Other illness

• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Diagnosis of any other malignancy during the last 3 years, except for in situ carcinoma of cervix uteri and cutaneous squamous cell carcinoma or other local tumors considered cured
• Patients with an active, known or suspected autoimmune disease. Patients with type I diabetes mellitus; hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection

Lab values

• Patient positive for actionable EGFR mutations or ALK or ROS1 rearrangement;

Other

• Pregnancy or lactating

• Male and female patients willing and able to give written informed consent
• Normal level of creatinine
• Female patient: childbearing potential either terminated by surgery, radiation, or menopause, or attenuated by use of highly effective contraception methods (see paragraph 12.1.2) during treatment and for the time detailed in paragraph 12.1. or Male patient: should practice complete abstinence or if sexually active with WOCBP must use highly effective contraceptive methods and they should not donate semen as detailed in paragraph 12.1.
• Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to treatment. Subjects with symptomatic tumor lesions that may require palliative radiotherapy within 4 weeks of first treatment are strongly encouraged to receive palliative radiotherapy prior to treatment. Patients are eligible if CNS metastases are adequately treated and patients are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization
• Patients must be either off corticosteroids, or on a stable or decreasing dose of =10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization
• Histological or cytological confirmed diagnosis of HLA-A2+ NSCLC with no evidence of EGFR mutations or ALK or ROS1 rearrangement
• Evidence of disease progression at the end of at least 4 cycles of chemoimmunotherapy or 2 cycles of chemo-immunotherapy followed by 2 cycles of immunotherapy (CheckMate9LA regimen) and eligible for treatment with docetaxel. Any chemotherapy is allowed, including chemotherapy containing platinum salts. This criterion implies that patients with immunotherapy primary resistance are excluded;
• Patients must have experienced progressive disease (PD), either during or within 3 months of discontinuing treatment with anti-PD-(L)1-based therapy, occurring after previous clear benefit (any complete –CR- or partial response -PR), or after previous stable disease (SD);
• Performance status 0-1 (ECOG)
• Patient compliance to trial procedures
• Age = 18 years
• Adequate BM function (ANC = 1.5x109/L, Platelets = 100x109/L, HgB > 9g/dl)
• Adequate liver function (bilirubin < G2, transaminases no more than 3xULN/<5xULN in present of liver metastases), no sever liver failure