A multicenter single-arm phase II interventional study to evaluate the activity and safety of the combination of Platinum-Pemetrexed based chemotherapy plus Lorlatinib in ALK positive Non-Small Cell Lung Cancer (NSCLC) with exclusively extracranial disease progression on Lorlatinib

Prior treatment

• Presence of toxicities contraindicating the continuation of therapy with Lorlatinib
• Concomitant use of potent CYP3A4/5 inducers

Other illness

• Known hypersensitivity reaction to one of the compounds or substances used in this protocol
• Diagnosis of any secondary malignancy within the last 3 years, except for: adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, definitively treated nonmetastatic prostate cancer or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy

Other

• Patients deemed unsuitable by the investigator for treatment of chemo-Lorlatinib combination

• Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained, and documented according to the local regulatory requirements
• Estimated life expectancy of at least 3 months irrespective of the diagnosis of ALK+ NSCLC
• For women of childbearing potential and males with partners of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 14 weeks after the last dose of study drugs
• Age at the time of signing the informed consent at least 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Histologically or cytologically confirmed diagnosis of stage IV ALK positive NSCLC. ALK positivity can be determined by fluorescence in situ hybridization assay (FISH), immunohistochemistry (IHC) or DNA-based next-generation sequencing (NGS)
• Patients must have measurable disease according to RECIST 1.1 by computed tomography (CT) and magnetic resonance imaging (MRI)
• patients must be in progression extracranially on Lorlatinib; Lorlatinib may be in first- or further-line, without limitations regarding previously received therapies. If a patient has already received platinum (e.g. in adjuvant setting), the eligibility for PT-pem chemotherapy treatment is at the Investigator discretion
• Radiologically confirmed multiple extracranial progression on Lorlatinib without progression in the central nervous system (CNS) defined as: • Absence of CNS metastasis • CNS metastasis stable on Lorlatinib and/or stereotactic brain irradiation (SBRT) • Prior radiotherapy must have been completed within 4 weeks of study entry; SBRT must have been completed at least 4 weeks before study entry; and whole-brain radiotherapy at least 4 weeks before study entry. • Patients with previously treated brain metastases are eligible provided they have been clinically stable for at least 4 weeks with no evidence of new or expanding brain metastases
• Adequate organ function (kidney, bone marrow and liver): - Hematology • Absolute Neutrophil Count (ANC) ≥1.5 x 109 / L • Platelets ≥100 x 109 / L • Hemoglobin ≥10 g/dL (≥6.2 mmol/L) - Hepatic function • Total bilirubin <1.25x UNL. In presence of a documented history of Gilbert syndrome the total bilirubin level must be <3.0x UNL • AST and ALT ≤1.5x UNL. If the liver has tumor involvement AST and ALT must be ≤5x UNL • Alkaline phosphatase ≤2.5x UNL - Renal Function • <1.25x ULN creatinine • Creatinine clearance ≥45 ml/min (according to Cockroft-Gault, if creatinine is above UNL)
• If feasible, fresh tissue biopsy demonstrating ALK translocation still present (obtained ≤ 3 months before study enrolment), assessed by local laboratory