Pyrotinib Plus Thalidomide in Advanced NSCLC Patients Harboring HER2 Exon 20 Insertions

Inclusion Criteria: * Aged 18-80 years. * ECOG performance status 0-1. * Life expectancy ≥12 weeks. * At least one measurable lesion according to RECIST 1.1. * Histologically or cytologically confirmed advanced (IIIB or IV) non-small-cell lung cancer according to the 7th edition of TNM classification and staging system for lung cancer published by IASLC. * HER2 exon 20 insertions confirmed by next generation sequencing or polymerase chain reaction (if blood samples are used, the mutation abundance should be ≥10%). * Disease progression during or after platinum-based chemotherapy, or refusing chemotherapy (patients are allowed to have prior therapy with PD-1/PD-L1 inhibitors and/or antiangiogenic agents). * No more than two prior chemotherapy regimens (a. replacing platinum drug due to toxicity is considered as a new regimen; b. adjuvant chemotherapy is not considered as a prior regimen if disease recurrence occurred at more than 6 months after the last dose). * No radiotherapy within 3 months, or prior radiotherapy with radiation area \<25% of bone marrow area at least 4 weeks before enrollment. * Required laboratory values including following parameters: ANC: ≥ 1.5 × 10\^9/L, Platelet count: ≥ 90 × 10\^9/L, Hemoglobin: ≥ 90 g/L, INR: ≤1.5, APTT: ≤1.5 × ULN, Total bilirubin: ≤ 1.5 × ULN, ALT and AST: ≤ 2 × ULN for liver metastases, BUN and creatine: ≤ 1.5 × ULN, creatine clearance rate: ≥ 50 mL/min, LVEF: ≥ 50%, QTcF: \< 470 ms for female, \< 450 ms for male. * Willingness to use highly effective contraception from the start of the study to 90 days after the last dose of study drug. * Written informed consent. Exclusion Criteria: * Prior HER2-targeting therapies. * Other gene alterations with available targeted drugs, such as EGFR mutations, T790M resistance mutations, ALK fusions, ROS1 fusions, RET rearrangements, BRAF V600E mutations, NTRK fusions, and MET exon 14 skipping. * Factors influencing the oral administration of drugs, such as inability to swallow, chronic diarrhea, intestinal obstruction, or other gastrointestinal diseases or abnormalities. * With third space effusion that can not be controlled by drainage or other methods. * Radiotherapy, chemotherapy, surgery, or other targeted therapy for non-small-cell lung adenocarcinoma within 4 weeks. * Active brain metastases, meningeal metastases, spinal compression, or CT or MRI revealing brain or leptomeningeal diseases at screening (patients with symptomatically stable brain metastases can be enrolled if no cerebral hemorrhage is found by brain MRI, CT or venography). * Uncontrolled hypokalemia or hypomagnesemia. * Allergy history to the components of study drug. * History of immunodeficiency disease (including positive test of human immunodeficiency virus, active hepatitis B/C, or other acquired or congenital immunodeficiency disease) or organ transplantation. * History of cardiac diseases, including angina, arrhythmia requiring drug therapy or of clinical significance, myocardial infarction, heart failure, and other cardiac diseases unsuitable for this trial as judged by the investigator. * Patients with thrombotic disease or previous history of thrombosis. * Other malignancies within 5 years, except for cured cervical cancer in situ, skin basal cell cancer, and skin squamous cell cancer. * History of neurological or mental disorders, such as epilepsy and dementia. * Respiratory syndrome (dyspnea ≥grade 2 using NCI CTCAE 5.0). * Coagulation disorders (INR \>1.5, prothrombin time \>ULN + 4 s, or APTT \>1.5×ULN), with bleeding tendency or receiving thrombolytic or anticoagulant therapy. * Renal dysfunction (urine protein ≥++, or 24-hour proteinuria ≥1.0 g). * Participating in other clinical trials within 4 weeks. * Pregnant or lactating woman. * Concomitant diseases seriously affecting the patient safety or the completion of study as judged by the investigator, such as uncontrolled severe hypertension, severe diabetes mellitus, and active infection. * Any other condition unsuitable for the study as judged by the investigator.