This is a Phase 2, open-label study to evaluate the efficacy and the safety/tolerability of pyrotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations or HER2 exon 20 insertion mutations. Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC.

Inclusion Criteria:

1. 18-80years，ECOG PS：0-2，Life expectancy of more than 3 months，with measurable lesion ( RECIST1.1).
2. Histologically or cytologic confirmed EGFR or HER2 Exon 20 Insertion Mutation positive advanced Non-small cell lung cancer who failed prior therapies.
3. ≥1 target lesion that has not received radiotherapy in the past 3 months and can be accurately measured in at least 1 direction；Previously received radiation therapy, but the radiotherapy area must be <25% of the bone marrow area, and radiation therapy must have closed for at least≥4 weeks at the time of enrollment.
4. Main organs function is normal.
5. Signed and dated informed consent.

Exclusion Criteria:

1. Patient has had previous treatment with Pyrotinib, Poziotinib or any other EGFR or HER2 exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study participation. The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible
2. Patients who planned to receive systemic anti-tumor therapy within 4 weeks prior to allocation or during the course of this study, including cytotoxic therapy, signal transduction inhibitors, immunotherapy (or receiving the Mitomycin C 6 weeks prior to medication). Extra-field radiotherapy (EF-RT) was performed 4 weeks prior to allocation or restricted radiotherapy for assessing tumor lesions within 2 weeks prior to allocation
3. With kinds of factors which affect oral medicine (e.g. failing to swallow, gastrointestinal tract getting resected, chronic diarrhea and ileus)
4. Subjects with uncontrolled hypokalemia and hypomagnesemia before study entry
5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Pyrotinib
6. History of immunodeficiency, including HIV-positive or other acquired, congenital immunodeficiency disease, or history of organ transplantation; active infection including hepatitis B (HBV DNA level ≥1000 copies /mL), hepatitis C and human immunodeficiency virus (HIV); Severe acute or chronic infections requiring systemic treatment
7. Subjects had any heart disease, including: (1) angina; (2) requiring medication or clinically significant arrhythmia; (3) myocardial infarction; (4) heart failure; (5) Any heart diseases judged by investigator as unsuitable to participate in the trial
8. Known history of neurological or psychiatric disease, including epilepsy or dementia
9. Has a history of malignant tumors. Except for patients with cutaneous basal cell carcinoma, superficial bladder cancer, cutaneous squamous cell carcinoma or orthotopic cervical cancer who have undergone curative treatment and have no disease recurrence within 5 years after the start of treatment
10. Respiratory syndrome (dyspnea≥CTC AE 2), severe pleural effusion, ascites, pericardial effusion
11. Abnormal blood coagulation (INR>1.5 or PT > ULN + 4s or APTT > 1.5 ULN), with bleeding tendency or receiving thrombolytic or anticoagulant therapy; Renal insufficiency: urinary protein ≥ ++, or 24-hour urine protein ≥ 1.0g
12. Patient has had other malignancies within the past 3 years, except for stable non-melanoma skin cancer, fully treated and stable early stage prostate cancer or carcinoma in situ of the cervix or breast without need of treatment
13. Patient is pregnant or breast-feeding
14. Judgment by the investigator that should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

De-identified individul participant data for all primary and secondary outcome measures will be made available.

Data will be available within 6 months of study completion

Data access requests will be reviewed by an external indepentent Review Panel. Requestors will be required to sign a Data Access Agreement.