This is a Phase Ⅰ/Ⅱa, multi-center, open-label study, aiming to evaluate the safety, tolerability, pharmacokinetic (PK), and efficacy of BR790 in combination with anlotinib in adult participants with advanced NSCLC.

This study is a Phase Ⅰ/Ⅱa, multi-center, open-label study of BR790 in combination with anlotinib with a dose escalation part followed by a dose expansion part in adult subjects with advanced NSCLC. Participants will be treated until disease progression per RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met, whichever occurs first.

Inclusion Criteria:

• Age ≥18 and ≤75 years old.
• Subjects with histologically or cytologically confirmed locally advanced or relapsed metastatic driver negative (EGFR, ALK, ROS, etc.) advanced NSCLC，whose disease progressed after at least 2 previous standard therapies.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Has at least one measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) .

Exclusion Criteria:

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has uncontrolled moderate to massive effusion.
• Central lung squamous carcinoma along with cavum, or non-small cell lung cancer along with hemoptysis (>50ml/day).
• Other kinds of malignancies within 5 years or for now.
• Has not enough organ functional reserve at baseline, which met at least one of the following criteria： ANC<1.5×10^9/L, PLT<100×10^9/L, Hb<100g/L; TBIL>1.5×ULN, ALT or AST>2.5×ULN (without liver metastases) , ALT or AST>5×ULN (with liver metastases);Cr >1.5×ULN, urine protein≥++，or confirmed 24h urine protein≥1.0g;INR >1.5×ULN, PT>1.5ULN or APTT >1.5×ULN.
• Previous use of other SHP2 inhibitors (such as TNO-155, JAB-3312, JAB-3068, RLY-1971, RMC-4630, etc.)
• Has used anlotinib before
• The first assessment of efficacy was PD, or occurred ≥grade 3 adverse reactions with antitumor angiogenesis small-molecule drugs (e.g. Apatinib, surufatinib, fruquintinib, etc.), or less than 6 months after the last antitumor vascular therapy.
• Has got non remissive toxic reactions derived from previous therapies, which is over level 1 in CTC AE (5.0), alopecia and grade 2 peripheral neuropathy are not included.