Inclusion
Inclusion Criteria Umbrella Phase 1b & 2:
- Histologically or cytologically confirmed locally advanced/metastatic (Stage IIIB-IV) NSCLC.
- At least one measurable lesion per RECIST v1.1 at Screening.
- ECOG Performance Status 0 or 1.
- Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1.
- Adequate hepatic, renal, and bone marrow function.
Additional Inclusion Criteria for Sub-Study A Phase 1b &2:
-BRAFV600E mutation in tumor tissue or plasma as determined by a local laboratory PCR or NGS assay and documented in a local pathology report.
Additional Inclusion Criteria for Sub-Study A Phase 1b only:
-Any line of therapy for locally advanced/metastatic NSCLC.
Additional Inclusion Criteria for Sub-Study A Phase 2 only:
-Previously untreated for locally advanced/metastatic NSCLC
Additional Inclusion Criteria for Sub-Study B Phase 1b only::
-Any line of therapy for locally advanced/metastatic NSCLC.
Additional Inclusion Criteria for Sub-Study B Phase 2 only:
- Previously untreated for locally advanced/metastatic NSCLC (Arms B1 & B2), or
- One or 2 prior lines of therapy for advanced/metastatic NSCLC (Arm B3), including immune checkpoint inhibitor treatment + chemotherapy, and have progressed during or after that therapy.
- PD-L1 TPS ≥1%
Exclusion
Exclusion Criteria Umbrella Phase 1b &2:
- Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
- Active non-infectious pneumonitis, pulmonary fibrosis, or known history of immune-mediated pneumonitis.
- Active infection requiring systemic therapy.
- Clinically significant cardiovascular disease.
- Other malignancy within 2 years of first dose, with exceptions.
- Symptomatic brain metastasis, with exceptions.
Additional Exclusion Criteria for Sub-Study A Phase 1b&2:
- EGFR mutation, ALK fusion oncogene, or ROS1 rearrangement.
- Prior treatment with any BRAF inhibitor or MEK inhibitor.
Additional Exclusion Criteria for Sub-Study A Phase 2 only:
-Prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents.
Additional Exclusion Criteria for Sub-Study B Phase 1b&2:
-Documentation of any tumor-driving molecular alteration (eg, BRAF, EGFR, ALK)
Additional Exclusion Criteria for Sub-Study B Phase 2 only:
- Prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents.(Arms B1 & B2)
- Confirmed progressive disease on 1st or 2nd imaging tumor assessment after initiation of therapy for advanced/metastatic NSCLC.