Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies

Key 1. Signed informed consent must be obtained prior to participation in the study. 2. Age ≥ 18 years. For Japan only: written consent is necessary both from the patient and his/her legal representative if he/she is under the age of 20 years. 3. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1. 4. Dose escalation part: Patients with advanced solid tumors, with evaluable disease as determined by RECIST version 1.1, and fit into one of the following groups: a. For TNO155 plus spartalizumab combination: i. Advanced EGFR WT, ALK WT NSCLC, after progression on or intolerance to platinum-containing combination chemotherapy and after progression on anti-PD-1 or anti-PD-L1 therapy. ii. Advanced HNSCC or esophageal SCC, after progression on or intolerance to platinum-containing combination chemotherapy. iii. Advanced CRC, after progression on or intolerance to all standard-of-care (SOC) therapy per local guidelines. b. For TNO155 plus ribociclib combination: Advanced solid malignancies with the exception of CRC or GIST, after progression on or intolerance to all SOC therapy per local guidelines. The exclusion of CRC applies only as of Protocol Amendment 4. 5. Dose expansion part: Patients with advanced solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who fit into one of the following groups: a. For TNO155 plus spartalizumab combination: i. Advanced EGFR WT, ALK WT, KRAS G12C NSCLC after progression on or intolerance to platinum-containing combination chemotherapy and after progression on anti-PD-1 or anti-PD-L1 therapy. ii. Advanced EGFR WT, ALK WT, KRAS WT NSCLC, after progression on or intolerance to platinum-containing combination chemotherapy and after progression on anti-PD-1 or anti-PD-L1 therapy. iii. Advanced HNSCC, after progression on or intolerance to, platinum-containing combination chemotherapy. b. For TNO155 plus ribociclib combination: i. Advanced EGFR WT, ALK WT, KRAS WT NSCLC, after progression on or intolerance to platinum-containing chemotherapy and anti-PD-1 or anti-PD-L1 therapy ii. Advanced HNSCC, after progression on or intolerance to all SOC per local guidelines 6. Patients with NSCLC whose tumors harbor genomic aberrations for which SOC targeted therapies exist and are locally approved and available must have had progression on or after, or intolerance to, the SOC targeted therapy/therapies as indicated 7. Patients must have a site of disease amenable to biopsy Key

1. Prior treatment with a MAPK pathway inhibitor 2. Clinically significant cardiac disease or risk factors 3. Use of any agent known to prolong the QT interval unless it can be permanently discontinued for the duration of study (see list in Section 6.2.2). 4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO 5. Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs 6. Symptomatic CNS metastases which are neurologically unstable 7. Insufficient bone marrow function at screening: 1. Absolute Neutrophil Count (ANC) \< 1.5 x 109/L. 2. Hemoglobin \< 9.0 g/dL. 3. Platelets \< 75 x 109/L for TNO155 plus spartalizumab combination; \< 100 x 109/L for TNO155 plus ribociclib combination. 8. Insufficient hepatic or renal function at screening: 1. Serum total bilirubin \> upper limit of normal (ULN) or, for TNO155 plus spartalizumab combination only, if liver metastases are present at baseline, serum total bilirubin \> 1.5 x ULN. An exception for either combination is for patients with Gilbert's syndrome, who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN 2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 x ULN for TNO155 plus spartalizumab combination or \> 2.5 x ULN for TNO155 plus ribociclib combination, or \> 5 x ULN for either combination if liver metastases are present. 3. Creatinine clearance \< 60 mL/min (calculated using Cockcroft-Gault equation). 9. Pregnant or breast-feeding (lactating) women. Additional