Background: Src homology region 2 domain-containing phosphatase-2 (SHP2) activation mediates targeted therapy resistance in various oncogene-driven cancers. In this phase 1 study (NCT04800822), the novel SHP2 inhibitor PF-07284892 (ARRY-558) was evaluated alone and in combination with different targeted therapies in patients (pts) with oncogene-driven tumors that progressed on prior targeted therapy. Unlike other phase I studies, the unique design of this trial allowed pts to receive combination therapy during dose escalation after a period of PF-07284892 monotherapy. This is critical given that monotherapy efficacy was deemed unlikely based on preclinical data. Methods: Eligible pts with advanced solid tumors were enrolled into escalating dose cohorts of PF-07284892 monotherapy. In the absence of dose limiting toxicity (DLT), matched targeted therapy (lorlatinib for ALK/ROS1 fusion+ cancers, encorafenib + cetuximab for BRAF^V600E colorectal cancers, and binimetinib for MAPK-mutant cancers) could be added after 6 weeks of monotherapy at the discretion of the investigator. Primary objectives were safety, tolerability, and recommended dose for further evaluation (RDE) determination. Secondary/exploratory objectives included analyses of pharmacokinetics (PK), circulating tumor DNA (ctDNA), and monotherapy/combination therapy objective response (RECIST v1.1). Results: As of 9/19/2022, 33 pts with oncogene-driven solid tumors were enrolled (20-80 mg, orally twice weekly, day 1 and 4 or day 1 and 2 schedule), of whom 18 received combination therapy (5 ALK/ROS1 fusion+ cancers, 4 BRAF^V600E+ CRCs, 9 MAPK mutant cancers). The median age was 54.5 y (range 32-78). The most common treatment-related adverse events (TRAEs; >15%) for monotherapy were anemia (21%), peripheral edema (18%), and increased AST (18%). Cycle 1 monotherapy DLTs occurred in 4 pts: G3 increased AST, ALT, and bilirubin (n=1); anemia (n=1); and increased AST and ALT, and thrombocytopenia (n=1); and G4 bilirubin (n=1). PF-07284892 PK was dose proportional. 40 mg twice weekly (day 1 and 2) was selected as the RDE. With combination therapy, confirmed RECIST v1.1 partial responses (PR) were observed in 3 treatment-refractory pts (2 lorlatinib and 1 binimetinib combination), and stable disease was observed in 6 treatment-refractory pts. ≥80% ctDNA founder mutation reduction was observed post combination therapy initiation in 2 of the responding pts. Conclusions: PF-07284892 was generally well tolerated alone and in combination with rational targeted therapies. This study design enabled combination therapy rescue of disease progression on PF-07284892 monotherapy with 3 pts achieving confirmed PR. Clinical trial information: NCT04800822.