Targeted therapy combinations are poised to transform cancer care, but traditional phase I trial designs make exploration difficult in early clinical development. After preclinically demonstrating that the novel SHP2 inhibitor PF-07284892 (ARRY-558) overcomes resistance to diverse targeted therapies, Drilon and colleagues used an alternative dose-escalation design in a phase I trial, allowing for oncogene-matched targeted therapy addition after a SHP2 inhibitor monotherapy lead-in period. In targeted therapy–resistant oncogene-driven cancers treated at dose level one, combination therapy led to rapid tumor and circulating tumor DNA reduction, providing proof of concept for an efficient and patient-centric paradigm for investigating novel–known drug combinations.
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