2020 Partner Awards Ibiayi Dagogo-Jack, MD Massachusetts General Hospital Boston MA Research Summary Despite initial sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), ALK-rearranged (ALK+) lung cancers invariably develop resistance. The majority of ALK+ lung cancers will eventually acquire ALK-independent survival mechanisms that allow them to escape ALK inhibition. These ALK-independent survival signals can originate from alternative growth receptors (“bypass tracks”). We have recently identified activation of MET signaling resulting from increased copies of the MET gene in approximately 20% of ALK+ tumors that are resistant to next-generation ALK TKIs. In the laboratory, combining lorlatinib with crizotinib (an ALK/MET TKI) overcame resistance caused by MET signaling. Based on these findings, we will conduct a trial to evaluate whether this promising combination can induce durable responses in ALK+ tumors with MET amplification. As many different bypass signals can mediate ALK-independent resistance in the remaining tumors, our trial will also evaluate whether dual targeting of ALK and MEK or SHP2 (proteins that serve as common signaling hubs for many different receptors) can broadly overcome resistance. During the study, serial biopsies will be performed to assess changes in gene and protein expression induced by treatment. This unique trial will also assess feasibility of using plasma findings to select patients with sensitive ALK+ NSCLC who may benefit from an early combination approach. The overarching goal of these studies is to develop multiple promising strategies for overcoming ALK-independent resistance. Technical Abstract With the development of increasingly potent and selective ALK tyrosine kinase inhibitors (TKIs), resistance is commonly mediated by ALK-independent mechanisms, such as bypass pathway activation. As bypass signaling dependencies vary across ALK-rearranged (ALK+) lung cancers, a multipronged approach is needed to broadly suppress potential bypass signals. We have identified MET activation in 20% of ALK+ tumors that are resistant to next-generation ALK TKIs. In preclinical studies, dual ALK/MET blockade re-sensitized MET-amplified ALK+ tumors to lorlatinib. MEK and SHP2 have recently been identified as important effector proteins downstream of several bypass signaling pathways. In ALK+ models harboring diverse bypass signals, pairing an ALK TKI with either a MEK or SHP2 inhibitor demonstrated broad anti-proliferative activity. Based on these findings, we will conduct a clinical trial to evaluate lorlatinib in combination with a MET, MEK, or SHP2 inhibitor for patients with ALK+ lung cancers with ALK-independent resistance. Serial tumor biopsies will be analyzed to characterize molecular determinants of response to combination therapy and identify expression changes induced by treatment. This innovative multi-arm trial will also assess whether dynamics of genetic alterations in plasma can be used to guide intensification of treatment from monotherapy to early combination therapy for patients who have not yet developed resistance to ALK-directed therapy. Collectively, the studies in this grant strive to develop diverse strategies for overcoming ALK-independent resistance, a heterogeneous molecular entity that undermines efficacy of current ALK therapeutics. Key words Acquired resistance Anaplastic lymphoma kinase (ALK) Biomarker or biomarker testing Circulating tumor DNA Metastatic Molecular profile or molecular testing Mutation profile Non-small cell lung cancer (NSCLC) Stage III Stage IV Tyrosine kinase inhibitors (TKIs)
