Subbiah et al. Page 4160

Brain metastases are a major cause of morbidity and mortality in patients with RET fusion-positive non-small cell lung cancers. Subbiah and colleagues present safety and efficacy results of the LIBRETTO-001 Phase I/II trial in patients with RET fusion-positive NSCLCs with intracranial metastases. Selpercatinib was well tolerated, achieving a high intracranial response rate, as well as prolonged intracranial duration of response and intracranial progression-free survival. These important trial findings will help to further support selpercatinib as a new standard of care therap. for the primary systemic treatment for RET fusion-positive NSCLC patients with brain metastases.

Cortot et al. Page 4168

For patients with EGFR-mutant NSCLC, EGFR-TKI treatment has been effective. However, acquired resistance ultimately leads to disease progression, suggesting that TKI targeting resistance mutations, such as osimertinib, be reserved for second-line treatment. Preclinical studies have suggested that double EGFR inhibition by TKI and antibodies may be superior to TKI alone. To assess this strategy, Cortot and colleagues assessed the combination of afatinib plus cetuximab for first-line treatment of EGFR-mutant NSCLC. Although the safety profile was manageable, no benefit of this combination was observed compared to afatinib alone. A shorter PFS was observed to be correlated with mutant EGFR allele frequency. Therefore, this combination does not warrant further consideration, and alternative strategies to delay osimertinib are needed.

Virtakoivu et al. Page 4205

Clever-1 is a receptor expressed on immunosuppressive macrophages in the tumor microenvironment. To explore its potential as an immunotherapeutic drug target, Virtakoivu and colleagues studied the immune signatures in advanced cancer patients receiving a humanized monoclonal antibody targeting Clever-1 (FP-1305, bexmarilimab). The results show that bexmarilimab activates T cells and drives antitumor immune responses in cold tumors that are not otherwise responsive to immunotherapy. These findings suggest that adaptive immune activation can be achieved by modulating the behavior of macrophages and further support Clever-1 as an immunotherapeutic drug target.

Wang et al. Page 4287

Adaptive immunity and protumorigenic inflammation coexist in tumor microenvironments in delicate balance. However, this balance in human specimens has remained understudied. Integrating bulk and single cell RNA sequencing data from urothelial cancers, Wang and colleagues demonstrated that tumor microenvironments with increased features of protumorigenic inflammation relative to adaptive immunity, quantified as the 2IR score, were resistant to PD-1/PD-L1 blockade. Further, the authors identified that single myeloid phagocytic cells with increased expression of proinflammatory genes and decreased expression of antigen presentation machinery genes, inferred to be polarized by IL-1, were key contributors of such tumor microenvironments. Therefore, targeting such myeloid phagocytic cells in urothelial tumors demonstrating increased features of protumorigenic inflammation relative to adaptive immunity may overcome a key mechanism of intrinsic resistance to PD-1/PD-L1 blockade.