Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42
De Sutter et al. Page 2859
During treatment, most gastrointestinal stromal tumors (GIST) will develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. De Sutter and colleagues tested the efficacy of IDRX-42, a novel specific KIT inhibitor, which showed significant antitumor activity in patient- and cell line-derived GIST xenograft models with volumetric responses, decreased mitotic activity, antiproliferative effects, and characteristic myxoid degeneration. Based on the promising results of this in vivo work, IDRX-42 is currently being investigated in a phase I first-in-human study (NCT05489237) in participants with advanced (metastatic and/or surgically unresectable) GIST.
Genome and Immunotherapy in Radiation-Induced Sarcomas
Hong et al. Page 2869
Radiation-induced sarcomas (RIS) show poor prognosis and lack effective treatment, along with showing increasing incidence globally. Hong and colleagues performed integrative analysis for genomic, transcriptomic, and immunological profile of RISs, revealing that this tumor has higher immune cell infiltration, higher PD-1/PD-L1 expression, and greater neoantigen burden than primary sarcoma. It is proposed that the combination of anti-PD-1 antibody and traditional chemotherapy could enhance treatment efficacy. These findings help to depict the genomic feature of these tumors and their related immunological landscape and provide evidence for the application of PD-1 blockade in RIS treatment.
A Novel Approach to Breast Radiation-Associated Angiosarcoma
Degnim et al. Page 2885
Radiation-associated angiosarcoma of the breast is a rare disease occurring after breast-conserving treatment, with an aggressive natural history and poor survival. Degnim and colleagues report on a novel trimodality treatment approach with neoadjuvant chemotherapy, concomitant chemoradiation, then wide surgical resection and reconstructive wound closure. Compared to mono- or dual-therapy approaches, trimodality therapy resulted in more frequent postoperative wound complications but demonstrated a high frequency of pathologic complete response (75%) and significantly better 5-year recurrence-free survival [93.8% vs 42.9%, P = 0.004, HR 7.6 (95% CI: 1.3–44.2)].
HLA Class II Loss and CD4 T cell Resistance in Melanoma
Stupia et al. Page 2894
CD4 T cells recently emerged as cytotoxic antitumor effectors, killing melanoma cells in a HLA-II-dependent manner. To unravel mechanisms of immune evasion, Stupia and colleagues determined HLA-II profiles of melanomas in longitudinal patient samples. Early lesions contained CD4 T cell-sensitive melanoma cells with HLA-II expression, either constitutive or inducible by IFNγ. In contrast, late outgrowing subclones showed stable HLA-II loss due to JAK1/2 inactivation, leading to cross-resistance to IFNγ and CD4 T cells. The association of HLA-II-low melanoma lesions with disease progression under immune checkpoint blockade suggests that patient outcome could be improved by restoration of cancer cell-intrinsic HLA-II expression.