Selected Articles from This Issue

Advanced progressive dedifferentiated liposarcoma (DDLS) tumors frequently harbor copy number alterations in chromosome 12q, which encompasses CDK4. Phase II clinical trials assessing CDK4/6 inhibitors have shown modest success in extending progression-free survival (PFS) in patients with liposarcoma, potentially by inducing cell senescence or enhancing antigen presentation in tumor cells. In this phase II trial, Gleason and colleagues evaluate the efficacy of the CDK4/6 inhibitor abemaciclib in patients with DDLS and investigate the mechanism by which abemaciclib exerts its antitumoral effects. The authors note a median PFS of 33 weeks, with 76.7% of patients progression-free at 12 weeks and no new adverse events. Additional preclinical work in liposarcoma cell lines identified ANGPTL4 as a regulator of cell progression from quiescence to senescence and inflammation. The authors found that senescence modulates the immune tumor microenvironment as demonstrated by an increase in CD4⁺ leukocyte infiltration, yet patients with both senescence and increased tumor-infiltrating leukocytes were more likely to develop resistance. In light of this, the authors propose a combination of abemaciclib with senescent cell-clearing senolytics to improve the duration of response in this subset of patients.

The use of tyrosine kinase inhibitors (TKI) targeting mutations in KIT and PDGFRA has become the standard of care in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST). Specific KIT mutations are known to affect response to certain TKI, highlighting the need for individualized treatments based on tumor genotypes. Avapritinib, a recently approved, highly selective KIT and PDGFRA inhibitor, has improved outcomes in the subset of patients with GIST harboring specific mutations in PDGFRA or KIT. In this study, Heinrich and colleagues investigate the efficacy of avapritinib in patients with non-PDGFRA-mutant GISTs from the phase I NAVIGATOR and phase I/II CS3007–001 NAVIGATOR-bridging trials and identify patient cohorts with KIT mutations who may benefit from avapritinib. The authors found that patients positive for KIT activating loop mutations (AL^pos) and negative for KIT ATP binding pocket mutations (ABP^neg) had a significantly higher overall response rate and significantly longer median progression-free survival than patients carrying other KIT mutations. Additionally, patients with mutations in KIT exon 9 who had received ≥4 treatment lines also were found to benefit from avapritinib treatment. Given the enhanced antitumor activity in patients with GIST harboring KIT AL^posABP^neg or exon 9 mutations, the authors stress the utility of personalized therapy selection based on genotype.

The interaction between angiopoietin-1 or -2 (Ang1/Ang2) and the Tie2 receptor is a critical regulator of angiogenesis implicated in breast cancer development and progression, providing a potential therapeutic target. Preclinical studies with trebananib–a peptide-Fc fusion protein blocking the Tie2 and Ang1/Ang2 interaction–demonstrated a reduction in tumor growth, increased vessel regression, and possible synergy with taxane-based chemotherapy. In humans, the combination of trebananib and taxane-based chemotherapies increased progression-free survival (PFS) in patients with advanced ovarian cancer. In the I-SPY2 neoadjuvant platform phase II trial, Albain and colleagues assess the efficacy of trebananib plus paclitaxel-based chemotherapy with or without the HER2-targeting immunotherapeutic trastuzumab in patients with stage II/III breast cancer. Trebananib was well tolerated, with no significant increase in adverse events compared to control patients without trebananib treatment. The addition of trebananib to paclitaxel-based chemotherapy increased 3-year event-free survival and increased the probability of higher pathologic complete response (pCR) rates compared to control in patients with HR-negative/HER2-positive and HR-negative/HER2-negative subtypes. An exploratory biomarker analysis of the Ang/Tie2 axis revealed that Tie2 and downstream effector activation levels could predict trebananib response in HER2-positive patients and increased expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative patients. These results warrant further study of the Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes.

Endocrine therapy (ET) is a standard-of-care treatment for patients with estrogen receptor (ER)-positive breast cancer, and the addition of CDK4/6 inhibitors has been shown to improve patient outcomes. Mutations in the ER-encoding gene ESR1, often lead to resistance during or after treatment. The development of novel ER-targeting therapies with acceptable safety profiles is needed to delay disease progression, overcome resistance, and prolong survival. The orally available ER-antagonist giredestrant has shown encouraging results in preclinical and clinical studies. In a phase Ia/Ib dose-escalation and expansion study, Jhaveri and colleagues assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of giredestrant alone or combined with the CDK4/6 inhibitor palbociclib in patients with ER⁺, HER2-negative (HER2⁻) locally advanced/metastatic breast cancer. The treatment was well tolerated, with no dose-limiting toxicities, and an ESR1 mutation-independent clinical benefit was observed in both patients treated with giredestrant alone or giredestrant with palbociclib. Given these promising results, the authors highlight a need for further evaluation in randomized trials of early- and late-stage disease.