Abdul Razak et al. Page 1087

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are both characterized by amplification of MDM2 and CDK4. Although inhibitors of both MDM2 and CDK4 have shown clinical promise as monotherapy, preclinical studies have revealed synergy between MDM2 and CDK4 inhibitors. To assess this combination treatment strategy, Abdul Razak and colleagues conducted a clinical trial combining siremadlin, a p53–MDM2 inhibitor, with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS. The toxicity profile of this combination was manageable. Furthermore, preliminary signs of clinical activity were observed, with 3 patients achieving a partial response and 38 achieving stable disease. These results suggest that the combination of siremadlin and ribociclib should be studied in future clinical trials.

Mehnert et al. Page 1098

The process of autophagy has been shown to lead to resistance to BRAF/MEK inhibition in BRAFV600-mutant melanoma. To investigate whether this resistance mechanism can be circumvented, Mehnert and colleagues conducted a phase I/II clinical trial assessing the combination of hydroxychloroquine (HCQ), an autophagy inhibitor, with dabrafenib and trametinib, in patients with BRAFV600-mutant melanoma. This combination was well tolerated but did not meet a previously determined criteria for success. That said, evidence of clinical activity was observed: a complete response rate of 41% was observed across the entire cohort, while a response rate of 88% was observed in patients with elevated LDH. A follow-up clinical trial is underway to further study this combination in patients with LDH-elevated, BRAFV600-mutant melanoma.

Bando et al. Page 1136

Ionizing radiation has been proposed to enhance the efficacy of checkpoint inhibitors. This combinatorial strategy has been shown to be effective in non-small cell lung cancer and other advanced cancer subtypes. To assess the efficacy of this strategy in patients locally advanced rectal cancer (LARC), Bando and colleagues conducted a phase I trial assessing chemotherapy followed by nivolumab and surgery. A pathological complete response (pCR) was observed in 30% and 60% of patients with MSS and MSI-H LARC, respectively. The authors observed elevated PD-L1 levels and CD8+/effector T-reg cell ratio in patients with pCR. Further clinical trials are needed to confirm these results and further establish prognostic biomarkers for this strategy.

Song et al. Page 1147

Tislelizumab is an anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fcγ receptors (FcγR) and subsequent antibody-dependent phagocytosis by macrophages. Song and colleagues conducted an extended three-year follow-up of a phase II clinical trial of tislelizumab in patients with relapsed/refractor classical Hodgkin lymphoma. Tislelizumab remained generally well-tolerated over this extended period. The overall response rate was 87.1%, and the complete response rate was 67.1%, with 3-year progression-free and overall survival rates of 40.8% and 84.8, respectively. Interestingly, FcγRI-positive macrophages did not correlate with CR or PFS. These results are encouraging, warranting further clinical investigation of tislelizumab.