Lheureux et al. Page 4206

As PARP inhibitors (PARPi), including olaparib, are incorporated into first-line treatment for many cancers, identifying mechanisms of acquired resistance to these agents is an urgent unmet need. In a pilot phase II study, Lheureux and colleagues assessed the combination of cediranib, a VEGF inhibitor, and olaparib in patients with high-grade serous ovarian cancer (HGSOC). This combination was tolerable in patients previously progressing on PARPi. Resistance mechanisms were identified, including reversions in BRCA1/2 and RAD51, upregulation of ABCB1, amplification of CCNE1, and downregulation of SLFN11. Patients with reversion mutations in HRD genes and overexpression of ABCB1 had poor prognosis and may not be ideal candidates for cediranib–olaparib treatment. Further study is necessary to identify effective treatment options for these patients.

Song et al. Page 4216

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with overall poor prognosis. Bruton's tyrosine kinase (BTK) inhibition has been shown to be an effective therapeutic strategy in MCL, but TP53 mutations are associated with poor outcomes using the first-generation BTK inhibitor, ibrutinib. Song and colleagues assessed the safety and efficacy of zanubrutinib, an investigational BTK inhibitor, in patients with relapsed/refractory MCL. Zanubrutinib demonstrated high response rates, with 84% and 68.6% of patients achieving a partial and complete response, respectively. Patients with mutant TP53 showed response rates similar to patients with wild-typ. TP53. Further study will be required to confirm these observations in a broader population of patients.

Norsworthy et al. Page 4280

Ivosidenib and enasidenib are FDA-approved IDH1 and IDH2 inhibitors, respectively, which can cause a differentiation syndrome (DS) in patients with IDH-mutated AML. To determine the incidence and characteristics of DS in patients with relapsed or refractory AML, Norsworthy and colleagues performed a systematic analysis of data from phase 1/2 trials of ivosidenib and enasidenib using standard diagnostic criteria. A higher incidence of DS was identified compared with initial reports, and baseline bone marrow and peripheral blood blast percentages were observed to be potential risk factors. Use of standardized diagnostic criteria may enhance early identification and treatment of DS.

Zugazagoitia et al. Page 4360

Checkpoint inhibition targeting PD-1 is a fundamental component of treatment for advanced- stage non-small-cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to anti-PD-1 monotherapy. Using digital spatial profiling (DSP), Zugazagoitia and colleagues identified 12 protein markers independently associated with benefit from single-agent PD-1 checkpoint blockade in spatial context. High expression of CD56 and CD4 in the CD45 compartment were associated with favorable clinical outcomes, whereas high levels of VISTA and CD127 in the tumor compartment were markers associated with immunotherapy resistance. Increased CD56+ cells in the tumor stroma were predictive for PFS and OS in the same set of patients, as validated by immunofluorescence. Additional validation of these candidate predictors is necessary to further determine their applicability to NSCLC.