Selected Articles from This Issue

Pharmacologic inhibition of the δ isoform of phosphatidylinositol 3-kinase (PI3Kδ) reduces proliferation, migration, and survival of the malignant B-cell leukemia and lymphoma cells. The novel orally active PI3Kδ inhibitor linperlisib has shown a notable efficacy in B-cell lymphomas, especially for a FL subgroup, in a previous phase I study. In this phase II trial, Wang and colleagues report that linperlisib demonstrated compelling efficacy and was generally well tolerated in the treatment of relapsed or refractory FL patients after two or more prior systemic therapies.

Enfortumab vedotin (EV) releases a cytotoxic agent into the urothelial cancer (UC) cell via binding to the surface protein NECTIN-4. Although EV is approved in the metastatic disease stage, the NECTIN-4 expression in metastatic UC tissue is insufficiently studied. Here, Klümper and colleagues demonstrate that NECTIN-4 expression decreases substantially during metastatic evolution and is absent in more than one-third of metastases. Further, loss of membranous NECTIN-4 expression predicts failure to EV. These data argue against the current assumption of ubiquitous NECTIN-4 expression in UC and suggest that NECTIN-4 receptor status should be determined (ideally in a metastatic lesion) before starting EV.

The clinical performance of plasma cell-free DNA (cfDNA) sequencing in non-small cell lung cancer (NSCLC), especially for the detection of rare fractions of oncogenic drivers, has not been fully investigated because a large-scale cohort is needed. To clarify this concern, Sugimotoa and colleagues examined concordance between plasma cfDNA sequencing and tissue assay using the largest screening cohort. Plasma cfDNA sequencing in advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. Plasma cfDNA sequencing may be an alternative assay only when tissue assay is unavailable due to insufficient DNA and RNA.

Pantel and colleagues describe mechanistic preclinical studies and early patient studies using the PET imaging agent, [18F]-FluorThanatrace ([18F]FTT) to predict ovarian cancer response to PARP inhibitors (PARPi) alone and in combination with ATR inhibition. This study builds on earlier work demonstrating the ability of [18F]FTT to quantify regional PARPi binding and by testing the ability of [18F]FTT PET to predict response to PARPi treatment and combinations in ovarian cancer. In particular, preclinical studies support the ability of serial [18F]FTT binding pre- and post-therapeutic doses of PARPi as a measure drug-target engagement, and clinical studies show that the decline in tracer uptake early post-PARPi predicts response to PARPi alone or in combination with an ATR inhibitor. These studies, the first of their kind on this topic, support future studies to investigate a possible role to guide PARPi drug selection and dosing for ovarian cancer patients.