Pseudoprogression (PsP) in Patients with Peripheral T-Cell Lymphoma (PTCL) Treated with the Novel Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2

Background: ALRN-6924, an α-helical stapled p53 peptide, is the first-in-class and only dual inhibitor of MDMX and MDM2 currently in clinical trials for both, solid and hematologic malignancies. In tumors with wild-type (WT) TP53, ALRN-6924 can induce p53-dependent cell cycle arrest and apoptosis and separately can invoke p53-mediated immunomodulatory effects, including but not limited to lymphocyte chemotaxis and diminution of PD-L1 expression on tumor cells. This report begins to describe the biologic underpinnings of PsP in selected PTCL patients (pts) treated with ALRN-6924. Despite imaging-based progressive disease (PD), careful monitoring for clinical benefit in light of conflicting imaging (PsP) results led to the decision to treat beyond radiologic progression and the observation of subsequent, delayed radiologic responses. Methods: Pts with relapsed or refractory PTCL received either 3.1 mg/kg ALRN-6924 on days 1, 8, and 15 of a 28-day cycle (QW) or Days 1, 3, and 5 of a 21-day cycle (TIW). Responses were assessed locally using IWG 2014 criteria as well as through independent radiology assessment. Treatment continued until symptomatic PD, unacceptable toxicity, or other indication for withdrawal. Continuation beyond radiologic PD was permitted for perceived clinical benefit. RNA-based immune profiles from pre- and post-treatment tumor biopsies from pts who were treated with ALRN-6924 were evaluated by gene expression panels. Clinical findings were correlated with CT26 and MC38 murine syngeneic tumor models, where immune cell infiltration after ALRN-6924 dosing was measured by flow cytometry. Results: PsP was observed in 3 PTCL pts who eventually achieved a PR. A pattern of transient tumor flare and new lesion formation was noted in one pt (pt 13-196) while the other 2 PsP pts (pt 3-159 and 11-155) had atypical PsP patterns, including tumor shrinkage by CT, but transient new and/or increased 18Fluorodeoxyglucose (FDG)-PET uptake. In one pt, there was rapid clinical improvement of malignant hypercalcemia and B symptoms despite formal IWG 2014 progression after 2 cycles of ALRN-6924 QW treatment plus an additional transient episode of PsP due to new FDG-avid lesions at cycle 8. Another pt had a similar PsP pattern with decrease in lesion size on CT but increased FDG-avidity of target lesions following 2, 4, and 6 cycles of QW-therapy with ALRN-6924, with new FDG-avid lesions that appeared, and then resolved in different anatomical locations at each i