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 imaging assessment. Local pathology reported findings consistent with PTCL upon post-baseline biopsy of one of these lesions. Pre- and post-baseline biopsies were analyzed for differences in RNA-expression of immune-related genes, and showed changes consistent with p53-mediated immunomodulatory effects. Despite formal progression due to transient PET-avid lesions, both pts remained on therapy, subsequently achieving a confirmed PR.

A pt treated with TIW ALRN-6924 (pt 13-196) exhibited worsening abdominal pain by Day 5 of ALRN-6924, with CT scans on days 6, 11, and 22 showing transient enlargement and increased number of nodes, splenomegaly, and ascites, consistent with progression. The pt continued therapy with resolution of clinical symptoms, and an efficacy assessment after 3 cycles showed dramatic reduction in lesion sizes and FDG-avidity, assessed as a PR (unconfirmed).

Preclinically, in mice treated with ALRN-6924, a significant increase in tumor-infiltrating CD8+ T cells and M1-polarized macrophages was found in murine TRP53-WT CT26 tumors as well as in TRP53-mutant MC38 tumors.

Conclusion: Treatment of PTCL with ALRN-6924 can be associated with PsP. Pts have benefitted from treatment beyond radiologic progression, with new FDG-avid lesions resolving over time. Murine tumor models plus changes in immune-related gene expression in pre- and post-baseline tumor samples from pts suggest that p53-mediated immune-activation may account for these findings. Transient tumor flare observed in pts, was consistent with increased immune cell infiltration that was detected after p53-activation in the tumor microenvironment of TRP53-mutant syngeneic models. ALRN-6924 is a promising anticancer agent that warrants further investigation and consideration should be given to possible pseudoprogression prior to discontinuing pts from treatment with ALRN-6924.