Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with TP53^WT Merkel cell carcinoma (MCC).

Abstract

9506 Background: MCC is a rare, aggressive, neuroendocrine skin cancer with a high risk of recurrence and metastases. A median survival of about 4 mo for pts with metastatic MCC who failed anti-PD-1/L1 therapy highlights an urgent need for novel therapies. In TP53WT MCC, oncoproteins from the Merkel cell polyomavirus (MCPyV) inhibit p53 tumor suppressor functions by activating murine double minute 2 (MDM2). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Methods: The dose-finding, phase 1b/2 KRT-232-103 study (NCT03787602) evaluated navtemadlin in adult TP53WT MCC pts who failed anti-PD-1/L1 therapy. Pts were randomly assigned to oral navtemadlin once daily in 21- or 28-day cycles: 240 mg 7 days (D) on/14D off or 5D on/23D off, 180 mg 5D on/23 D off or 7D on/21D off, or 120 mg 7D on/14D off, until disease progression or unacceptable toxicity. The primary endpoint was Recommended Phase 2 Dose (RP2D); objective response rate (ORR) was assessed per RECIST v1.1. Results: As of Nov 30, 2021, 31 pts were enrolled with median age 66 y (range, 25-82); 52% had visceral disease and 71% had received ≥2 lines of prior therapy. Baseline tumor profiling of available samples showed low tumor mutation burden, MCPyV-positivity, and nonamplified MDM2 gene in 100%, 92%, and 100% of pts, respectively. Treatment-emergent adverse events (TEAEs) were observed in 100% (68% grade 3/4) of pts. The most common Grade 3/4 TEAEs were hematologic: 32% anemia, 32% lymphopenia, and 19% thrombocytopenia. Navtemadlin doses ≤180 mg were well tolerated with fewer dose reductions and longer treatment durations; subsequently the 240 mg arms were closed to further enrollment. Evaluable pts receiving 180 mg 5D on/23D off showed a 25% confirmed ORR, a 38% unconfirmed + confirmed ORR, and a 63% disease control rate (Table); median duration of response was not reached (range, 6-16.2+ mo) and median time to treatment response was 4.1 mo (range, 1.2-7). Notably, one responder, following a prolonged partial response, achieved complete metabolic remission by PET/CT after 2 y on treatment. The 120 mg arm was closed due to a low response rate. The 180 mg dose has been selected for further evaluation. Conclusions: Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/L1 therapy. This study demonstrates that upregulation of the p53 pathway is a viable therapeutic strategy in MCC. Clinical trial information: NCT03787602. [Table: see text]

The Development of p53-Targeted Therapies for Human Cancers

“…The efficacy of KRT-232 to treat wtp53 Merkel cell carcinoma (MCC) after the failure of anti-PD-1/L1 therapy was reported at the 2022 ASCO Annual Meeting, showing a confirmed ORR of 25%, a disease control rate (DCR) of 63%, and a median remission time of 4.1 months. Notably, one patient achieved CR confirmed by PET/CT after 2 years of treatment with sustained PR [25]. This study suggests that the upregulation of the p53 pathway would be a viable therapeutic strategy for MCC.…”

Polyomavirus-positive Merkel cell carcinoma: the beginning of the beginning

“…However, LTA retains its ability to target tumor-suppressor proteins such as retinoblastoma protein (Rb) and p53. The recent demonstration of meaningful therapeutic activity of an MDM2 inhibitor targeting the p53 pathway in patients with MCC indicates the oncogenic importance of this pathway ( 3 ).…”

Modern diagnostics and treatment of Merkel cell carcinoma

“…Novel therapeutic approaches currently investigated in clinical studies, either as monotherapies or combined with ICI, include the MDM2 inhibitor navtemadlin, which is intended to restore the activity of the tumor suppressor p53 in patients with p53 wild type MCC, 158 the VEGF (Vascular Endothelial Growth Factor) antibody bevacizumab, 159 and the modified herpes simplex type 1 virus RP1 160 . Another potentially promising option is intralesional treatment with the oncolytic virus talimogene laherparepvec (T‐VEC), with or without concomitant ICI treatment 161 or radiotherapy.…”