Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with TP53WT Merkel cell carcinoma (MCC).

Author:

Wong Michael K.K.1,Burgess Melissa Amber2,Chandra Sunandana3,Schadendorf Dirk4,Silk Ann W.5,Olszanski Anthony J.6,Grob Jean-Jacques7,Jang Sekwon8,Grewal Jaspreet Singh9,Lewis Karl D.10,Fecher Leslie Anne11,Rabinowits Guilherme12,Lebbe Celeste13,Shen Annalise14,Chan Tiffanie14,McGreivy Jesse S.14,Rothbaum Wayne P.14,Hanna Glenn J.5,Kelly Ciara Marie15

Affiliation:

1. The University of Texas MD Anderson Cancer Center, Houston, TX;

2. University of Pittsburgh School of Medicine Hillman Cancer Center, Pittsburgh, PA;

3. Northwestern University Feinberg School of Medicine, Chicago, IL;

4. University Hospital Essen, West German Cancer Center, Essen, Germany;

5. Dana-Farber Cancer Institute, Boston, MA;

6. Fox Chase Cancer Center, Philadelphia, PA;

7. Aix-Marseille University, APHM Hospital France, Marseille, France;

8. Inova Schar Cancer Institute, Melanoma and Skin Cancer Center, Fairfax, VA;

9. Norton Cancer Institute, Louisville, KY;

10. University of Colorado School of Medicine, Aurora, CO;

11. University of Michigan Health, Rogel Cancer Center, Ann Arbor, MI;

12. Miami Cancer Institute, Miami, FL;

13. Department of Dermatology and CIC, Université de Paris, AP-HP, Paris, France;

14. Kartos Therapeutics, Inc., Redwood City, CA;

15. Memorial Sloan Kettering Cancer Center, New York, NY;

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]

Funder

Kartos Therapeutics, Inc.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Cited by 10 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Polyomavirus-positive Merkel cell carcinoma: the beginning of the beginning;Journal of Clinical Investigation;2024-04-15

2. Moderne Diagnostik und Therapie des Merkelzellkarzinoms;JDDG: Journal der Deutschen Dermatologischen Gesellschaft;2023-12

3. Modern diagnostics and treatment of Merkel cell carcinoma;JDDG: Journal der Deutschen Dermatologischen Gesellschaft;2023-10-24

4. Current and preclinical treatment options for Merkel cell carcinoma;Expert Opinion on Biological Therapy;2023-09-20

5. The Development of p53-Targeted Therapies for Human Cancers;Cancers;2023-07-10

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