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Navtemadlin (KRT-232) in combination with avelumab for patients with anti-PD-1/L1 treatment-naïve TP53WT Merkel cell carcinoma (MCC)

      Background and aims: Murine double minute 2 (MDM2) is the key negative regulator of the tumor suppressor protein p53. Upregulation of MDM2 contributes to MCC oncogenesis by inhibiting p53, thus promoting tumor proliferation. MDM2 is, therefore, a rational target in TP53WT MCC. Navtemadlin, a potent, selective, orally available MDM2 inhibitor, restores p53 function and drives tumor cell apoptosis. Preliminary analysis of the navtemadlin monotherapy cohort of the KRT-232-103 trial documents an ORR of 33% and an acceptable safety profile in 11 patients with advanced MCC who were relapsed/refractory to anti-PD-1/PD-L1 immunotherapy (Wong 2020). Murine tumor models suggest therapeutic synergy from the combination of MDM2 inhibitors and anti-PD-1/L1 immunotherapy. MDM2 inhibition can promote T-cell infiltration and host interferon response, postulated to underlie the resensitization of refractory tumors to anti-PD- 1/L1 rechallenge (Zhou 2021). Combination treatment promoted antitumor immunity in the tumor microenvironment, resulting in increased therapeutic activity (Wang 2021; Fang 2019). These preclinical studies demonstrate the potential for MDM2 inhibitors to enhance the activity of checkpoint inhibitors, supporting evaluation of this combination in MCC patients naïve to anti-PD-1/L1 therapy. Methods: To evaluate the navtemadlin and avelumab combination, the KRT-232-103 trial (NCT03787602) includes a cohort of patients with TP53WT metastatic MCC who are naïve to anti-PD-1/L1 therapy. This cohort is enrolling up to 12 patients treated with oral navtemadlin once daily on D1-7 of a 28-day cycle at doses of 120 or 180 mg. Avelumab is dosed at 800 mg IV on D1 and 15 of each cycle. Analysis of activity and safety will contribute to establishing the recommended phase 2 dose of navtemadlin plus avelumab; then an expansion cohort will enroll up to 27 patients. The primary endpoint is objective response rate (RECIST v1.1). Secondary endpoints include safety, duration of response, progression-free survival, and overall survival. Results: This trial is ongoing and enrolling patients at 26 global sites. Conclusions: The encouraging single-agent efficacy of navtemadlin in relapsed/refractory MCC, together with the strong biologic rationale for combining MDM2 inhibition with anti-PD-1/L1 therapy, support evaluation of navtemadlin plus avelumab in metastatic MCC patients who have not been treated with immune checkpoint inhibitors.