An open-label, multicenter, phase 2 study of the safety and efficacy of navtemadlin (KRT-232) in patients with TP53 wild-type relapsed/refractory small cell lung cancer.
Authors: Dowlati Afshin , Juan-Vidal Oscar , Hiret Sandrine , Rittmeyer Achim , Sukumaran Shawgi , Vicente Baz David , Rios-Perez Jorge Arturo , Harris Eric Michael , McCune Steven L. , Johnson Melissa Lynne , Croft Brandon , McGreivy Jesse S. , Rothbaum Wayne P. , de Castro Carpeño Javier 
Published: June 2022

TPS8600 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early metastasis and a high recurrence rate with currently available treatment options. Although SCLC is generally sensitive to initial chemotherapy, responses are not durable and most patients eventually relapse. Prognosis is poorer in the relapsed/refractory (R/R) setting and currently available treatment options, including checkpoint inhibitors, are associated with a median overall survival of 2-9 months (Chauhan 2020; Trigo 2020; Chung 2020). Approximately 15% of patients have a TP53 wild-type ( TP53WT) gene. In patients with extensive-stage SCLC, TP53WT is paradoxically associated with an inferior response to chemotherapy (Dowlati 2016). Thus, the presence of TP53WT may help identify a small subset of patients with an even greater unmet need. Murine double minute 2 (MDM2) is the key negative regulator of the tumor suppressor protein, p53, which can induce apoptosis of malignant cells by shifting the balance between prosurvival and proapoptotic BCL-2 family members. In SCLC cell lines, MDM2 inhibition restored p53 function leading to downregulation of prosurvival Bcl-2 and Mcl-1 proteins, and upregulation of the proapoptotic Bim protein, thereby inducing cancer cell death (Yu 2019). Navtemadlin (KRT-232) is a potent, selective, orally available MDM2 inhibitor that restores p53 function to drive apoptosis of TP53WT malignancies. Treatment with navtemadlin may be an effective strategy for patients with TP53WT SCLC. Methods: The open-label, multicenter Phase 2 KRT-232-112 study (NCT05027867) is evaluating navtemadlin in TP53WT patients with R/R SCLC. Eligibility criteria include age ≥18 years, ECOG performance status ≤2, presence of measurable disease and demonstrated radiographic progression after ≥1 prior platinum-containing therapy with no curative therapy available. Patients must have received a checkpoint inhibitor if available and not contraindicated. Patients with symptomatic or uncontrolled central nervous system metastases or those with prior MDM2 inhibitor treatment will be excluded. In part 1 of the study, approximately 20 patients will be randomly assigned to receive oral navtemadlin once daily in 21-day cycles at 240 mg 7 days (D) on/14D off (Arm A) or 180 mg 7D on/14D off (Arm B) until disease progression or unacceptable toxicity. In part 2, an additional 18 patients will be enrolled in each arm selected for expansion. The primary endpoint is objective response rate per RECIST v1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, and safety. This trial is ongoing and will enroll patients at approximately 40 global sites. Clinical trial information: NCT05027867.