Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma

Abstract

Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. Patients were given prexasertib 105 mg/m as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed. Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress. Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m was confirmed as the recommended phase II dose. .

A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib

“…Hauge et al [32] reported that excessive p21 limits S phase DNA damage caused by the WEE1 inhibitor MK1775 (adavosertib), again supporting the notion that negative regulators of CDK2 may limit cytotoxicity to agents that target the ATR-CHK1-WEE1 pathway. Although these observations have supported cyclin E-centered hypothesis for prexasertib response, clinical actionability of this marker is limited by insufficient predictive power [12,13]. In addition, our preclinical data further supports this limitation in applicability as a single marker for patient selection.…”

“…Prexasertib is a small molecule kinase inhibitor displaying high selectivity for CHK1 followed by CHK2 [5]. An initial search for predictive biomarkers in these patients revealed a signal centered on cyclin E1, such as LOF mutations in the E3 ubiquitin ligase FBXW7 [12] and elevation of cyclin E1 protein levels [13]. Here, we confirmed that FBXW7 knockdown is associated with elevation of cyclin E1 protein levels, CDK2 activation, CHK1 signaling, and increased RS (as measured by pRPA2) and DNA damage (evidenced by γH2AX).…”

“…Previously, loss-of-function mutations in BRCA1 and FBXW7, an E3 ubiquitin ligase that marks cyclin E for proteolytic destruction [15], were associated with clinical benefit in patients with HNSCC or SCCA [12]. We hypothesized that loss of FBXW7 would lead to increased cyclin E1 and thus shift the equilibrium of CDK2 towards its active state, resulting in elevated basal level of RS and sensitivity to CHK1 inhibition.…”

“…Although our understanding of the causes and consequences of RS and its relevance to the ATR-CHK1 pathway has advanced considerably, these insights have not translated into the identification of biomarkers with the necessary predictive power for clinical implementation. A phase 1 clinical trial (NCT01115790) of single-agent prexasertib in head and neck squamous cell carcinoma (HNSCC) and squamous cell carcinoma of the anus (SCCA) identified loss-offunction (LOF) mutations in the E3 ubiquitin ligase FBXW7 in patients with clinical benefit [12]. High cyclin E1 expression, as measured by immunohistochemistry, was linked to clinical benefit of prexasertib monotherapy in a heavily pre-treated high-grade serous ovarian cancer (HGSOC) patient population [13].…”

Artificial T Cell Mimetics to Combat Melanoma Tumor Growth

“…Checkpoint inhibitors are a powerful new class on immunotherapies that are actively being investigated in several other types of cancers 19,20 . Anti-PD-1 antibodies have demonstrated durable response and prolonged overall survival in a broad variety of cancer types 4,21 including advanced melanoma.…”