Pacritinib Demonstrates Safety in Solid Tumors Harboring 1q21.3 Amplifications

Treatment with pacritinib (Vonjo) at 200 mg given twice daily was found to be tolerable with a reasonable safety profile in patients with solid tumors harboring 1q21.3 copy number amplifications, according to data from a phase 1b/2 trial (NCT04520269) presented at the 2024 ASCO Breakthrough Conference.

Regarding treatment toxicity, 2 dose-limiting toxicities (DLTs) of grade 3 transaminitis were recorded at dose level 1 of 200 mg twice per day; 2 patients treated at this dose level also experienced intolerable grade 2 rashes, although these toxicities were resolved with antihistamines. No DLT were reported when pacritinib was dosed at 200 mg in the morning and 100 mg at night (dose level 2). When pacritinib was re-escalated to 200 mg twice per day (dose level 3), no additional DLTs occurred.

The adverse effect (AE) profile of the agent was similar to the known toxicity profile of pacritinib. Overall, 5 patients experienced grade 3 transaminitis; notably, all of these patients had known liver metastases, and 4 were found to have worsening liver disease progression. All toxicities resolved without sequelae after pacritinib was discontinued.

Regarding efficacy, no patients (n = 24) with solid tumors harboring 1q21.3 copy number alterations experienced responses. Two patients had stable disease. One patient with pancreatic cancer had a progression-free survival (PFS) of 24.9 weeks, and 1 patient with cholangiocarcinoma had a PFS of 15.9 weeks.

“While no objective responses were observed thus far, meaningful disease control was observed in 2 patients with pretreated hepatobiliary tumors,” Joline Lim, MD, of the National University Cancer Institute, in Singapore, said during a presentation of the data.

Copy number alterations of 1q21.3 are more frequently observed in recurrent and metastatic diseases vs primary tumors or healthy individuals, and detection of this copy number alteration and immunohistochemistry testing has revealed a correlation between 1q21.3 copy number alterations and IRAK1 overexpression. The JAK2 inhibitor pacritinib, which is approved by the FDA for treating select patients with intermediate- or high-risk primary or secondary myelofibrosis, has also shown activity against IRAK1.

The phase 1b/2 study assessed the safety and effectiveness of pacritinib in patients with refractory solid tumors using plasma 1q21.3 copy number alterations as a biomarker for selection.

The study used a 3+3 dose-escalation design, initially followed by dose expansion in 2 cohorts: 1 for patients with breast cancer and another for those with other solid tumors. Due to patient enrollment challenges, the investigation was modified to a single dose-expansion cohort. Serial tumor and plasma samples were also collected for translational studies to explore the mechanistic impact of IRAK1 inhibition on the tumor microenvironment and its effects on immune function and biomarker modulation.

Investigators pre-screened 555 patients for 1q21.3 copy number alterations, of which 461 patients passed quality control with readout. A total of 28.6% of these patients (n = 132) tested postitive for 1q21.3 copy number alterations. Of patients who tested positive, they presented with the following tumor types: colorectal (35.7% of screened patients positive for 1q21.3 copy number alterations), breast (36.6%), hepatobiliary (20.0%), lung (34.6%), gynecological (22.0%), genitourinary (19.4%), upper gastrointestinal (9.1%), musculoskeletal (22.2%), head and neck (40.0%), and other (18.2%).

At dose level 1, 6 patients were treated with 200 mg twice daily; at dose level 2, 3 patients received pacritinib at 200 mg once in the morning and 100mg once at night; at dose level 3, 3 patients received pacritinib at 200 mg twice daily; and in the expansion cohort, 12 patients were treated with pacritinib at 200 mg twice daily, where 2 patients were ongoing treatment.

In the 24 patients enrolled on the study, the median age was 60 years (range, 25-78), and the median 1q21.3 copy number alterations was 1.28 (range, 1.14-2.50). Patients received a median of 5 prior lines of treatment in metastatic setting (range, 2-11), including 25% of patients who underwent prior immunotherapy. Moreover, patients presented with colorectal (37.5%), breast (8.3%), hepatobiliary (33.3%), lung (8.3%), other (8.3%), or gynecological (4.2%) tumors.

Notably, 3 patients with paired tumor biopsies at baseline and 2 weeks after starting pacritinib treatment did not experience statistically significant changes in the percentage of various immune cell subpopulations. In these patients, there was a trend toward an increase in CD8-positive cytotoxic T cells (2.77% vs 8.57%; P = .07) and a potential increase in the population of PD-L1–positive cells (0.77% vs 3.00%; P = .12).

"Further translational studies to understand the effects of pacritinib using serial tumor and plasma samples are underway," Lim concluded.

Disclosures: Dr Lim reported speaking, consultancy, and advisory relationships with AstraZeneca, DKSH, Eisai, Gilead, MSD, Novartis, Pfizer, Pierre-Fabre, and Roche; and research relationships with Sobi Inc, Dalichi Sankyo, Taiho pharmaceuticals, Synthon pharmaceuticals.

Reference

1. Lim JSJ, Yee AM, Yeong J, et al. phase lb/ll study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients with solid tumors harboring the 1q21.3 copy number amplification. J Clin Oncol. 2024;42(suppl 23):43. doi:10.1200/JCO.2024.42.23_suppl.43