ZN-c3 Shows Preliminary Efficacy, Safety in Recurrent/Advanced Uterine Serous Carcinoma

Funda Meric-Bernstam, MD

The investigational Wee1 inhibitor ZN-c3 was found to be safe and to produce a disease control rate (DCR) of 90.9% (95% CI, 58.7%-99.8%) and an objective response rate (ORR) of 27.3% (95% CI, 6.0%-61.0%) in patients with advanced or recurrent uterine serous carcinoma, according to preliminary cohort dose-expansion findings from the phase 1 ZN-c3-001 trial (NCT04158336) that were presented during the 2022 AACR Annual Meeting.¹

Of the 11 patients with uterine serous carcinoma who had measurable disease and at least 1 post-baseline tumor assessment, the unconfirmed complete response (CR) rate with ZN-c3 was 9.1% and the confirmed partial response (PR) rate was 18.2%. Moreover, 63.6% of patients had stable disease for at least 12 weeks (36.3%) or less than 12 weeks (27.3%); 9.1% of patients experienced progressive disease.

Of the 3 patients who responded to treatment, the median duration of response (DOR) was 5.55 months (95% CI, 4.11–not available). Additionally, the median progression-free survival (PFS) was 4.2 months.

“ZN-c3 appears to be safe and well tolerated as a single agent and demonstrated clinical activity in subjects with recurrent or advanced uterine serous carcinoma,” lead study author Funda Meric-Bernstram, MD, chair of the Department of Investigational Cancer Therapeutics—the Phase I Program at The University of Texas MD Anderson Cancer Center, said in a presentation on the findings. “Although this group is small, there is preliminary efficacy in [this patient population].”

ZN-c3 is a selective and orally bioavailable small molecule inhibitor of Wee1, which is a crucial component of the G2/M cell cycle checkpoint that prevents cells from entering mitosis. It also allows for repair of DNA damage prior to cell cycle progression. By inhibiting Wee1, the cancer cells can proceed to mitosis without DNA damage repair, which in turn leads to premature mitotic entry and apoptosis.

In human xenograft tumor models, ZN-c3 was found to demonstrate significant growth inhibition and to induce apoptosis in vitro in multiple cell lines and antitumor activity in vivo.²

Uterine serous carcinoma, which is the most common gynecologic cancer in the United States, is molecularly characterized by frequent cell cycle alterations and high levels of replication-related stress. The Wee1 inhibitor adavosertib previously showed clinical benefit in this patient population with a 29.4% ORR and a median PFS of 6.1 months.³

In the ZN-c3-001 trial, investigators enrolled 80 patients with solid tumors who received daily doses of ZN-c3 ranging from 25 mg to 450 mg, as of January 21, 2022. Previously, the dose-escalation phase of the trial focused on determining the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the agent, which was identified as 300 mg given continuously once daily.⁴

At the 2022 AACR Annual Meeting, investigators presented on initial findings from the dose-expansion phase of the trial of patients with uterine serous carcinoma, of which ZN-c3 was given at 2 dose levels: 300 mg daily and 200 mg daily continuous dosing in 21-day cycles.

To be eligible for enrollment, patients had to have histologically confirmed recurrent or persistent uterine serous carcinoma, measurable disease as per RECIST v1.1 criteria, an ECOG performance status of 0 to 2, and had received at least 1 prior platinum-based chemotherapy for advanced or metastatic disease. Patients with known microsatellite instability–high/mismatch repair status must have received prior treatment with a PD-1/PD-L1 inhibitor as a monotherapy or in combination or have been ineligible for such treatment. Exclusion factors included carcinosarcomas and prior treatment with a Wee1 inhibitor.

Key outcome measures included safety and tolerability; MTD; RP2D; efficacy according to RECIST v1.1 criteria with regard to ORR, DOR, PFS, and clinical benefit rate; plasma pharmacokinetics; and evaluation of exploratory biomarkers.

Fourteen patients with uterine serous carcinoma were enrolled to the trial and received ZN-c3 at daily doses of at least 300 mg or higher. The median age of patients was 65 years (range, 55-72), more than half (57.1%) of patients were White, and 85.7% had an ECOG performance status of 1. Patients either had stage I (7.1%), II (7.1%), III (28.6%), or IV disease (57.1%).

The median prior lines of therapy received for advanced/metastatic disease was 2 (range, 1-5), and 57.1% of patients had previously received pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for their disease.

The median duration of treatment was 12.4 weeks (range, 2-36 weeks).

Of the 32 patients with solid tumors who were treated with ZN-c3 at 300 mg, safety findings showed that the most common treatment-related treatment-emergent adverse effects (TEAEs) were nausea (all-grade, 71.9%; grade ≥3, 3.1%), fatigue (53.1% and 18.8%, respectively), diarrhea (46.9% and 6.3%), vomiting (all-grade, 46.9%), and decreased appetite (31.3% and 6.3%). Neutropenia was reported in 6.3% of patients, 3.1% of which were reported as grade 3 or higher cases.

Additionally, 15.6% of patients required 1 dose reduction, and 12.5% of patients required 2; 40.6% of patients required dose interruptions. Moreover, 9.4% of patients required dose discontinuations due to AEs. The median relative dose intensity was 100%, and the mean relative dose intensity was 88.3%.

Upper gastrointestinal–related AEs are being addressed with prophylactic antiemetic treatment, Meric-Bernstram noted.

Meric-Bernstram also shared details pertaining to the 3 patients who responded to Zn-c3. The first was a 72-year-old White female with stage IV disease who had metastases to the peritoneum and lymph node and who received 2 prior lines of therapy. The patient also had a tumor that harbored a TP53 mutation. Following the starting dose of 350 mg daily in December 2020, CA-125 levels decreased from 36 U/mL at baseline to a minimum of 12 U/mL following approximately 3 months of treatment. The patient a confirmed PR with a 49% overall reduction in disease burden. Treatment was given for 199 days until radiologic disease progression.

The second responder was a 69-year-old African American female with stage IV disease who had metastases to the lymph nodes and lung and an ECOG performance status of 0; the patient previously received 4 lines of therapy, which included pembrolizumab plus lenvatinib. This patient also had a tumor harboring a TP53 mutation. Upon receiving ZN-c3 at a starting dose of 300 mg daily in January 2021, her CA-125 levels decreased from 440 U/mL at baseline to less than 50 U/mL after 2 months of treatment. The patient experienced a confirmed PR, with a 43% overall reduction in disease burden. Treatment was administered for 230 days until radiologic disease progression.

Finally, the third patient was a 60-year-old White female with stage IV uterine serous carcinoma who had metastases to the peritoneum and an ECOG performance status of 1. The patient previously received 2 lines of treatment, which included pembrolizumab plus lenvatinib; this patient also had a tumor that harbored a TP53 mutation. ZN-c3 was started at 300 mg daily in April 2021 and was given for 252 days until clinical disease progression. Data on CA-125 levels were not collected at baseline, but the patient experienced an unconfirmed CR, with a 100% reduction in disease overall.

The dose-expansion study in patients with uterine serous carcinoma patients is still enrolling at both the 200- and 300-mg daily dose levels, and Meric-Bernstram shared that genomic data are currently being analyzed.

Furthermore, the phase 2 ZN-c3-004 trial (NCT04814108) is evaluating the efficacy, safety, pharmacokinetics, and related biomarkers of ZN-c3 in patients with recurrent or persistent uterine serous carcinoma.

References

1. Meric-Bernstram F, Chalasani P, Mamdani H, et al. Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC). Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT029.
2. Huang PQ, Boren BC, Hegde SG, et al. Discovery of ZN-c3, a highly potent and selective Wee1 inhibitor undergoing evaluation in clinical trials for the treatment of cancer. J Med Chem. 2021;64(17):13004-13024. doi:10.1021/acs.jmedchem.1c01121
3. Liu JF, Xiong N, Campos SM, et al. Phase II study of the WEE1inhibitor adavosertib in recurrent uterine serous carcinoma. J Clin Oncol. 2021;39(14):1531-1539. doi:10.1200/JCO.20.03167
4. Tolcher A, Mamdani H, Chalasani P, et al. Clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors. Cancer Res. 2021;81(suppl 13):CT016. doi:10.1158/1538-7445.AM2021-CT016