The potent and selective CDK2 inhibitor INCB123667 has the potential to offer patients with platinum-resistant ovarian cancer (PROC) a convenient and effective treatment option due to its ability to be administered orally and promising early-phase data, according to Premal H. Thaker, MD, MS.
“For a long time, we have known that cyclin E1 is a negative prognostic factor; overexpression by amplification can mean patients [with] high-grade ovarian, as well as endometrial, cancers can have poor outcomes,” Thaker said in an interview with OncLive®. “We have not had a good way to target that pathway, [but] with the newer CDK inhibitors like CDK2 [inhibitors], we’re able to now target that pathway in a way that can actually cause a therapeutic benefit for these patients.”
Thaker is the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology, the director of gynecological oncology clinical research, and the chief of the Division of Gynecologic Oncology at Washington University Medicine in St Louis, Missouri.
What prior data have been reported with INCB123667?
INCB123667 was examined in patients with advanced or metastatic solid tumors who experienced disease progression on standard treatment in the dose-escalation portion (part 1A) of a phase 1 trial (NCT05238922).1 Part 1B of the trial enrolled patients with platinum-resistant or -refractory epithelial/ovarian/primary peritoneal carcinoma. Patients were permitted to have received up to 4 prior lines of systemic therapy and were also mandated to have CCNE1 amplification or central cyclin E1 overexpression, as well as an ECOG performance status of 0 or 1.
Patients who received INCB123667 at any dose in part 1B (n = 45) experienced treatment-emergent adverse effects (TEAEs) at a rate of 97.8%. Treatment-related (93.3%), serious (15.6%), and grade 3 or higher (35.6%) TEAEs were all reported; notably, there were no instances of fatal TEAEs. Dose discontinuation (2.2%), interruption (33.3%), and reduction (6.7%) due to TEAEs were also reported.
The most common any-grade TEAEs included nausea (55.6%), constipation (40.0%), and anemia (37.8%). Grade 3 or higher TEAEs consisted of intestinal obstruction (6.7%), anemia (4.4%), fatigue (4.4%), abdominal pain (2.2%), and neutropenia (2.2%).
In terms of efficacy, the best response rates in part 1B were observed at the 100-mg daily dose of INCB123667 (n = 14). The overall response rate (ORR) at this dose was 35.7% (95% CI, 12.8%-64.9%); all responses were partial. The disease control rate was 71.4% (95% CI, 41.9%-91.6%). The median duration of response (DOR) and progression-free survival (PFS) values were 3.6 months (95% CI, 1.9-not evaluable) and 4.5 months (95% CI, 2.0-6.2), respectively.
In the combined dataset of patients treated at 50 mg or 100 mg (n = 30), the ORR was 33.3%, the median DOR was 3.6 months, and the median PFS was 5.3 months. Cyclin E1 overexpression was noted in 11 of 12 responders with the lone exception having unknown cyclin E1 status due to limited tissue. Notably, responses were reported in patients with CCNE1 amplification (n = 7/29) and without CCNE1 amplification but with cyclin E1 overexpression (n = 5/16).
INCB123667 in Platinum-Resistant Ovarian Cancer
- Early phase 1 data with the oral CDK2 inhibitor INCB123667 demonstrated encouraging antitumor activity in patients with cyclin E1–overexpressing PROC, with a 35.7% (95% CI, 12.8%-64.9%) ORR at the 100-mg dose and a manageable safety profile without fatal TEAEs.
- The phase 3 MAESTRA 2 trial is comparing INCB123667 with investigator’s choice of chemotherapy in patients with cyclin E1–overexpressing PROC, with PFS and OS as the dual primary end points.
- Investigators believe CDK2 inhibition could address a longstanding unmet need by targeting the cyclin E1 pathway, whereas the agent’s oral administration route and potential for future combination strategies with immunotherapy, PARP inhibitors, or other targeted therapies may further expand its role.
The study authors concluded that, “the observed safety, tolerability, and encouraging antitumor activity of single-agent INCB123667 provides proof of concept and supports the advancement of INCB123667 into pivotal studies in patients with advanced or recurrent ovarian cancer.”
What are the key design characteristics of MAESTRA 2?
Following the positive data from the phase 1 study, INCB123667 is being further evaluated in patients with PROC in multiple ongoing clinical trials. The single-arm MAESTRA 1 trial (NCT07023627) is evaluating the agent in patients with PROC harboring cyclin E1 overexpression, whereas the phase 3 MAESTRA 2 study (NCT07214779) is comparing the agent with investigator’s choice of chemotherapy in the same group.2,3
In order to be eligible for enrollment in the MAESTRA 2, patients must be at least 18 years of age with a historical diagnosis of high-grade serous epithelial, ovarian, fallopian tube, or primary peritoneal cancer.4 Patients are required to have received 1 to 4 prior lines of systemic therapy after which single-agent chemotherapy is considered an appropriate next line of treatment. Other key eligibility criteria include having tumor cyclin E1 overexpression per immunohistochemistry, having received prior bevacizumab (Avastin) unless contraindicated, and having received prior mirvetuximab soravtansine-gynx (Elahere) if the patient has folate receptor alpha–positive disease.
Eligible patients will be randomly assigned 1:1 to receive INCB123667 at 50 mg twice daily or investigator’s choice of chemotherapy. Chemotherapy choices include weekly paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan.
“CDK2 [inhibitors] have a real role because they’re an oral medication; patients like oral medications given the option because we don’t have many of those,” Thaker commented.
The dual primary end points are PFS by blinded independent central review (BICR) per RECIST 1.1 criteria, and overall survival. ORR by BICR per RECIST 1.1 criteria represents the key secondary end point. Other secondary end points include DOR, PFS, investigator-assessed ORR, safety and tolerability, and health-related quality of life.
MAESTRA 2 is being conducted at approximately 150 sites in 15 countries. The study will include approximately 466 patients, the first of whom was enrolled in December 2025.
“There are [opportunities for this agent] to be combined if we see success with monotherapy,” Thaker noted. “There is some thought that CDK2 inhibitors can overcome resistance to CDK4/6 inhibitors. This could be an option for patients who may have responded for a [period], and then over time develop resistance, because they work on different parts of the cell cycle. Additionally, [CDK2 inhibitors] might augment some of the effects of immunotherapy, such as PD-L1 [inhibitors]; [they] might be able to be combined because they have different mechanisms of action. Lastly, because [CDK2 inhibitors] are causing issues with cell replication, [combining them with] PARP inhibitors might also be a potential [avenue and may even be] a nice maintenance strategy. In my mind, maintenance strategies that are oral are better than having to come in for intravenous infusions.”
References
- Damian S, Lorusso D, Simonelli M, et al. Safety and preliminary efficacy from a phase 1 study of INCB123667, a selective CDK2 inhibitor, in patients with advanced platinum-resistant and refractory ovarian cancer (OC). J Clin Oncol. 2025;43(suppl 16):5514. doi:10.1200/JCO.2025.43.16_suppl.5514
- A study of INCB123667 in participants with platinum-resistant ovarian cancer with cyclin E1 overexpression (MAESTRA 1). ClinicalTrials.gov. Updated July 6, 2026. Accessed July 8, 2026. https://clinicaltrials.gov/study/NCT07023627
- Study to evaluate INCB123667 versus investigator’s choice of chemotherapy in participants with platinum-resistant ovarian cancer with cyclin E1 overexpression (MAESTRA 2). ClinicalTrials.gov. Updated July 6, 2026. Accessed July 8, 2026. https://clinicaltrials.gov/study/NCT07214779
- Kristeleit R, Hasegawa K, Lorusso D, et al. A phase 3, randomized, open-label study of INCB123667 versus investigator’s choice of chemotherapy in patients with platinum-resistant ovarian cancer with cyclin E1 overexpression (MAESTRA 2, ENGOT-OV95, GOG-3137). J Clin Oncol. 2026;44(suppl 16):TPS5642. doi:10.1200/JCO.2026.44.16_suppl.TPS5642
