INCB123667 Plus Bevacizumab Shows Antitumor Activity in Recurrent Epithelial Ovarian Cancer

INCB123667 plus bevacizumab (Avastin) induced objective responses in heavily pretreated patients with platinum-resistant or platinum-refractory ovarian cancer and cyclin E1 overexpression, according to preliminary data from a phase 1 study (NCT05238922) presented at the 2026 ESMO Congress.^¹

At a median follow-up of 7.4 months, the objective response rate (ORR) was 48% (95% CI, 27%-69%) among efficacy-evaluable patients treated with the combination (n = 23); the confirmed ORR was 43% (95% CI, 23%-66%), with 10 of 11 responses confirmed. Moreover, the disease control rate (DCR) was 91% (95% CI, 72%-99%). The median duration of response (DOR) was 5.7 months (95% CI, 3.7-9.4), and the median progression-free survival (PFS) was 7.4 months (95% CI, 5.7-9.3).

Among patients whose disease progressed on a prior PARP inhibitor (n = 14), the ORR was 43% (95% CI, 18%-71%). Among those who previously received bevacizumab (n = 19), the ORR was 42% (95% CI, 20%-67%) and the confirmed ORR was 37% (95% CI, 16%-62%).

Lorusso presented the findings during a rapid oral session at the meeting.

"INCB123667, a novel, selective, oral small-molecule CDK2 inhibitor, in combination with bevacizumab, showed promising antitumor activity in heavily pretreated patients with platinum-resistant ovarian cancer and cyclin E1 overexpression,” Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome and Humanitas San Pio X in Milan, Italy, said in a presentation of the data.

What has previously been reported with INCB123667?

The CDK2/cyclin E1 complex drives cell-cycle progression and DNA replication, and cyclin E1 overexpression identifies a subgroup of patients with ovarian cancer who have a poor prognosis and derive less benefit from standard therapies. INCB123667 is a selective, oral, small-molecule CDK2 inhibitor. Prior data from the phase 1 study showed that when the agent was administered as a monotherapy at a dose of 50 mg twice daily, it elicited an ORR of 31% in patients with platinum-resistant ovarian cancer.² Moreover, when paired with bevacizumab, it enhanced tumor growth inhibition vs either agent alone in a CCNE1-amplified ovarian cancer model.¹

How was the phase 1 study of INCB123667 plus bevacizumab in platinum-resistant ovarian cancer designed?

The open-label, multicenter, dose-escalation and dose-expansion phase 1 study is examining INCB123667 in combination with anticancer therapies, including bevacizumab, paclitaxel, palbociclib (Ibrance), ribociclib (Kisqali), and olaparib (Lynparza), in patients with advanced solid tumors. Patients with platinum-resistant ovarian cancer received INCB123667 at 50 mg orally twice daily plus bevacizumab at 10 mg/kg intravenously every 2 weeks in 28-day cycles, in either dose escalation (n = 3) or dose expansion (n = 20). Bevacizumab was continued until disease progression, unacceptable toxicity, or 15 months of treatment.

Dose expansion enrolled patients with advanced or metastatic epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who had received prior first-line platinum-taxane chemotherapy and had CCNE1 amplification or cyclin E1 overexpression; the number of prior lines of therapy was not limited.

The primary end points of the study were safety, tolerability, and dose-limiting toxicities; secondary end points included ORR, DCR, DOR, and pharmacokinetics.

At this year’s congress, Lorusso shared preliminary phase 1 efficacy and safety data with INCB123667 plus bevacizumab in patients with platinum-resistant ovarian cancer.

What were the baseline characteristics of patients treated with INCB123667 plus bevacizumab?

The median age was 60 years (range, 45-78), and 73.9% of patients had an ECOG performance status of 0. Serous histology was reported in 78.3% of patients, all of whom had high-grade serous disease; 13.0% had clear cell histology. The primary platinum-free interval was less than 3 months in 8.7% of patients and 3 to 6 months in 21.7%, and all patients had a last platinum-free interval of 6 months or less.

Overall, 43.5% of patients had received 4 or more prior lines of therapy, 82.6% had received prior bevacizumab, and 65.2% had received a prior PARP inhibitor. Among PARP inhibitor–pretreated patients (n = 15), 93.3% had disease progression during PARP inhibitor treatment. Cyclin E1 overexpression was detected in 87.0% of patients, 35.0% of whom had CCNE1 amplification; cyclin E1 expression was unknown in 13.0% of patients. Homologous recombination deficiency (HRD) was present in 30.4% of patients, all of whom had BRCA mutations; 21.7% were HRD negative, and HRD status was unknown in 47.8%.

What was the safety profile of INCB123667 plus bevacizumab in PROC?

The median duration of exposure to the combination was 7.6 months (range, 1.9-16.9). Any-grade INCB123667-related treatment-emergent adverse effects (TEAEs) occurred in all patients (n = 23), and 78% of patients had a bevacizumab-related TEAE. Grade 3 treatment-related adverse effects (TRAEs) occurred in 52% of patients, and 1 patient had a grade 4 TRAE of thrombocytopenia. One patient had a grade 5 TEAE of sepsis that was not considered to be related to treatment. Serious adverse effects occurred in 17% of patients and were treatment related in 1 patient.

The most common any-grade TEAEs were anemia (69.6%), constipation (47.8%), neutropenia (47.8%), nausea (43.5%), hypertension (39.1%), and thrombocytopenia (39.1%). The most common grade 3 TEAEs were proteinuria (21.7%), intestinal obstruction (13.0%), and neutropenia (13.0%). No patients discontinued INCB123667 because of TEAEs; 2 patients discontinued bevacizumab because of TEAEs, 1 each for fistula and proteinuria.

The phase 3 MAESTRA 3 trial (NCT07797283) of INCB123667 plus bevacizumab vs bevacizumab alone as first-line maintenance therapy in patients with epithelial ovarian cancer overexpressing cyclin E1 is expected to begin in 2026.³

References

1. Lorusso D, Damian S, Hasegawa K, et al. Preliminary efficacy of INCB123667 (CDK2 inhibition) with bevacizumab in recurrent epithelial ovarian cancer (rEOC). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 1241RO.
2. Lorusso D, Simonelli M, Homicsko K, et al. First-in-human phase 1 dose-finding study of INCB123667, a selective CDK2 inhibitor, in patients with advanced solid tumors. Presented at: 2025 ESMO Congress; October 17-21, 2026; Berlin, Germany. Poster 974P.
3. Phase 3 study of INCB123667 plus bevacizumab versus bevacizumab alone as first-line maintenance therapy in ovarian cancer overexpressing cyclin E1 (MAESTRA 3). ClinicalTrials.gov. Updated October 2, 2026. Accessed October 24, 2026. https://clinicaltrials.gov/study/NCT07797283