The expanding role of antibody-drug conjugates (ADCs) in platinum-resistant ovarian cancer (PROC) has reshaped the treatment landscape, and questions around sequencing agents that share topoisomerase-1 payloads and managing overlapping toxicities will be central to the discussion of where new therapeutic classes such as CDK2 inhibitors can help fill the greatest unmet need, according to Premal H. Thaker, MD, MS.
Against that backdrop, the phase 2 MAESTRA-1 trial (NCT07023627) is evaluating INCB123667, a selective CDK2 inhibitor in patients with PROC whose tumors overexpress cyclin E1, a protein whose dysregulation is associated with poor prognosis in ovarian cancer.1,2 Data from a phase 1 study (NCT05238922) presented at the 2025 ASCO Annual Meeting showed that INCB123667 administered at either 50 mg twice daily or 100 mg daily (n = 30) produced˙ an objective response rate (ORR) of 33.3% (n = 10) in heavily pretreated patients with PROC and CCNE1 amplification or cyclin E1 overexpression.2 Additionally, more than 70% of patients across 3 dose levels experienced a reduction in tumor size from baseline. The median time to response was 2.1 months (range, 1.6-7.7), the median duration of response was 3.6 months, and the median progression-free survival was 5.3 months.
“CDK2 inhibitors have a real role, partly because they’re oral medications. For some patients, even though ADCs may be [administered] once every three weeks, it’s still an infusion. It requires chair time in addition to a clinic visit,” Thaker said. ˙
Thaker is the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology; Director, Gynecological Oncology Clinical Research; and Interim Chief, Division of Gynecologic Oncology, at Washington University Medicine in St. Louis, Missouri.
In an interview with OncLive®, Thaker discussed the biologic rationale for targeting CCNE1 in ovarian cancer, the design strengths of MAESTRA-1, and the potential for INCB123667 to combine with PARP inhibitors, CDK4/6 inhibitors, or checkpoint inhibitors in future strategies.
Key Points on CDK2 Inhibition and the MAESTRA-1 Trial in PROC
- Cyclin E1 is a negative prognostic factor that can be targeted by inhibiting the CDK2 pathway.
- MAESTRA-1 is enrolling patients with PROC who have received up to 4 prior lines of therapy, including platinum-based therapy and bevacizumab.
- INCB123667 will be administered orally at a starting dose of 50 mg twice daily. If monotherapy activity is confirmed, the agent may be suitable for combination strategies with PARP inhibitors, CDK4/6 inhibitors, or PD-L1 inhibitors in the future.
OncLive: How do you consider treatment sequencing and patient selection in the platinum-resistant setting, and what would fill the biggest unmet needs today?
Thaker: ADCs have really revolutionized our next treatment paradigm. We’re still learning about ADCs in terms of knowing how to sequence them because a lot of the payloads are topoisomerase-1. There may not be an ability to give sequential ADCs if it has the same [type of] chemotherapy backbone. Mirvetuximab soravtansine-gynx [Elahere] has a different backbone, but it seems like all the newer ADCs that are in clinical trials all have topoisomerase-1 payloads with slightly different ADC concentrations. But we worry that there could be a diminished return when you sequence one ADC after the other. That is something we won’t learn from clinical trials because the fact is [prior exposure to an ADC often represents] exclusionary criteria.
Some of these ADCs are not also tumor agnostic, meaning that some will require a cutoff [for a certain biomarker]. We’re going to have more capability to be able to provide precision medicine for our patients. We’re going to have to decide what sort of adverse effect [AE] profiles, especially if patients have multiple targets, they’re willing to accept, especially if the ORRs appear to be still in the 50% to 60% range. We’re now getting spoiled by seeing this [magnitude of efficacy] at least in the phase 2 [setting], but we need the confirmatory phase 3 [data to validate that].
CDK2 inhibitors are another mechanistic class under investigation in tumors with cyclin E1 overexpression. Can you discuss the biologic significance of cyclin E1 in high-grade ovarian cancer and how it may contribute to platinum resistance or therapeutic vulnerability?
For a long time, we have known that cyclin E1 is a negative prognostic factor. Overexpression by amplification can mean that patients with high-grade ovarian cancer and endometrial cancer have poorer outcomes. However, we’ve not had a good way to target that pathway. With the newer CDK inhibitors like CDK2, we’re able to now target that pathway and provide therapeutic benefit for these patients.
Diving into MAESTRA-1, what are your thoughts on the study design, particularly in the context of a heavily pretreated population that may have already received bevacizumab (Avastin) and mirvetuximab soravtansine?
We don’t completely understand platinum resistance. The nice thing about MAESTRA-1 is it really makes sure that patients receive the [right] prior PROC treatments, so we’ll know when we see the efficacy, it’s not because of a favorable population, but really represents a real-world population that we would anticipate [to have had] previous treatments. That’s important because we always otherwise look in retrospect and ask, what happens if they had had received other PROC treatments?
The other part of it is, patients really need options when they’ve even had only two or three prior lines [of treatment]. This trial, [which is enrolling patients who have received up to] four lines, gives an opportunity for patients to participate and for us to really learn more about how to sequence [these drugs] and help patients. A lot of times we’ll be able to then get at least a hypothesis [as to where the agent is most active] when we look and stratify [outcomes] based on lines of therapy. [With that data we can determine whether there] is an optimal time to give the medication as opposed to guessing that earlier is better.
Given the current therapeutic landscape, how do you envision CDK2 inhibition fitting into the landscape if the results from MAESTRA-1 are positive?
Patients like oral medications, if given the option. It makes a lot of sense that inhibition of the pathway could prove a little more [active in] patients who have overamplification and higher expression. But the other cohorts [of MAESTRA-1] we didn’t mention do explore patients with lower CCNE expression, so we can understand if there are lower doses or ultra-low doses of this medication that can still be very helpful. It goes back to the biology of CDK2, because it causes dysregulated cell progression and uncontrolled proliferation is what causes cancer. Having an inhibitor of CDK will allow there to be more arrest of those cells so that they hopefully don’t continue to proliferate. Having this inhibition with CDK2 is important because it seems to be that it can cause potentially a G1 arrest or even a G2/M arrest depending on whether the tumor is more CDK2 dependent or independent. Depending on where it is in the cell cycle, it can help in several ways. That’s also where this seems to have more of a global [application]. Patients with a CCNE1 amplification have more of this issue with dysregulation, so that’s why they seem to be much more susceptible to CDK inhibitors. It will at least give us a biological target, but there’s also a good opportunity that this might work for other cancers than just the ones that are amplified.
If the greatest activity is reported in tumors with overexpression, what practical challenges do you anticipate in implementing a biomarker-driven strategy in routine clinical practice?
It’s going to come down to what our patients’ goals are, because a lot of patients will like an oral therapy that they’ll be able to take. In the trial this medication is being looked at a starting dose of 50 mg twice daily, which is not an overly burdensome commitment. On top of that, these will ideally be 50-mg pills, so if patients have to be dose reduced to 25 mg, it’s not like you’re taking five pills. Sometimes you’ll have to take multiple pills, and you’ll feel like you’re taking almost a meal to take your pills. That’s one thing that’s really of benefit.
The AEs are really thought to be more like myelosuppression. We don’t see any of the toxicities that we sometimes worry about with ADCs like pneumonitis or ocular toxicity. For patients these are toxicities that they’re a bit more aware of from prior chemotherapy, so some patients [may prefer] another option that doesn’t give them these other AEs like mucositis for some of the TROP2-directed ADCs. It’s going to ultimately depend on the response rate that we see, because the patient would take the most AEs [as long as comes with] the most durable response and the best ORR.
Could this agent be combined with other classes if it has a cleaner AE profile than other available agents?
A couple of agents could be combined with CDK2 inhibitors. There is some thought that CDK2 inhibitors can overcome resistance to CDK4/6 inhibitors. I only mention that because we sometimes are starting to use CDK4/6 inhibitors with anti-hormonal treatments like aromatase inhibitors in our low-grade ovarian cancers after recurrence and endometrial cancers. Combining a CDK2 inhibitor with a CDK4/6 inhibitor could be an option for those patients who may have responded for a while and then over time develop resistance because they work on different parts of the cell cycle.
Additionally, there is some thought that it might augment some of the effects of immunotherapy such as PD-L1 [inhibitors]. CDK2 inhibitors might be able to be combined with [checkpoint inhibitors] because they have different mechanisms of action.
Lastly, because CDK2 causes issues with cell replication, DNA damaging agents like PARP inhibitors in combination with CDK2 inhibitors might also be another avenue that we could explore. If that is the case, it might make sense to explore those combinations as a maintenance strategy. We don’t have anything for our homologous recombination–proficient patients. Could we use CDK2 inhibitors with PARP inhibitors in the maintenance setting? We had initially seen some signals in those patient populations, and while the agents have been retracted from the FDA, this could be a way to [provide better] synergy and subsequent outcomes. These are two oral agents, and maintenance strategies that are oral are better than having to come in for intravenous infusions, so there is the potential for combination approaches if we see success with monotherapy.
References
- A study of INCB123667 in participants with platinum-resistant ovarian cancer with cyclin E1 overexpression (MAESTRA 1). ClinicalTrials.gov. Updated June 1, 2026. Accessed June 16, 2026. https://clinicaltrials.gov/study/NCT07023627
- 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
