WEE-1 Inhibition Identified as a Potential Treatment Strategy for Recurrent Uterine Serous Carcinoma

The aggressive endometrial cancer, uterine serous carcinoma (USC) is hypothesized to have a unique sensitivity to WEE-1 inhibition, based on the fact that TP53 mutations are seen in 90% of cases. In a single-arm phase 2 clinical trial (NCT03668340), this hypothesis was tested with the single-agent WEE-1 inhibitor adavosertib (AZD1775) in patients with recurrent disease.

In 34 evaluable patients, treatment with adavosertib achieved an objective response rate of 29.4% (95% CI, 15.1-47.5%), which included 9 confirmed responses and 1 pending response. In terms of survival, the progression-free survival (PFS) rate at 6 months was 58.7% (95% CI, 39.5-73.7%). The median PFS was 6.1 months, and the median duration of response observed with adavosertib was 9.0 months.

The safety profile showed some grade 3 or higher adverse events (AEs), which were most frequently neutropenia (32.3%), anemia (20.6%), and fatigue (23.5%).

Overall, the clinical activity of adavosertib in patients with recurrent USC was promising and warrants further study of the agent in a larger population of patients.

In an interview with Targeted Oncology, Joyce F. Liu, MD, MPH, discussed the details of the phase 2 study of adavosertib in recurrent USC and the implications of this research for clinical practices.

TARGETED ONCOLOGY: Can you provide background on the study?

Liu: The idea of the study was that if you think about a WEE-1 inhibitor, WEE-1 is a protein that is involved in cell cycle regulation, and it's 1 of the major regulators of the G2M checkpoint. We were looking for cancers that might have a combination of features that might make them vulnerable to the WEE-1 inhibition, predominantly a combination of cell cycle deregulation andincreased replication stress because another thing that WEE-1 inhibition does is increases replications stress.

USCs are a histological distinct type of uterine cancer that are morphologically and molecularly different from any of the other cancers that exist. Two of the things that they have are cell cycle deregulation and high replication stress, for reasons that are from other cancers. Their cell cycle deregulation may have p53 mutations, and this is seen in over people 90% of patients. In addition, a number of them actually have additional molecular alterations in cell cycle regulation, most commonly cyclin e amplification.

Patients can also have oncogenically-driven replication stress. This include a lot of oncogenes, HER2, PIK3CA, MIK amplifications, all of which are reasons that patients could be under replication stress with cell cycle deregulation. Then, if you come in and you add WEE-1, you increase replication stress and take away their second safety mechanism of this G2M checkpoint, patients can potentially go into mitosis with incorrectly repaired, or under-replicated, DNA, which results in a mitotic catastrophe.

TARGETED ONCOLOGY: Can you explain the study design and methods implemented in this study?

Liu: This was a single-arm, 2-stage trial of the WEE-1 inhibitor adavosertib as treatment of women with USC that had either recurred or persisted after at least one line of platinum-based therapy. We didn't have any limitations on a number of treatments because we wanted to allow a broad spectrum of participants.

Patients were administered adavosertib, andit's an oral drug. They took it one day 1, 5, and 8 through 12 of 21-day cycle, and they were able to continue that until their cancer progressed.

TARGETED ONCOLOGY: What were the results of the study?

Liu: The study was designed to enroll up to 35 patients and we did enroll 35 patients over slightly more than a year. Thirty-four of the patients were evaluable. One patient was not evaluable because she did withdraw from the study for personal reasons that had nothing to do with the adverse events or progression of her disease.

In the 34 patients, we saw what I would consider to be a quite impressive response rate of about 29.4%, in women who were heavily pretreated with at least a median of 3 lines of prior therapy.

TARGETED ONCOLOGY: What is important to note of the safety of this drug in this patient population?

Liu: The AEs that were seen were ones that have been described previously with this drug. We observed hematologic AE, and we also saw things like fatigue or diarrhea. Overall, we had only 2 people who discontinued treatment because of AEs.

Although AE events did occur, they were toxicities that were manageable with dose modifications and adjustments for all patients.

TARGETED ONCOLOGY: What are the clinical implications of these findings to gynecologic oncology practice?

Liu: For me, these are exciting findings. I think this is a novel drug that has never been tested in USC before. We are able to see this level of activity and unselected patients with no limitations on the lines of therapy. Some of the patients who responded actually had a large number of prior lines of therapy, which is promising.

The number of therapies we have available for uterine serous cancer is very limited. Upfront, we have combination platinum- and taxane-based therapy, and for patients who progress on that, we have the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima). There are other therapies that are recommended by the National Comprehensive Cancer Network, but, in general, those have low response rates.

Viably, this treatment would be better if we can confirm these results in a larger population of patients. We are interested in finding a biomarker that defines those patients who are most likely to respond. I think this could represent a novel therapy for USC.

TARGETED ONCOLOGY: Are there any future steps planned with this research?

Liu: Within the context of this study, we are looking at biomarker data. Our initial analyses do not pull out a single biomarker that tells us who might be most likely to be responsive. However, we've seen in some of our deep responders that there are particular molecular profiles that include loss of p53, replication stress, and loss of cell cycle dysregulation. Dysregulation is that something we're going to look into more deeply within the available molecular data that we have on the current cohort of patients.

We also have 2 additional cohorts of patients planned for the study. We’ve opened a new cohort of carcinosarcoma patients, which is a different type of uterine cancer, but it

has a very similar molecular profile to serous uterine cancer. We're very interested to see whether we might see similar activity. Carcinosarcomas are cancers with very few treatment options.

We have also planned a translational biopsy cohort in uterine serous cancer to delve into the biomarker component and hopefully, further validate the clinical findings we've reported.

_Reference:

_{Liu JF, Xiong N, Campos SM, et al. A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma. J Clin Oncol. 2020:38 (suppl; abstr 6009). doi: 10.1200/JCO.2020.38.15_suppl.6009}