Matulonis provides insight into the progress of the gynecological treatment landscape

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“Team science is important to be open-minded [and] think outside the box.

The gynecologic oncology landscape continues to rapidly evolve, with the FDA approving several treatments for ovarian, endometrial, and uterine cancer in recent years. Additionally, researchers continue to explore new combinations of treatments to give patients more options and help improve survival.

In an interview with ONCOLOGY®, Ursula A. Matulonis, MD, discussed clinical trials that have had a significant impact on the standard of care (SOC), as well as ongoing studies that have practice-changing potential. She also talked about several trials that will be presented at the upcoming Society of Gynecologic Oncology (SGO) conference.

Matulonis detailed what led her to change her own practice and described the trends seen in the community. She even talked about the advice she gives to new professors starting their work in clinical trials.

Q:Can you give a brief overview of the recent gynecological treatment landscape?

A: The number one spot goes to cervical cancer because of what’s happened in the last year, [with immuno-oncology (IO) agents becoming available for] patients with newly diagnosed advanced or recurrent cervical cancer. The testing and introduction of IO agents in the SOC treatment of cervical cancer was recently published [KEYNOTE-826; NCT03635567] in the New England Journal of Medicine [with the addition of] pembrolizumab [Keytruda] with carboplatin and paclitaxel more or less bevacizumab [Avastin].1

In uterine cancer, SOC now relates to IO drugs as monotherapy, in particular pembrolizumab and dostarlimab [Jemperli]which won accelerated FDA approval in 2021 for microsatellite instability or mismatch repair-deficient endometrial cancer.2 Pembrolizumab is approved as a single agent for TMB [tumor mutational burden]–high (i.e. greater than 10 mutations per megabase) [disease] and for diseases deficient in microsatellites as well.3.4 It is a viable option after chemotherapy for patients with recurrent endometrial cancer.

CONFERENCE-775 [NCT03517449]which was published in the New England Journal of Medicine, [also investigated and showed benefit of] pembrolizumab and lenvatinib [Lenvima] vs chemotherapy for recurrent uterine cancer with microsatellites that have progressed through at least 1 platinum cycle [chemotherapy].5

Ovarian cancers are a different story, and the only approved IO agent in ovarian cancer is pembrolizumab for microsatellite instability or elevated BMR [tumor-agnostic indications], but IO has no formal indications at this time. In addition, new therapies are being tested, in particular
antibody-drug conjugates [ADCs].

Finally, there is a tendency to target specific drugs to specific tumors with ADCs. All OIs, to some extent, have targets with either microsatellite instability or stability as a biomarker. ADCs like tisotumab vedotin do not have a marker, but FDA approval does not indicate that [there must be] tissue factor present.6 Other ADCs, namely mirvetuximab, which require a biomarker are being tested.

Q: Which biomarkers, if any, should be explored in clinical research?

A: Basket tries are good if there is a real target. If a target is being considered, for example, [targeting] HER2 with DS-8201a [trastuzumab deruxtecan; T-DXd]which is an anti-HER2 ADC – investigators can get an idea of ​​what the level of HER2 expression must be [to see efficacy].

Some tumors in gynecological cancers have RAS mutations, such as low-grade serous mucinous cancers of the ovary and endometrioid cancers of the uterus, but they cannot be targeted. [Gynecologic] cancer [can] to have [RAS] G12D and G12V mutations, [and] they cannot yet be targeted by known inhibitors. Yes [we] had a drug that could potentially target those mutations, so [we] could align the various gynecological cancers that have these RAS mutations. Basket trials are a convenient way to avoid having to [conduct] 10 different phase 2 studies, but all combined in one trial.

Q: What role do you think PARP inhibitors play? Are there any practice-changing trends on the horizon?

A: Three PARP inhibitors are approved in the United States for newly diagnosed advanced stage cancer. One is based on the SOLO-1 trial [NCT01844986]with 2 years of olaparib maintenance [Lynparza] for patients who have BRCA1/2-cancer mutated after response to chemotherapy.7 SOLO-1 has certainly been a practice-changing trial since that initial presentation a few years ago at the [European Society for Medical Oncology] Congress. My practice immediately changed because the improvement in progression-free survival was significantly better in SOLO-1 compared to placebo.

The second trial is PRIMA [NCT02655016]using niraparib [Zejula] maintenance for about 3 years, which extends to high-grade serosa [cancer] without BRCA mutation regardless of homologous recombination deficiency [HRD] status.8 Next, the PAOLA-1 trial [NCT02477644]add olaparib to bevacizumab [Avastin] maintenance for patients who receive bevacizumab for at least 3 cycles during their initial chemotherapy with carboplatin or paclitaxel.9 Olaparib has received approval for cancers with HRD. If the tumor is judged [homologous recombination proficient] by an FDA-approved test, then olaparib [maintenance is not indicated].

Rucaparib [Rubraca] then came for one or the other BRCA– mutated or platinum-sensitive HRD [disease]; you can also use it in this setting, then as a maintenance treatment.ten

Q: Should clinicians be aware of other agents?

A: The drug adavosertib in recurrent uterine serous cancers [is a Wee1 inhibitor]. The concept is that the entire genome is under stress from different mechanisms, with the loss of p53 allowing the agent to function. There is cyclin E amplification, MEK amplification and HER2 overexpression. These data were published in the Journal of Clinical Oncology, which showed a 29% response rate with adavosertib monotherapy in recurrent uterine serous cancers. This led to a larger trial called ADAGIO [NCT04590248]; it is closed at the moment, but it will reopen.11

Moreover, the [combination of] Abemaciclib CDK4/6 inhibitor [Verzenio] plus letrozole has data that is presented at the SGO Women’s Cancer Annual Meeting at [mid-March]. This is a phase 2 trial [NCT03675893] in recurrent estrogen receptor-positive endometrial cancers.

Another trial of DS-8201a plus olaparib, a [National Cancer Institute]–sponsored trial [NCT04585958] for HER2 positive gynecological cancers, is
most [looking at] serous endometrial cancers.

[Yet another trial] studies mirvetuximab, which is an ADC against the α folate receptor, plus pembrolizumab in recurrent uterine serous cancers. About 30% of serous uterine cancers are folic acid receptor positive, and we pre-screened these patients [beforehand].

Q: What advice do you have for new clinicians?

A: They need to understand the patient they are treating to have ideas about what needs to be done. Currently, per year in the United States, there are fewer than 13,000 cases of cancer of the cervix, about 20,000 of the ovary and 66,000 of the uterus. [These clinicians must] become experts. [They begin by] write it down [a trial] and present it at a meeting. [When working on this], everyone should be onboarded, from surgeons to medical oncologists, radiation oncologists, pathologists and basic scientists, depending on the project you want to start. Team science is important for having an open mind and thinking outside the box.

The references

1. Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N English J med. 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435

2. FDA grants accelerated approval for dostarlimab-gxly for advanced dMMR solid tumors. FDA. August 17, 2021. Updated February 1, 2022. Accessed February 10, 2022. https://bit.ly/3HKBNY7

3. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 17, 2021. Accessed February 11, 2022. https://bit.ly/3BthkFb

4. FDA Grants Accelerated Approval of Pembrolizumab for First Tissue/Site Agnostic Indication. FDA. May 23, 2017. Updated May 30, 2017. Accessed February 11, 2022. https://bit.ly/3sSnNWj

5. Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N English J med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330

6. FDA grants accelerated approval for tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. September 21, 2021. Accessed February 10, 2022. https://bit.ly/3Bhei6O

7. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N English J med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

8. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N English J med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

9. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance therapy in ovarian cancer. N English J med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

10. FDA approves rucaparib for maintenance treatment of recurrent cancer of the ovary, fallopian tubes, or primary peritoneum. FDA. April 6, 2018. Accessed February 11, 2022. https://bit.ly/3Js2wtb

11. Liu JF, Xiong N, Campos SM, et al. Phase II study of adavosertib, a WEE1 inhibitor, in recurrent uterine serous carcinoma. J Clin Oncol. 2021;39(14):1531-1539. doi:10.1200/JCO.20.03167

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