Monk Breaks Down Recent Advances Across the Gynecologic Cancer Paradigm

Bradley J. Monk, MD, FACS, FACOG

The treatment landscape of gynecologic cancers continues to evolve with the addition of new clinical trials in the space, said Bradley J. Monk, MD, FACS, FACOG. To continue to push the paradigm forward, Monk said finding the right clinical trials for the right patients can help investigators find new applications for drugs and get patients the proper therapies to manage their disease.

“The pace of discovery is unbelievable. To bring these medicines to the clinic, you need 4 things. You need patients, and you need an investigator, a treating physician that is passionate about clinical trials. You need a study, which is my passion and is what I do. Most importantly, you need an institution. No matter what the study is, and no matter how sick your patient is or how motivated you are, if you don’t have institutional support, you’re not going to be successful,” Monk said in an interview with OncLive^® following a State of the Science Summit^™ on ovarian cancer.

In the interview, Monk, who chaired the meeting, discussed the future of ovarian cancer treatment, ongoing and future trials, as well as combination therapies that may benefit patients with ovarian cancer, cervical cancer, and endometrial cancer. Monk is a professor in the Division of Gynecologic Oncology at Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, a medical oncologist at Creighton University School of Medicine at St. Joseph’s Hospital, the medical director of the Gynecologic Program at US Oncology Research Network, and a co-director at GOG Partners.

OncLive^®: Your colleague Ivor Benjamin, MD, of HonorHealth, discussed frontline maintenance in ovarian cancer. What are the optimal treatment strategies for patients in the frontline setting?

Monk: The meeting was kicked off by Ivor Benjamin, MD, who discussed first-line maintenance treatment for newly diagnosed advanced ovarian cancer. There was a consensus that every patient needs genetic testing and maintenance treatment. If [testing] is negative for BRCA mutations, then reflex to somatic tumor testing, [for which] there are multiple vendors.

In the BRCA-mutated population, there are 3 options: niraparib [Zejula], olaparib [Lynparza], or olaparib plus bevacizumab [Avastin]. In the homologous recombination–deficient [HRD] population, the combination of olaparib and bevacizumab or niraparib [can be used]. In the homologous recombination [HR]–proficient or HRD-negative population, you could do bevacizumab or niraparib. [This applies] to every patient unless there’s a contraindication.

Dana Chase, MD, of HonorHealth, discussed second-line maintenance in ovarian cancer. How does choice of frontline treatment affect treatment in the second-line setting?

The second presentation was given by Dana Chase, MD, who talked about second-line maintenance. Since most patients are getting PARP inhibitors in the frontline setting, this may not be as relevant [anymore], but she highlighted that there are a few patients that slip through and [have the] opportunity for second-line [PARP inhibition]. If they’re PARP inhibitor–naïve and respond to second-line platinum-based chemotherapy, they can receive PARP maintenance with all 3 agents this time. Rucaparib [Rubraca] was added to the mix based on the phase 3 ARIEL3 trial [NCT01968213]. The biomarker is not molecular [in this case]. It was response to platinum-based chemotherapy.

If patients receive bevacizumab in the frontline setting, it still works in the second-line setting. The opportunity to use a PARP inhibitor after a PARP inhibitor has been established by the phase 3 OReO trial [NCT03106987], but that opportunity is very limited. If a patient gets a PARP inhibitor in the frontline setting, they need bevacizumab, they’ll receive a PARP inhibitor plus bevacizumab. [Those patients] still need bevacizumab [maintenance]. If patients are PARP inhibitor–naïve and platinum sensitive in the maintenance setting, they require a PARP inhibitor if they respond to platinum-based chemotherapy.

Lyndsay Willmott, MD, of HonorHealth, discussed updates in cervical cancer. What has moved the landscape to where it is today?

Lyndsay Willmott, MD, had a difficult task of discussing 2 tumor types at the same time: cervical cancer and endometrial cancer. It was clear that checkpoint inhibitors work in both tumor types. In cervical cancer, initially we had a second-line indication for pembrolizumab [Keytruda] in PD-L1–expressing tumors from June 2018. Ultimately, in October 2021, pembrolizumab received another indication in combination with frontline carboplatin [and] paclitaxel with or without bevacizumab.

If a patient is immunotherapy-naïve in the second-line setting, just as if a patient is PARP inhibitor–naïve in the second-line setting in ovarian cancer, patients should receive it. However, immunotherapy does not work after immunotherapy in most tumors, including cervical cancer. The [regimen] from the phase 3 KEYNOTE-826 trial [NCT03635567] of frontline chemotherapy plus pembrolizumab with or without bevacizumab has every metric [of superiority], including overall survival [OS], progression-free survival [PFS], and patient-reported outcomes.

In the second-line setting, because immunotherapy doesn’t work after immunotherapy, patients should receive tisotumab vedotin-tftv [Tivdak], which was approved through the accelerated approval mechanism in second-line cervical cancer, regardless of the biomarker, because the target tissue factor is expressed on every cervical cancer. The only contraindication for tisotumab vedotin is neuropathy because it causes the typical neuropathy that anti-tubulin molecules produce.

Dr Willmott is be congratulated for talking about this. Although there are some adverse effects [to the eyes], they can be mitigated with drops, vasoconstriction, corticosteroids, lubrication, and cold packs. This is a very exciting opportunity. I personally have treated patients with tisotumab vedotin in that setting, and I’ve seen responders. The tolerability is well documented, if you do the eye mitigation strategy.

What trials did Lyndsay Willmott, MD, highlight when discussing updates in endometrial cancer?

Willmott continued her talk on endometrial cancer. In endometrial cancer, every second-line patient needs a checkpoint inhibitor, unless there is a contraindication. She talked about biomarkers, and the biomarker-negative patient population, including patients that are not mismatch repair deficient [dMMR] or microsatellite instability high [MSI-H], needs 2 medications: pembrolizumab and lenvatinib [Lenvima]. This is based on the phase 3 KEYNOTE-775 trial [NCT03517449], which showed an improvement in [all end points], including OS and PFS.

You have to test for biomarkers in ovarian cancer, and [PD-L1 testing] in cervical cancer [is important]. Now in endometrial cancer, you must check for dMMR in every patient. In the second-line setting, if the patient is not dMMR, they need pembrolizumab/lenvatinib. However, if the patient is dMMR or MSI-H, the patient can get pembrolizumab or the second checkpoint inhibitor, dostarlimab-gxly [Jemperli].

We are moving [different agents into earlier treatment settings] in all our tumor types, particularly in endometrial cancer with the addition of checkpoint inhibitors to frontline carboplatin and paclitaxel. [Moreover], we’re studying PARP inhibitors with niraparib in the phase 3 RUBY trial [NCT03981796] and olaparib in the phase 3 DUO-E trial [NCT04269200], and we’re trying to transition to chemotherapy-free opportunities. For example, the phase 3 KEYLYNK-001 trial [NCT03740165] is evaluating [pembrolizumab alone followed by olaparib maintenance therapy] in the dMMR population. In the non-dMMR population, pembrolizumab plus lenvatinib [is being evaluated] in the frontline setting in the phase 3 LEAP-001 trial [NCT03884101], just like we did with KEYNOTE-775.

Finally, Michael Janicek, MD, of HonorHealth, discussed emerging agents in ovarian cancer. Based on this discussion, what biomarkers are coming down the pipeline?

Michael Janicek, MD, discussed antibody-drug conjugates [ADCs]. I have alluded to the fact that tisotumab vedotin was the first ADC ever approved in a gynecologic malignancy. Dr Janicek discussed mirvetuximab soravtansine, an ADC directed toward the folate receptor. That agent [was explored] in the phase 3 SORAYA trial [NCT04296890]. Data, presented at the 2022 Society of Gynecologic Oncology Annual Meeting, showed a 32% response rate. Those data have been submitted to the FDA and will likely lead to the next approval in a gynecologic cancer and the second ADC in recurrent ovarian cancer.

Dr Janicek then discussed another ADC against NaPi2b, [upifitamab rilsodotin (UpRi)]. With all our medications, we need doses that are effective but tolerable. The maximum dose is not always the best dose; it’s the minimally effective dose, and the minimally effective dose is 36 mg/m2 for UpRi. [That agent] is now in a pivotal cohort study: the phase 1/2 UPLIFT trial [NCT03319628].

[We will keep trying to move therapies into] earlier and earlier settings. We have combinations with bevacizumab. We have 2 ADCs in development in ovarian cancer, and 1 already approved in cervical cancer: tisotumab vedotin. Tisotumab vedotin does not need a biomarker because the tissue factor target is ubiquitous. But in ovarian cancer, we’re using biomarkers and have a lot of biomarker experience with mirvetuximab soravtansine.

You presented on the future of ovarian cancer treatment. What were the key highlights from your discussion?

I talked about how medications are brought to patients in the clinic initially through later lines of therapy. [This includes] tisotumab vedotin in cervical cancer, pembrolizumab and PARP inhibitors in ovarian cancer, and pembrolizumab/lenvatinib and dostarlimab in endometrial cancer, which are all clear examples. We’ve had 6 accelerated approvals, which were all confirmed in the phase 3 setting in gynecologic cancers.

Regarding ongoing developments in later lines of therapy, if you can’t shrink tumors, then you need to do a randomized trial because accelerated approval is based on tumor shrinkage, duration of response, percentage of complete responders, and safety.

I discussed 2 studies which have completed enrollment. One is the phase 3 OVAL trial [NCT03398655], which is examining an adenovirus gene therapy, VB-111 [ofranergene obadenovec], that selectively delivers an anti-vascular opportunity that creates local immune modulating inflammation but as an antiangiogenic. The trial has completed enrollment with more than 400 patients, and it will probably be the next phase 3 trial to report this summer.

The other randomized late-line therapy with paclitaxel as the backbone is being investigated in the phase 3 INNOVATE-3 [NCT03940196]. That study takes tumor-treating fields and adds it to weekly paclitaxel vs weekly paclitaxel alone in this heavily pretreated, platinum-resistant, recurrent ovarian cancer [population]. This trial has enrolled more than 500 patients, and it will be reported very soon.

What current trials are you and your institution involved with?

We’re completing trials with the 2 ADCs in platinum-resistant, recurrent ovarian cancer: mirvetuximab soravtansine and UpRi. We’re also looking at a novel AKT inhibitor in the phase 2 PROFECTA-II study [NCT04374630], also with weekly paclitaxel.

We’re trying to create other opportunities where weekly paclitaxel is not the backbone, or where there are other physician’s choice opportunities. We’re imminently opening a study called the phase 3 ARTISTRY-7 trial [NCT05092360], which is evaluating a combination of the engineered IL-2 [agent], nemvaleukin alfa, plus pembrolizumab. Checkpoint inhibitors do not work well alone, but if you can add a co-stimulatory molecule, such as a CTLA-4 or IL-2 [inhibitor], we can be successful. Preliminary data [from the phase 1/2 ARTISTRY-1 trial (NCT02799095)] were presented at the SGO 2022 Winter Meeting, and that study is investigating pembrolizumab in combination with the next generation IL-2 [agent] nemvaleukin vs physician’s choice chemotherapy.

How would you evaluate the current state of treatment options in gynecological cancers?

In summary, we have new medications. The institutional support that we have at [HonorHealth] is a 3-party collaboration between the Arizona Center for Cancer Care, HonorHealth Research Institute, and the HonorHealth hospital system. There are 8 of us gynecologic oncologists to cover the entire city, not just in the HonorHealth hospital system. It’s important to bring expertise to the entire metropolitan area and carry it forward. We teach the residents in both medical schools here at the University of Arizona and Creighton. It’s my pleasure to be affiliated with these wonderful people.

We closed the meeting on the survivors. We applauded a long-term survivor who’s still fighting ovarian cancer today, celebrating her enrollment in a clinical trial, and her benefit from targeted therapies that have been discussed here. We’ll continue to collaborate with our patients and with our organizations, as we evolve the standard of care.