Advancements in Gynecologic Cancer Research with Dr. Noelle Cloven

There were exciting developments in gynecologic cancer shared at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting. Noelle Cloven , MD, Sarah Cannon Research Institute (SCRI) at Texas Oncology I The US Oncology Network , discusses the groundbreaking research presented at #ASCO23 that she is most excited about, and what it means for people facing cancer.

What Was the Biggest Advancement in Gynecologic Cancer at ASCO 2023?

It is exciting to be a gynecologic oncologist right now because breakthroughs are happening more rapidly than ever. If I had to pick the biggest news in gynecologic cancer research coming out of ASCO this summer - and it is hard to pick just one - I would choose the MIRASOL study, which was a positive phase 3 study combining the antibody drug conjugate (ADC) mirvetuximab?soravtansine versus investigator's choice chemotherapy. The eligibility criteria included patients with platinum-resistant ovarian cancer with a high expression of the folate receptor (greater than 75% of cells with at least 2+ expression). Patients had to have measurable disease. The MIRASOL study showed a 35% improvement in progression-free survival (PFS) in patients who received mirvetuximab?versus investigator's choice chemotherapy. It essentially doubled the overall response rate (ORR) and in the mirvetuximab group, there were 12 complete responses versus 0 complete responses in the patients receiving chemotherapy.

This is the first novel treatment to demonstrate an overall survival benefit in patients with platinum-resistant ovarian cancer in a phase 3 trial. It was both clinically meaningful, as well as statistically significant. The improvement was in response rate, PFS and overall survival (OS) compared to chemotherapy, and patients on the experimental arm had fewer side effects as well. I believe this is a practice-changing study, and that mirvetuximab?should be considered the standard of care treatment in patients with recurrent platinum-resistant ovarian cancer who have high expression of the folate receptor.

As we look ahead, there are 2 additional trials studying other folate receptor targeted ADCs currently under development and which will be opening soon at SCRI sites. We identified the folate receptor as a target – and we have been successful – however, not all patients have tumors with a high expression of folate receptor. There is a need to study low expression as well, and these trials will include patients with tumors that have low expression of the folate receptor.

What Additional Research Did You Find Interesting at #ASCO23?

RAMP 201: While all gynecologic cancers are technically considered rare, low-grade serous ovarian cancer is even more so. Chemotherapy is less effective, and it is traditionally treated with hormonal therapies and targeted agents such as bevacizumab or MEK inhibitors. RAMP 201 enrolled patients with recurrent low-grade serous ovarian cancer with measurable disease. The tumors could either have or not have a KRAS mutation, and prior treatment with a MEK inhibitor was allowed, as well as unlimited prior therapies, so this was a heavily pretreated group of patients. RAMP 201 is important because low-grade serous ovarian cancer is a high unmet need, and patients need treatment options. RAMP 201 was a phase 2 study that looked at avutometinib?versus avutometinib?and defactinib, both oral agents. Avutometinib already has breakthrough designation from the FDA based on earlier studies. RAMP 201 had impressive results that showed the majority of patients had tumor shrinkage. The combination did work better than the single treatment, but interestingly, even though the patients with KRAS mutations had better responses, KRAS mutation was not necessary for a response. There are 2 main takeaways: (1) the combination did work better than single agent and targeting multiple steps of the MEK/RAS pathway is important (2) the mutation is not necessary for a response. This trial is close to completion, but we are preparing to open additional slots across our SCRI sites to finalize the dose. The plan is to then move forward with a phase 3 study, which SCRI is working on opening across its network.

KEYNOTE -826: KEYNOTE-826 is a study looking at a combination of immunotherapy with chemotherapy with or without bevacizumab in patients with recurrent or metastatic cervical cancer. Final OS data with 39 months of follow-up were presented at ASCO 2023, and showed that there continues to be a substantial and significant clinical benefit to adding pembrolizumab?to chemotherapy combinations in this patient population. Additionally, the benefit in both OS and PFS was in all patients, including those with CPS scores greater than 1, greater than 10, and also the entire population. Given that we know immunotherapy is effective in the metastatic setting, we are looking now to potentially move it up to the front-line setting. eVOLVE is a new trial in early development that explores using immunotherapy as maintenance for patients who have completed chemotherapy and radiation for advanced cervical cancer. SCRI hopes to open the eVOLVE study later this year.

RUBY Trial: The RUBY trial is a phase 3 trial looking at the immunotherapy drug dostarlimab?with chemotherapy for advanced and recurrent endometrial cancer. This presentation was an update which included blinded independent central review (BICR). Patients who were eligible for the RUBY trial had recurrent or primary stage 3 are stage 4 endometrial cancer. Carcinosarcomas were eligible for this trial, which is unique compared to the other trials of immunotherapy combined with chemotherapy, and they were stratified by MSI-high versus MSI-low. Dostarlimab or placebo was continued as maintenance for up to 3 years. In the results, there was a doubling of the PFS in patients with MSI-high tumors. This study was published in the @New England Journal of Medicine on June 8 (DOI: 10.1056/NEJMoa2216334), and on July 31, dostarlimab?was approved by the FDA for front-line treatment. This study was conducted within the SCRI network, with 4 authors included in the New England Journal of Medicine publication. The current FDA approval for dostarlimab?is for patients with MSI-high, or MMR-deficient advanced endometrial cancer, and patients who are not eligible do have other options. SCRI currently has the XPORT-EC-042 trial open, which is evaluating a different treatment as maintenance therapy for patients who have completed chemotherapy. There are plans to open another maintenance study using navtemadlin in p53 WT endometrial cancer. For patients with hormonally-sensitive tumors, SCRI has a trial that is exploring endocrine therapy in endometrial cancer. It is exciting to see that we are getting to the point where there may even be a non-chemotherapy treatment option, or deescalating therapy in some patients, and escalating therapy in patients who might need more treatment.

What Is The Most Important Thing to Know About Gynecologic Cancer Research?

Overall, we now have the ability to more carefully target specific molecular markers for cancer, and have FDA approved therapies that are specific to each of these biomarkers. Over the last few years, we have not only discovered that there are many factors that distinguish cancer cells from normal cells, but also have developed treatments that can target them specifically.

Breakthroughs like these are due to clinical trials, and the reason that these effective therapies are available to patients. In the past 5 years, multiple novel therapies that have been approved by the FDA – pembrolizumab for cervical cancer, PARP inhibitors and mirvetuximab for ovarian cancer, dostarlimab?in combination with chemotherapy for endometrial cancer - we are making changes rapidly, so hold on to your seats!

I personally have also seen a difference - people are living longer and having better quality of life than ever before. I hope that, at some point, we get to a time when we do not use cytotoxic chemotherapy, and instead we use specialized treatment that is developed for a specific person’s tumor, not only their tumor type.

#ASCO23 #Research #Oncology #GynecologicCancer #WomenInStem #FemaleLeadership #ScientificAdvancements #ClinicalTrials #ResearchNews

#MIRASOL #RUBYtrial #KEYNOTE 826 #RAMP201