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Selecting and Sequencing New Treatment Strategies in Gynecologic Cancers

Jubilee Brown, MD

Professor and Division Director
Gynecologic Oncology
Levine Cancer Institute, Atrium Health
Charlotte, North Carolina

Jubilee Brown, MD: researcher: Olympus, Tesaro/GlaxoSmithKline.

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Elisabeth Diver, MD

Clinical Assistant Professor
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Stanford University
Stanford Cancer Institute
Stanford University Hospital and Clinics
Stanford, California

Elisabeth Diver, MD: consultant: EMD Serono, GlaxoSmithKline; researcher: Aravive, EMD Serono, GlaxoSmithKline.

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Released: July 5, 2022

In this commentary adapted from a discussion between Jubilee Brown, MD, and Elisabeth Diver, MD, the experts address important clinical questions on molecular classification in endometrial cancer and sequencing therapy for patients with cervical cancer.

What do you think about the use of molecular characterization in endometrial cancer to inform ongoing trials such as SIENDO?

Jubilee Brown, MD:
I think the SIENDO study is a great example of how molecular subclassification will redefine how we practice medicine. SIENDO is an ongoing phase III study of maintenance selinexor vs placebo in patients with recurrent endometrial cancer. Overall, median investigator-assessed progression-free survival (PFS), which was the primary endpoint, was significantly prolonged in the selinexor group at 5.7 months vs 3.8 months with placebo (HR: 0.705; 1-sided P = .024). P53 status really affects the utility of this medication in this patient population. We saw a 10-month improvement in median PFS with use of selinexor in patients with wild-type p53. However, in patients who had mutant/aberrant P53 disease, median PFS was only 3.7 months with selinexor and 5.6 months with placebo, a difference that was not statistically significant.

How do you currently apply data from the GARNET study of dostarlimab in microsatellite stable (MSS) endometrial cancer?

Elisabeth Diver, MD:
The phase I GARNET study looked at the PD-1 inhibitor dostarlimab in patients with advanced or recurrent solid tumors. In the cohort of 143 patients with endometrial cancer that was mismatch repair deficient or microsatellite instability–high, there was an impressive overall response rate (ORR) of 45%. Among 156 patients with MSS or mismatch repair proficient (MMRp) endometrial cancer, ORR was 15%. I think many of us may consider this a reasonable response rate in this latter population. The KEYNOTE-775 study reported an ORR of 30% with use of lenvatinib plus pembrolizumab in advanced endometrial cancer, suggesting that we can increase response rate in the MSS/MMRp population with the addition of a second drug. That said, dostarlimab monotherapy does seem more tolerable—one third of patients discontinued lenvatinib/pembrolizumab for adverse events (AEs) in KEYNOTE-775. For a patient with an MSS/MMRp tumor who cannot have combination therapy or will not tolerate it, it is reasonable to try single-agent immunotherapy because if they do respond, there is potential for considerable clinical benefit.

How do you choose between the various PARP inhibitors in ovarian cancer?

Elisabeth Diver, MD:
Currently, we do not have head-to head data on PARP inhibitors for ovarian cancer, and I do not know that we will. I tend to choose a PARP inhibitor based on toxicity profile and the patient’s experience of chemotherapy (CT). For example, did they have issues with thrombocytopenia during treatment? Available length of follow-up data also is influential. Some drugs have been around longer, and healthcare professionals might have more experience using them. But all 3 PARP inhibitors (olaparib, olaparib/bevacizumab, and niraparib) that are approved by the FDA in ovarian cancer have excellent activity.

How do you sequence therapy in cervical cancer?

Jubilee Brown, MD:
The results from the KEYNOTE-826 trial led to FDA approval of pembrolizumab in combination with CT with or without bevacizumab for patients with persistent recurrent or metastatic cervical cancer whose tumors express PD-L1. My key take-home from KEYNOTE-826 is that the addition of pembrolizumab to CT, with or without bevacizumab, increased PFS in all subgroups, including those who had or had not received prior chemoradiotherapy. This changed the way that I would sequence therapy in stage IV recurrent or metastatic disease in that I anticipate incorporating immunotherapy earlier in treatment.

Elisabeth Diver, MD:
I agree. I am using quadruplet therapy (pembrolizumab in combination with platinum-doublet CT and bevacizumab) upfront in stage IV recurrent or metastatic disease. There was also an overall survival benefit with pembrolizumab in KEYNOTE-826, again regardless of prior chemoradiotherapy and histology. These are patients who, in general, do not have a great prognosis, so if they have an Eastern Cooperative Oncology Group performance status below 2 (as in KEYNOTE-826) and no contraindications, I use this quadruplet regimen. There are some patients with cervical cancer who are perhaps not the best candidates for bevacizumab, such as those with fistula or after extensive prior chemoradiation.

Jubilee Brown, MD:
I have been impressed with how well patients tolerate the quadruplet regimen. It sounds daunting, but patients tolerate it quite well in my, albeit limited, experience.

What would you do if patients with cervical cancer progress while receiving pembrolizumab and CT?

Jubilee Brown, MD:
Tisotumab vedotin received the FDA’s accelerated approval as a second-line treatment for recurrent or metastatic cervical cancer and disease progression on or after CT, which means we do now have options in this group of patients.

Elisabeth Diver, MD:
I agree. It is exciting to have tisotumab vedotin for those who experience progression. We have recently seen new data on tisotumab vedotin combined with pembrolizumab in recurrent or metastatic cervical cancer in the innovaTV 205 study. Although that particular combination is not yet approved by the FDA, it is great that we are thinking about new combinations and novel ways to treat patients with advanced cervical cancer. These patients do need more options for therapy.

What do you think about the ocular AEs associated with tisotumab vedotin?

Jubilee Brown, MD:
We have seen ocular toxicities with various antibody–drug conjugates (ADCs), and although these are a concern, we are now able to mitigate them through close ophthalmic monitoring and prophylactic ocular lubrication. I think most healthcare professionals are more comfortable with managing ocular AEs with ADCs than they were when tisotumab vedotin was initially approved. In the earlier days, we were looking for ophthalmologists to help monitor and comanage these ocular AEs, but that proved limiting. We now find that optometrists can also be helpful and are often easier to access.  

Elisabeth Diver, MD:
Most of the ocular toxicity seen with tisotumab vedotin is lower grade in severity. I think it is daunting to patients to hear about it, but I am learning how to counsel them better about these toxicities. Having an ophthalmologist who is on your team and willing to see these patients is really helpful.

Your Thoughts?
What are your thoughts and questions on new management approaches for your patients with endometrial, ovarian, and cervical cancer receiving ADCs? Please answer the polling question and join the conversation by posting a comment in the discussion section below.

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