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Gyn Conferences 2022

CME

Expert Analyses of Key Clinical Developments and Updates Across Gynecologic Malignancies

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: January 23, 2023

Expiration: January 22, 2024

CME/CE Information

Activity

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Course Completed

Molecular Characterization in Patients With Endometrial Cancer

Jubilee Brown, MD:
I think the SIENDO study is a great example of how molecular subclassification will redefine how we practice medicine.6 As previously mentioned, SIENDO is an ongoing phase III study of maintenance selinexor vs placebo in patients with recurrent endometrial cancer, which is quite novel in its own right because there are currently no maintenance treatments in endometrial cancer unlike with ovarian cancer.

SIENDO Preliminary Subgroup Analyses: PFS in Patients With Wild-Type/Mutant P53 Endometrioid Carcinoma

Jubilee Brown, MD:
We also saw an updated report from SIENDO at ASCO 2022, which showed that P53 gene status might affect the utility of this medication in this patient population. Specifically, we saw a 10-month improvement in median PFS with the use of selinexor in patients with wild-type P53 gene (13.7 vs 3.7 months; P = .0003). In patients who had disease with mutant P53 gene, the median PFS was only 3.7 months with selinexor and 5.6 months with placebo, but that difference was not statistically significant.

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Applying Data From the Phase I GARNET Trial in Endometrial Cancer

Elisabeth Diver, MD:
As you may remember, the phase I GARNET study looked at the PD-1 inhibitor dostarlimab in adult patients with recurrent/advanced endometrial cancer with ≤2 previous lines of treatment for recurrent or advanced disease and progressive disease after platinum doublet therapy and no previous anti–PD-L1. The study had a cohort 1A for tumors with MMRd or MSI-H status and cohort A2 for tumors with MMR-proficient (MMRp) or MSS status.9 The coprimary endpoints were ORR and duration of response by BICR, and safety. At ASCO 2022, we saw updated data presented for both cohorts.

 

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GARNET Cohorts A1 and A2 Update: Responses

Elisabeth Diver, MD:
In the cohort A1, consisting of 143 patients with endometrial cancer that was MMRd/MSI-H, there was a remarkable ORR of 45%. Among the 156 patients with MMRp/MSS endometrial cancer in cohort A2, the ORR was 15%. I think many of us may still consider this a reasonable response rate in the latter population.

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KEYNOTE-775: Lenvatinib + Pembrolizumab vs CT in Advanced/Recurrent Endometrial Cancer

Elisabeth Diver, MD:
The KEYNOTE-775 study reported an ORR of 30% with the use of lenvatinib plus pembrolizumab in MMRp/MSS advanced endometrial cancer, suggesting that we can increase response rate in the MMRp/MSS population with the addition of a second drug.10,11

GARNET Cohorts A1 and A2 Update: Safety

That said, dostarlimab monotherapy does seem more tolerable than the combination, as one third of patients discontinued lenvatinib/pembrolizumab for AEs in KEYNOTE-775 vs approximately 9% with dostarlimab alone.10,11 For a patient with an MMRp/MSS tumor who cannot have combination therapy or will not tolerate it, it might be reasonable to try single-agent immunotherapy, because if they do respond, there is potential for considerable clinical benefit.

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KEYNOTE-826 of Pembrolizumab + CT vs Placebo + CT in Cervical Cancer

Jubilee Brown, MD:
At ASCO 2022, we also saw results presented from the ongoing phase III KEYNOTE-826 study of pembrolizumab plus CT vs placebo plus CT, both with or without bevacizumab (N = 548).12,13 The coprimary endpoints are OS and PFS. It is important to note that results from this phase III 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 (CPS ≥1), as determined by an FDA-approved test.14

The KEYNOTE-826 study 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 OS benefit with pembrolizumab in KEYNOTE-826, again regardless of previous chemoradiotherapy (yes vs no, HR: 0.64 vs 0.71) and histology (squamous vs nonsquamous, HR: 0.61 vs 0.76). 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 previous 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 limited experience.

 

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Considering Next Therapy for Cervical Cancer After Pembrolizumab and CT Progression

Jubilee Brown, MD:
As previously discussed, our go-to treatment for advanced/recurrent cervical cancer after immunotherapy and/or CT progression has been tisotumab vedotin. 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,8 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 also recently seen new data, at ASCO 2022, for tisotumab vedotin combined with pembrolizumab in recurrent or metastatic cervical cancer from the innovaTV 205 study.15 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/recurrent cervical cancer. These patients do need more options for therapy.

Anticipating and Mitigating Ocular AEs With Tisotumab Vedotin

Jubilee Brown, MD:
We have seen ocular toxicities with various 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 now 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 for the provider and the patient.

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

At ASCO 2022, Makker and colleagues presented data for the ongoing phase III SIENDO trial of maintenance selinexor vs placebo in patients with stage IV endometrial cancer following a partial response (PR) or complete response (CR) to 12 or more weeks of first-line therapy with taxane-carboplatin. Based on the data presented for that study, which of the following biomarkers should you assess to determine her likelihood of benefit from selinexor maintenance therapy?

At the 2022 ASCO Annual Meeting, Tewari and colleagues reported the subgroup analyses from the phase III KEYNOTE-826 trial of pembrolizumab combined with chemotherapy (CT) with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Based on data presented in that report, which of the following statements is correct regarding the various subgroups evaluated?
Your patient is a 56-year-old woman with history of endometrial cancer. She was previously treated with standard of care chemoradiation followed by systemic CT. She recently presents to you with recurrent endometrial cancer and residual peripheral neuropathy from previous chemoradiation and is currently receiving hydrochlorothiazide for hypertension and fluid retention in her lower extremities. Her PD-L1 CPS score is 2 (positive), and tumor testing showed MLH1 and PMS2 protein loss by immunohistochemistry. As you are planning your next steps for this patient, which of the following treatment strategies would be most appropriate to manage her recurrent endometrial cancer?