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Gynecologic Oncology Department
Clinical Research Unit
Fondazione Policlinico Gemelli IRCCS
Domenica Lorusso, MD, PhD, has disclosed that she has received consulting fees from Amgen, AstraZeneca, Clovis, GlaxoSmithKline, MSD, and Pharmamar; fees for non-CME/CE services from MSD; and other financial or material support from AstraZeneca, Clovis, GlaxoSmithKline, and Pharmamar.
One of the most important steps forward in the management of endometrial cancer was when it became understood that the outdated model of histologic classification should be informed by incorporating molecular profiling. The new molecular reclassification of endometrial tumors has clear clinical implications, both in terms of prognosis and in helping to identify patients who will benefit from immunotherapy. This is particularly relevant to older patients, who are more fragile in general and often have multiple comorbidities, such as diabetes, hypertension, and cardiopathy.
Advances in Immunotherapy for Endometrial Cancer With MSI-H/MMRd Status
The recent advancements with immunotherapy have led to an awareness that patients with high microsatellite instability (MSI-H) or defective mismatch repair (MMRd) endometrial cancer seem to have a decreased benefit from chemotherapy compared with immunotherapy. In particular, women 65 years of age or older remain vulnerable because of their comorbidities. Of importance, the chemotherapies available in the second‑line setting have limited benefit in recurrent endometrial cancer.
In 2021, the anti–PD-1 monoclonal antibody dostarlimab was approved by the FDA for adult patients with MMRd recurrent or advanced endometrial cancer based on a positive overall response rate (ORR) benefit in the phase I GARNET trial; dostarlimab also received approval by the European Medicines Agency as monotherapy for adult patients with MSI‑H/MMRd recurrent or advanced endometrial cancer with progression on or after platinum-containing therapy. In the GARNET trial, 290 participant made up the cohort of patients with recurrent or advanced endometrial cancer who had received ≤2 previous lines of therapy and progressed after platinum-doublet therapy regardless of MSI status. The ORR of 45% in patients with MSI status vs 13% in patients who were microsatellite stable supported the indication being only in patients with MSI-H/MMRd recurrent endometrial cancer.
The European Medicines Agency also has approved the combination of lenvatinib plus pembrolizumab for advanced or recurrent endometrial cancer in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation. This approval is based on results from the randomized phase III KEYNOTE-775 study showing significantly improved progression-free survival (PFS), overall survival (OS), and ORR for the combination vs physician’s choice chemotherapy of weekly paclitaxel or anthracyclines. Of note, pembrolizumab plus lenvatinib is indicated independent of MSI status.
In our clinic, I treat patients with MSI‑H status with the single-agent immunotherapy dostarlimab and use the combination of lenvatinib plus pembrolizumab for patients with microsatellite stable disease, as in Italy the combination has been reimbursed. Although it is not clear exactly if there is a difference in terms of efficacy between single-agent immunotherapy and the combination of pembrolizumab plus lenvatinib in MSI-H cancer, because of the lack of a direct comparison between the 2 strategies, yet safety remains a substantial concern with the combination. At times, I am reluctant to offer the combination to patients who are older and fragile and who have a poor performance status and multiple comorbidities. In KEYNOTE‑775, 66% of patients experienced dose reduction and 33% discontinued the treatment because of toxicity. It is likely those percentages would be even higher in a population 70 years of age or older with comorbidities. In real-world clinical practice, approximately 1 of 3 patients with endometrial cancer must discontinue lenvatinib due to toxicity and continue with single-agent pembrolizumab.
GARNET: Single-Agent Dostarlimab in Endometrial Cancer
Oaknin and colleagues presented a substudy analysis of GARNET at the 2022 Society of Gynecologic Oncology meeting showing the activity and safety of single‑agent dostarlimab in patients older than 65 years of age. ORRs were similar across age groups, regardless of MSI-H and MMRd status. Of importance, rates of grade ≥3 treatment-related adverse events (AEs) were low across all patient subgroups; single-agent dostarlimab immunotherapy is very well tolerated in an older patient population. Moreover, patients 75 years of age or older had comparable rates of grade ≥3 AEs. For example, in patients with MSI-H or MMRd status, diarrhea was the most common AE, affecting 19.7% of those younger than 65 years of age and 22.0% of those older than 65 years. Similarly, nausea was seen in 10.6% of those younger than 65 years of age, 11.8% of those 65-75 years, and 25.0% of the 12 patients older than 75 years. However, fatigue was seen in only 7.6% of patients younger than 65 years of age but in approximately 30% of older patients.
GARNET is a single‑arm phase Ib trial, so there is no comparison with other strategies as in a randomized study. But clearly, age is not a predictive biomarker of additional response to immunotherapy. In the MSI-H/MMRd population, the ORR was approximately 45% across all 3 age groups (≤65 years, 65 to <75 years, ≥75 years). Disease control rates were similar across groups as well, ranging from 51% to 64%. At 1 year, percentages for patients remaining in response were 84.6% for those aged 65 years or younger, 100% of those aged 65 to <75 years, and 80% of the older population. Based on these data, I am very confident using single-agent immunotherapy in women with endometrial cancer, specifically including older and more fragile patients.
With regard to patient selection for the combination of lenvatinib and pembrolizumab, we don’t use an age cutoff but instead conduct a more general evaluation of the patient, which is supported by our geriatrics physicians. Geriatric assessment encompasses multiple domains, including functional status, psychological health, polypharmacy, comorbidity, nutrition, social support, and cognition. Nearly all of our patients older than 70 years of age are evaluated using any of several well‑defined geriatric assessment tools to determine their risk (vulnerability) and fitness for treatment. These include the Geriatric 8 screening instrument (Table), as well as the Vulnerable Elders Survey 13, Triage Risk Screening Tool, Groningen Frailty Indicator, abbreviated Comprehensive Geriatric Assessment, Fried frailty criteria, and Senior Adult Oncology Program 2.
Table. Geriatric 8 Screening Instrument
Ongoing Clinical Trials in Older Patients With Endometrial Cancer
Improved treatment for patients older than 65 years of age with endometrial cancer remains an area of active clinical investigation. The ongoing phase III ENGOT/LEAP-001 trial is an important study comparing first-line treatment with pembrolizumab plus lenvatinib vs chemotherapy in 720 patients with newly diagnosed stage III/IV or recurrent endometrial cancer that can be MMRd or mismatch repair proficient (NCT03884101). The coprimary endpoints are PFS and OS, and the estimated primary completion date is April 2023. If this trial is positive, it has the potential to change the standard of care. Other important ongoing trials of chemoimmunotherapy in endometrial cancer include the following.
Lastly, there is interest in substituting immunotherapy for first-line chemotherapy in the MSI-H/MMRd population specifically. Two ongoing phase III trials are comparing first-line pembrolizumab (KEYNOTE-C93, NCT05173988) and dostarlimab (DOMENICA, NCT05201547) with platinum-doublet chemotherapy in patients with MMRd advanced or recurrent endometrial cancer. I hope these studies will provide another step toward eliminating chemotherapy as the standard of care in patients with endometrial cancer.
I strive to treat my patients, even those with comorbidities, according to the best clinical practice. It is not acceptable to offer undertreatment with chemotherapy to older patients instead of pembrolizumab plus lenvatinib or single-agent dostarlimab according to MSI status because we are concerned about the toxicity management. After 2 decades with no progress in OS benefit, we have seen tremendous improvement with the use of immunotherapies as second-line treatment for advanced, recurrent endometrial cancer. Finding ways to retain that benefit while managing the toxicity profile of novel treatments is paramount.
What are some of your current dilemmas in treating older patients with endometrial cancer? Share your thoughts in the comment box below.