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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.
For several years, we were convinced that endometrial cancer was comprised of only two isotypes: either endometrioid isotype (83%) or the more aggressive non‑endometrioid isotype (17%; including serous and clear cell. One of the most important steps forward in the management of endometrial cancer was the moment when clinicians realized that the outdated model of histologic classification should be informed by incorporating molecular profiling for endometrial tumors. The new molecular reclassification of endometrial tumors has clear clinical implications, both in terms of prognosis and helping to identify patients who will benefit from immunotherapy.
Reclassification of Endometrial Cancer
With the use of exome sequencing, we are now able to test tumor samples for somatic copy number alterations (SCNAs) that can potentially affect all of the protein coding regions. In an article published in Nature (2013) by Levine and colleagues, investigators used SCNA analysis and unsupervised hierarchical clustering to reclassify endometrial carcinoma into 4 distinct tumor subgroups: the POLE‑ultramutated tumors (7%), which are characterized by elevated tumor infiltration and high genomic instability; microsatellite instability (MSI) high (20% to 28%), which are associated with elevated PD-L1 expression, elevated tumor‑infiltrating lymphocytes, and genomic instability; the copy number high tumors (26%), which are characterized by a very aggressive phenotype; and the copy number low tumors (40%), which are associated with a good prognosis—not as good as POLE‑ultramutated tumors, but a good prognosis nonetheless. We know now that POLE‑ultramutated and MSI‑high tumors—also called “hot” tumors—are more likely to respond to immunotherapy. Conversely, the copy number low and the copy number high serous‑like tumors—also called “cold” tumors—are less likely to respond to immunotherapy.
Advent of Immunotherapy for Endometrial Cancer
In 2017, the FDA approved the first anti–PD-1 inhibitor, pembrolizumab, for adult and pediatric patients with unresectable or metastatic, MSI-high or mismatch repair deficient (dMMR) solid tumors that have progressed following previous treatment and who have no satisfactory alternative treatment options. This meant that any solid tumor with an MSI-high profile qualified for anti–PD-1 inhibitor therapy, including endometrial cancers. In nonbiomarker-selected patients with endometrial cancer, ORRs with immunotherapy were quite disappointing, ranging from 3% to 13%. The responses improved in the patients with a particular molecular profile—namely, using MSI-high or dMMR status—now ranging from 30% to 60%. However, immunotherapy remained unavailable for patients with endometrial cancer in Europe for several years, which is about to change thanks to the GARNET trial and the imminent approval of immunotherapy for endometrial cancers in Europe.
The multicenter phase I GARNET trial evaluated dostarlimab, an anti–PD-1 monoclonal antibody, in patients with advanced or recurrent endometrial cancer who had 2 or more previous lines of treatment, including previous platinum-based chemotherapy. Of note, the trial enrolled patients with both dMMR tumors and proficient MMR (pMMR) tumors. Responses were seen in approximately 45% of patients with dMMR tumors, and in approximately 13% of patients with pMMR tumors. This contrasts favorably to chemotherapy which, in this disease setting, yields an ORR of < 10%. Responses reported in patients with dMMR tumors were quite remarkable, particularly for a population that has already received at least 2 previous lines of chemotherapy. Moreover, responses were quite durable in this trial, with 89.1% of patients having ongoing responses at data cutoff with a median follow-up of 60 months—again, a prolonged response with immunotherapy.
Treatment Options for Copy Number Low and Serous-like Endometrial Tumors
In Europe, single-agent immunotherapy may potentially become a treatment option for MSI‑hypermutated and possibly for POLE‑ultramutated endometrial tumors. But what can we offer to patients with non MSI tumors? In the not-so-distant future, we hope to be able to offer a combination of checkpoint inhibition plus other strategies. There are several ongoing trials evaluating immunotherapy-based combinations with either a PARP inhibitor, anti‑VEGF tyrosine kinase inhibitor (TKI), chemotherapy, or radiotherapy.
Of particular interest is the combination of lenvatinib, an anti-VEGF TKI with effects on tumor angiogenesis, with immunotherapy. In a recent Journal of Clinical Oncology article by Makker and colleagues, results from a phase I/II KEYNOTE-146 trial evaluating the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer were reported. The trial enrolled patients with MSI‑high and MSI‑low metastatic endometrial tumors who had been treated with 1 previous line of therapy. The response rate was 36% in patients with MSI‑low/pMMR tumors (n = 94) and 64% in patients with MSI-high/dMMR tumors (n = 11). Moreover, it was exciting to see responses in endometrial cancer isotypes that we typically consider to be more aggressive and less likely to respond to chemotherapy, namely non-endometrioid tumors, serous type, and clear‑cell tumors. In addition, it is important to note that responses were seen both in patients with chemotherapy-naive tumors and those who had previously received chemotherapy. Based on results from this phase I/II single‑arm trial, the FDA approved lenvatinib in combination with pembrolizumab for patients with advanced endometrial carcinoma without MSI mutation in 2019.
In Europe, the EMA reported that it would consider lenvatinib plus pembrolizumab for approval after reviewing the results from the ongoing randomized phase III KEYNOTE-775 study comparing the combination against physician’s choice chemotherapy. KEYNOTE-775 has recently completed accrual. Positive results from this study have been previously reported on a company press release and will be presented at the upcoming SGO meeting. I would expect that in the next few months, this combination will be approved for use in Europe as well.
Future of Immunotherapy in Endometrial Cancer?
There at least 5 large, randomized phase III immunotherapy trials ongoing, with 3 of them evaluating immunotherapy and chemotherapy combinations (RUBY, AtTEnd, NRG-GY018), 1 combining immunotherapy with an anti-VEGF TKI in the first-line setting (KEYNOTE-775), and 1 combining immunotherapy with a PARP inhibitor (DUO-E/ENGOT-EN10). Of note, the phase III RUBY trial is evaluating dostarlimab plus platinum-based chemotherapy followed by dostarlimab maintenance vs platinum-based chemotherapy and placebo maintenance in patients with advanced/recurrent endometrial cancer and no previous chemotherapy. In advanced or recurrent endometrial cancer, KEYNOTE-775 is exploring pembrolizumab plus lenvatinib vs platinum-based chemotherapy in the first‑line setting. Finally, the phase III DUO-E/ENGOT-EN10 trial is evaluating durvalumab plus platinum-based chemotherapy followed by durvalumab maintenance with or without olaparib in newly diagnosed advanced/recurrent endometrial cancer. I am confident that, in the near future, the results from these trials may support new approvals for immunotherapy-based combinations and increase the number of available treatments for our patients with endometrial cancers.
Patients with endometrial cancers who harbor tumors characterized by significant genomic instability, namely MSI‑high/dMMR tumors, have experienced tremendous benefit from checkpoint inhibitor therapy. In patients with MSI-low or pMMR status, the combination of pembrolizumab and lenvatinib is highly effective and has been shown to achieve responses in non‑endometrioid tumors, serous type, and clear‑cell tumors, which are highly aggressive and typically have low responses to chemotherapy. Moreover, DNA damage induced by chemotherapy may be synergistic and enhance the response to immunotherapy of endometrial cancer, which is being explored in ongoing trials combining immunotherapy and chemotherapy in advanced disease. Finally, in the coming years, we hope to see results from the highly anticipated randomized phase III trials combining immunotherapy with an antiangiogenic agent (KEYNOTE-775) or a PARP inhibitor (DUO-E/ENGOT-EN10).
How do you currently use molecular profiling to subclassify endometrial cancers? How do you currently manage your patients with MSI-high and/or MSI-low endometrial cancer? Answer the polling question and join the conversation by posting a comment in the discussion section.