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ICI in Advanced/Recurrent EC
Managing Advanced or Recurrent Endometrial Cancer With Immune Checkpoint Inhibitors

Released: June 28, 2021

Expiration: June 27, 2022

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Whereas patients diagnosed with early-stage localized endometrial cancer (EC) can potentially be cured with surgery and/or adjuvant treatment, patients with advanced or recurrent disease are more challenging to manage and are likely to experience disease relapse. For several years, platinum-based chemotherapy with carboplatin and paclitaxel was the only available option for patients with advanced/recurrent EC, but more recently, single-agent immunotherapy with anti–PD-1 monoclonal antibodies, either dostarlimab or pembrolizumab, being approved options for patients with recurrent microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) EC, or pembrolizumab in combination with lenvatinib in non–MSI-high or dMMR recurrent disease have expanded the treatment armamentarium for EC.

Recent Approvals for Immunotherapy in Advanced or Recurrent EC
In 2017, the FDA approved the first anti–PD-1 monoclonal antibody, pembrolizumab, for adult and pediatric patients with unresectable or metastatic MSI‑H or dMMR solid tumors and who had progressed following previous treatment and who have no satisfactory alternative treatment options. MSI-H/dMMR recurrent EC represents 25% to 30% of cases approximately. For them, the overall response rate (ORR) for pembrolizumab monotherapy was reported to be approximately 57%, which is highly encouraging in this disease setting.

In 2021, dostarlimab, another anti–PD-1 monoclonal antibody, was approved by the FDA for adult patients with dMMR, recurrent or advanced EC based on results from the phase I GARNET trial; dostarlimab also received approval by the European Medicines Agency as monotherapy for adult patients with MSI‑H/dMMR recurrent or advanced EC progression on or after platinum-containing regimen. In the GARNET trial, 290 patients made up the cohorts of recurrent or advanced endometrial cancer who had received ≤2 previous lines of therapy and progressed after platinum-doublet therapy regardless of MSI status. Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 cycles followed by 1000 mg intravenously every 6 weeks. The primary endpoint was ORR. After a median follow-up of 20.4 months, dostarlimab showed an impressive ORR of 44.7% (95% CI: 34.9%-54.8%) in patients with EC and dMMR status. After a median follow-up time of 11.5 months, ORR was 13.4% (95% CI: 8.3%-20.1%) in the pMMR cohort. I hope that with these approvals all patients with MSI-H/dMMR EC will be able to receive these treatments and that the results in everyday clinical practice will be as good as those seen in clinical trials.

The Rationale for Immunotherapy and Combinations in EC
There is substantial rationale for single-agent immunotherapy in patients with dMMR EC, yet patients with pMMR EC experience a lower magnitude of benefit with single-agent immunotherapy, suggesting a combination strategy could improve outcomes for these patients. Consequently, several ongoing clinical trials are assessing the combination of immunotherapy with other treatment modalities, including with chemotherapy with or without PARP inhibitors. The phase III NRG-GY018 trial (NCT03914612) is evaluating pembrolizumab plus carboplatin and paclitaxel followed by pembrolizumab maintenance vs placebo plus carboplatin and paclitaxel followed by placebo maintenance in 810 patients with stage III-IV recurrent EC with no previous therapy or who completed adjuvant chemotherapy ≥12 months prior to registration. The phase III RUBY/ ENGOT-EN6/GOG 3031 trial (NCT03981796) is evaluating the combination of dostarlimab plus carboplatin and paclitaxel followed by dostarlimab vs dostarlimab plus carboplatin and paclitaxel followed by dostarlimab and niraparib, and placebo plus carboplatin and paclitaxel followed by placebo in 740 patients with recurrent or primary advanced EC. The phase III AtTEnd trial (NCT03603184) is evaluating the combination of atezolizumab plus carboplatinand paclitaxel in 550 patients with advanced or recurrent EC not amenable for surgery or radiation therapy.

In September 2019, results from the phase I/II KEYNOTE-146 led to FDA accelerated approval for lenvatinib in combination with pembrolizumab for patients without MSI-H or dMMR status. KEYNOTE-146 enrolled patients with MSI‑H and MSI‑low metastatic endometrial tumors who had been treated with ≤2 previous lines of therapy. The response rate was 36% in patients with MSI‑low/ proficient MMR (pMMR) tumors (n = 94) and 64% in patients with MSI-H/dMMR tumors (n = 11).

Recently, the confirmatory phase III KEYNOTE-775 trial (NCT03517449) evaluated the combination of lenvatinib and pembrolizumab vs chemotherapy (doxorubicin or paclitaxel) in 827 patients with advanced, metastatic, or recurrent endothelial cancer with disease progression after 1 previous platinum-based chemotherapy regimen. Patients enrolled on this trial are not candidates for curative surgery or radiotherapy and have tumors that are either dMMR or pMMR. The primary endpoints are progression-free survival (PFS) (by blinded independent central review) and overall survival (OS). Data presented at the Society of Gynecologic Oncology annual meeting showed, after a median follow-up of 11.4 months, a significant improvement for PFS (7.2 vs 3.8 months; P <.0001) and OS (18.3 vs 11.4 months; P <.0001) in the lenvatinib/pembrolizumab arm vs the chemotherapy arm for the all-comer population, including patients with pMMR or dMMR tumors. More data on the effect of combination in MMRd or MSI-H tumors are needed to clarify if adding lenvatinib to pembrolizumab improves results compared with immunotherapy alone in this subgroup of patients. These results are very encouraging, and although the lenvatinib/pembrolizumab combination is not yet approved by the European Medicines Agency, I hope that it will be in the near future based on these data, giving us more options for the treatment of patients with advanced, metastatic, or recurrent EC.

Advantages of Immunotherapy
The use of immunotherapy has changed how we manage patients with EC. Immunotherapies have a distinct toxicity profile compared with chemotherapy and are generally well tolerated. The common adverse events associated with immunotherapy include problems with thyroid gland function, skin toxicities, and various laboratory abnormalities, which are easily resolved once we learn how to manage these adverse events. Of course, there is a learning curve about how to treat immune-related toxicities, but I think that medical oncologists are familiar with the new treatments for EC because we are using them in other tumor types. We also have learned how to manage toxicities and how to select patients who can receive these treatments without worsening preexisting conditions and note that most of patients with EC are older and with comorbidities (eg, autoimmune disease, diabetes, or hypertension). Another advantage of immunotherapy is that in patients who experience responses, the responses are quite durable. In GARNET, more than 90% of patients had a duration of response longer than 6 months. Long responses with a well-tolerated treatment can have a significant impact in a patient’s quality of life.

Future Directions
In the future, I think we will continue to see studies on the efficacy of immunotherapy combined with other targeted therapies. There will also be new options for therapies, now that we have new methods for molecular reclassification of endometrial tumors and a better knowledge of molecular subtypes and biomarker expression. At the 2021 American Society of Clinical Oncology annual meeting, we saw results from the TAPUR study (abstract 5508) where investigators evaluated the combination of pertuzumab and trastuzumab for patients with advanced uterine cancer with HER2 overexpression. Another strategy being explored is the combination of an anti–PD-1 with other tyrosine kinase inhibitors. And of course, I think that in the future, we will be able to match patients to the most beneficial treatment based on new biomarkers.

Your Thoughts
Are you currently using immunotherapy either as single agents or in combinations for patients with recurrent or advanced EC? Answer the polling question and join the conversation by posting a comment in the discussion section below.

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