Time for a Radical Change in the Treatment of Endometrial Cancer: KEYNOTE-775 and Beyond

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I had the privilege of sitting in a meeting on the treatment of endometrial cancer as a junior investigator in January 2015 where a representative from the U.S. Food and Drug Administration was present. The topic of the meeting was on how to design the next endometrial cancer trials. I remember distinctly listening over and over to a statement made by nearly all the presenters. “There is no standard second-line therapy for recurrent endometrial cancer.” Profound change was needed to find agents that would treat these cancers and give patients more time.

Primary treatment of metastatic recurrent endometrial cancer has been relatively unchanged since the early 2000s. Despite primary surgery and chemotherapy and even radiation therapy, disease recurrence rates in advanced-stage cases are high. Long-term survival is diminished for women with stage III or IV cancers, with most series suggesting just a 25% survival rate at 5 years. Single-agent chemotherapy with doxorubicin or weekly paclitaxel has been evaluated as therapy for recurrence, but response rates have been extremely low (eg, 12% with doxorubicin,1 26.4% with weekly paclitaxel2). Agents such as bevacizumab, everolimus plus letrozole, and tamoxifen plus megestrol acetate have demonstrated varying efficacy, but durable responses are uncommon. A radical shift in cancer treatment was clearly needed for this disease.

It remains to be seen whether the fundamental change from chemotherapy to immunotherapy will be complete in endometrial cancer.
— B.J. Rimel, MD

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Focus on Microsatellite Instability

The remarkable finding that microsatellite instability could be exploited to induce an immune response by checkpoint inhibitors was just such a change. KEYNOTE-158 examined the use of the anti–PD-1 antibody pembrolizumab in microsatellite instability–high (MSI-H) tumors, including 49 women with endometrial cancer.3 The response rate in this group of patients was a startling 57% (95% confidence interval [CI] = 42.2%–71.2%). Median overall survival was also dramatic—22.7 months (95% CI = 2.5 months to not reached). This type of durability implies both efficacy and reasonable tolerance. Treatment-related grade 3 or 4 adverse events were reported in just 14.7% of patients in the study. These data led to the approval of pembrolizumab for patients with MSI-H tumors, which includes nearly 25% of those with endometrial cancer.

Building off these remarkable responses, investigators examined whether the addition of other agents to pembrolizumab could achieve for microsatellite-stable (MSS) tumors the same results as these initial findings. Preclinical data suggested that antiangiogenesis agents might reduce VEGF-mediated immune suppression and thus potentially synergize with immunotherapy agents.4 Dr. Vicky Makker and colleagues began a phase II open-label study with lenvatinib and pembrolizumab, which was published in 2019. The study reported its findings early due to remarkable responses seen in MSS tumors and an overall response rate of 39.6%.5

Study 309/KEYNOTE-775: ‘Far-Reaching’ Results

The phase III Study 309/KEYNOTE-775 trial, recently reported by Makker et al and summarized in this issue of The ASCO Post, is far-reaching in providing a definitive improvement over chemotherapy in previously treated mismatch repair–proficient advanced endometrial cancer.6 Lenvatinib and pembrolizumab were clearly superior in terms of response rate (30.3% vs 15.1%), progression free survival (median = 6.6 vs 3.8 months, hazard ratio [HR] = 0.60, 95% CI = 0.50–0.72, P < .001), and overall survival (median = 17.4 vs 12.0 months, HR = 0.68, 95% CI = 0.56–0.84, P < .001) to single-agent doxorubicin or weekly paclitaxel in this population.

The combination does have significant toxicity leading to its discontinuation, with one-third of patients in the lenvatinib/pembrolizumab arm needing to stop treatment, compared with 8% of those on chemotherapy. Lenvatinib is associated with significant hypertension, diarrhea, and nausea/vomiting/weight loss. Pembrolizumab is associated with more immunologic toxicities, such as hypothyroidism. These side effects are particularly difficult to manage in the older population of patients with endometrial cancer. Management of these toxicities is critical to patients’ being able to maintain benefit from these agents. Like all sweeping changes, massive education around the management of these side effects will help to ensure that patients and providers are comfortable with the new problems as they arise.

More to Learn

It remains to be seen whether the fundamental change from chemotherapy to immunotherapy will be complete in endometrial cancer. Answers to this question may be provided by the awaited results of the phase III LEAP-001 study, comparing lenvatinib/pembrolizumab vs chemotherapy in newly diagnosed advanced or recurrent endometrial cancer. In the meantime, we can offer this new combination to our patients with previously treated advanced endometrial cancer. 

Dr. Rimel is Associate Professor, Gynecologic Oncology, and Medical Director of Cancer Clinical Trials Office, Cedars Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles.

DISCLOSURE: Dr. Rimel has received honoraria from Genentech and served as a consultant or advisor to AstraZeneca, Tesaro, Genentech, Roche, Deep 6 AI, and Clovis Oncology.


1. Moreira E, Paulino E, Ingles Garces ÁH, et al: Efficacy of doxorubicin after progression on carboplatin and paclitaxel in advanced or recurrent endometrial cancer: A retrospective analysis of patients treated at the Brazilian National Cancer Institute (INCA). Med Oncol 35:20, 2018.

2. Homesley HD, Meltzer NP, Nieves L, et al: A phase II trial of weekly 1-hour paclitaxel as second-line therapy for endometrial and cervical cancer. Int J Clin Oncol 13:62-65, 2008.

3. Marabelle A, Le DT, Ascierto PA, et al: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 38:1-10, 2020.

4. Ott PA, Hodi FS, Buchbinder EI: Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: An overview of rationale, preclinical evidence, and initial clinical data. Front Oncol 5:202, 2015.

5. Makker V, Rasco D, Vogelzang NJ, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: An interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20:711-718, 2019.

6. Makker V, Colombo N, Casado Herráez A, et al: Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 386:437-448, 2022.


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