Anti-angiogenesis + immunotherapy succeeded again, new standard of treatment for advanced endometrial cancer NEJM

The incidence of endometrial cancer continues to increase worldwide, with approximately 10% to 15% of patients presenting at an advanced stage, and the 5-year survival rate of these patients is only 17%
.

There is currently no widely accepted standard treatment regimen for advanced or recurrent endometrial cancer
.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor that inhibits multiple important pathways affecting angiogenesis and cell proliferation, including vascular endothelial growth factor receptors 1-3 (VEGFR 1-3), fibroblasts Cell growth factor receptors 1-4 (FGFR 1-4), platelet-derived growth factor receptor alpha (PDGFR alpha) and proto-oncogenes RET and KIT
.

Lenvatinib has limited efficacy as a second-line treatment for recurrent endometrial cancer, with an objective response rate of only about 14.
3% (95% CI, 8.
8-21.
4)
.

Previous studies have shown that checkpoint inhibitors, including pembrolizumab, have favorable antitumor effects in patients with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR)
.

However, only 16% to 31% of endometrial cancer patients have MSI-H or dMMR
.

A phase 1b/2 clinical trial (111–KEYNOTE-146) suggests that lenvatinib combined with pembrolizumab has a good effect in previously treated patients with advanced endometrial cancer, and can be treated with supportive care and dose adjustment.
Control of high-grade adverse events, the probability of discontinuation is relatively low [1]
.

Investigators conducted a multicenter, large, phase 3 clinical trial (Study 309–KEYNOTE-775) to further confirm the findings of the previous study
.

The trial compared the efficacy and safety of lenvatinib plus pembrolizumab and chemotherapy in patients with advanced endometrial cancer whose tumors had progressed after at least one platinum-based chemotherapy
.

The trial results were published online in the New England Journal of Medicine on January 19, 2022 [2]
.

 The patients were older than 18 years old and had advanced or recurrent endometrial cancer; pathological types were not limited, but sarcomas and carcinosarcoma were excluded; patients should have received at least one platinum-based chemotherapy regimen before tumor progression, However, they must have never received vascular endothelial growth factor (VEGF) or programmed death-1 (PD-1) targeted therapy
.

Patients were randomized 1:1 into two groups: one group received lenvatinib (20 mg, orally, once daily) combined with pembrolizumab (200 mg, intravenously, once every 3 weeks); The group received the chemotherapy regimen selected by the doctor (doxorubicin 60 mg/m2, intravenous injection, once every 3 weeks; or paclitaxel 80 mg/m2, intravenous injection every week, alternating 3-week administration period and 1-week withdrawal period)
.

 The primary endpoints were progression-free survival and overall survival
.

Secondary endpoints included objective response rate, safety and side effects, health-related quality of life, and the exposure-safety relationship of lenvatinib
.

Endpoints were assessed in both patients with normal mismatch repair function (pMMR) and overall patients
.

 Results A total of 827 patients were included in the trial, of which 697 had pMMR and 130 had dMMR
.

411 patients were enrolled in the lenvatinib plus pembrolizumab group and 416 in the chemotherapy group
.

 The trial results showed that the median progression-free survival of the lenvatinib plus pembrolizumab group was longer than that of the chemotherapy group
.

In pMMR patients, median progression-free survival was 6.
6 months in the lenvatinib plus pembrolizumab group compared with 3.
8 months in the chemotherapy group (hazard ratio [HR] for disease progression or death, 0.
60, 95 %CI, 0.
50-0.
72; P<0.
001)
.

For overall patients, median progression-free survival was 7.
2 months in the lenvatinib plus pembrolizumab group, compared with 3.
8 months in the chemotherapy group (HR, 0.
56; 95% CI, 0.
47-0.
66; P < 0.
001) (Figure 1)
.

 Figure 1.
Progression-free survival[2] Overall survival was also better in the lenvatinib plus pembrolizumab group than in the chemotherapy group (pMMR patients: median 17.
4 months vs.
12.
0 months; HR, 0.
68; 95 %CI, 0.
56-0.
84; P<0.
001; overall patients: median 18.
3 months vs.
11.
4 months, HR, 0.
62; 95% CI, 0.
51-0.
75; P<0.
001) (Figure 2)
.

 Figure 2.
Progression-Free Survival[2] 88.
9% of patients in the lenvatinib plus pembrolizumab group experienced grade 3 or higher adverse events during treatment, compared with 72.
7% in the chemotherapy group
.

 The relatively short follow-up period was one of the major limitations of the study
.

This may lead to under-observation of the subsequent development of the treatment response
.

In addition, although the "efficacy analysis" has met the requirements set by the trial protocol, long-term monitoring of safety and efficacy is still ongoing
.

 Conclusions For advanced endometrial cancer, both pMMR patients and overall patients, the lenvatinib + pembrolizumab group had significantly longer progression-free survival and overall survival than the chemotherapy group
.

Translation, rewriting: Li Mu, Dana-Farber Cancer Institute at St.
Elizabeth's Medical Center Reference 1.
Makker V, Taylor MH, Aghajanian C, et al.
Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer.
JClin Oncol 2020;38:2981 -92.
2.
MakkerV, Colombo N, Casado Herráez A, et al.
Lenvatinib plus pembrolizumab foradvanced endometrial cancer.
N Engl J Med 2022 Jan 19.
DOI:10.
1056/NEJMoa2108330 (Epub ahead of print).
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