Levantinib in combination with pembrolizumab in second line treatment the advanced stage endometrial cancer

Phase III data from the 309- KEYNOTE-775 study demonstrate that the combination of levantinib plus pembrolizumab was beneficial for patients with advanced endometrial cancer who had diseases progression after receiving prior platinum-based systemic therapy

The incidence of endometrial cancer is increasing worldwide. Approximately 10 to 15% of patients with this type of cancer have advanced stage disease, and the 5-year survival among patients with distant metastases has been reported to be 17%.

No treatment has been globally accepted as the standard of care for advanced or recurrent endometrial cancer after failure of platinum-based chemotherapy. Targeted therapies and chemotherapy had limited efficacy, substantial toxic effects, or both. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has limited efficacy as a second-line treatment for recurrent endometrial carcinoma.

In study 111–KEYNOTE-146, treatment with lenvatinib in combination with pembrolizumab was effective in patients with previously treated advanced endometrial carcinoma.

The 309–KEYNOTE-775 study was conducted to confirm the results of the previous study comparing the efficacy and safety of lenvatinib in combination with pembrolizumab compared with the physician’s choice of chemotherapy with doxorubicin or paclitaxel in patients with advanced endometrial cancer who got disease progression after receiving at least one platinum-based therapy.

Therefore, this phase III study randomized in a 1:1 ratio patients with advanced endometrial cancer, who received at least 1 platinum-based chemotherapy regimen, to receive or lenvatinib 20 mg administered orally once daily plus pembrolizumab 200 mg injected intravenously every 3 weeks or chemotherapy of choice the physician with 2 options: doxorubicin 60 mg per m² of body surface, every 3 weeks or paclitaxel at 80 mg per m², 3 week cycle treatment and 1 week break.

The two primary endpoints were progression-free survival and overall survival. Outcomes were evaluated in patients who presented disease without DNA mismatch repair problems (DNA (mismatch repair-proficient – pMMR) and in all patients. More than that, the safety of the treatment was also evaluated.

A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomized to receive lenvatinib + pembrolizumab (n=411) or chemotherapy (n=416 ). Median progression-free survival was higher with lenvatinib + pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; HR 0.60; 95% IC, 0.50 to 0.72; P < 0.001; general population: 7.2 vs. 3.8 months; HR 0.56; 95% IC, 0.47 to 0.66; P < 0.001). Median overall survival was higher for lenvatinib + pembrolizumab than chemotherapy (pMMR population: 17.4 vs. 12.0 months; HR, 0.68; 95% CI, 0.56 to 0.84; P < 0.001 ; general population: 18.3 vs. 11.4 months; HR, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Grade 3 or greater adverse events occurred in 88.9% of patients who received lenvatinib + pembrolizumab and in 72.7% who received chemotherapy.

Therefore, levantinib + pembrolizumab demonstrating to significantly longer progression-free survival and overall survival compared to chemotherapy, both in the pMMR population and in the general population of patients with advanced endometrial cancer who had disease progression after receiving previous systemic therapy platinum based.

Reference:

Makker V, et al., Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. doi: 10.1056/NEJMoa2108330. Epub 2022 Jan 19. PMID: 35045221.