Novel Drug and Chemotherapy Combination Shows Potential in Endometrial Cancer


The combination of a novel mTORC1/2 inhibitor with paclitaxel could present a new way of targeting metastatic or persistent endometrial cancer.

Illustration of endometrial cancer -

Illustration of endometrial cancer -

A phase 2 study (NCT02725268) of sapanisertib (CB-228), a selective dual inhibitor of mTORC1/2, in combination with paclitaxel in patients with recurrent, metastatic, or persistent endometrial cancer showed that, while the primary end point of progression-free survival (PFS) was not met, improvements were still seen regarding clinical benefit rate (CBR).1

A total of 234 patients were randomized to receive paclitaxel (n =87), paclitaxel plus sapanisertib (n = 86), sapanisertib monotherapy (n = 41), or sapanisertib plus serabelisib (TAK-117), a PI3K inhibitor (n = 20). The latter 2 groups were closed due to futility.

With a median follow-up of 14.4 months for the paclitaxel arm and 17.2 months for the paclitaxel plus sapanisertib arm, the median PFS was 3.7 months vs 5.6 months, respectively (HR, 0.82; 95% CI, 0.58-1.15; P =.139). Among patients with an endometrioid histology (n = 116), the median PFS was 3.3 months vs 5.7 months in the paclitaxel and combination arms, respectively (HR, 0.66; 95% CI, 0.43-1.03).

“Although chemotherapeutic treatment options for advanced endometrial cancer remain limited, there have been significant advances in immunotherapy in this setting in the last 5 years,” study authors wrote. “As treatment for advanced and recurrent endometrial cancer shifts towards combined chemotherapy and immunotherapy, additional combination strategies, such as with mTOR inhibitors may be worth investigating.”


The median overall survival (OS) was 14.6 months in the paclitaxel arm vs 13.7 months in the combination arm (HR, 1.01; 95% CI, 0.67-1.53; P =.954). Among patients with endometrioid histology, the median OS was 11.6 months with paclitaxel vs 15.2 months with paclitaxel plus sapanisertib (HR, 0.83; 95% CI, 0.50-1.38).

The overall response rate (ORR) was 18.4% in the paclitaxel arm, consisting of 2 complete responses (CRs) and 14 partial responses (PRs). In the combination arm, the ORR was 24.4% with 2 CRs and 19 PRs. The CBR was 57.5% in the paclitaxel arm vs 80.2% in the combination arm. Further, the CBR in patients with endometrioid histology was 55% with paclitaxel vs 84% with the combination.

In the paclitaxel arm, 62.2% of patients went on to receive subsequent anticancer therapies, while 51.1% of patients did in the combination arm. The most frequent subsequent therapies were doxorubicin, carboplatin, paclitaxel, and gemcitabine.


The most common any-grade treatment-emergent adverse events (TEAEs) occurring in 20% or more occurring in the paclitaxel vs combination arms were nausea (33.3% vs 60.5%), anemia (36.8% vs 55.8%), diarrhea (35.6% vs 55.8%), fatigue (44.8% vs 46.5%), and alopecia (35.6% vs 31.4%).

Grade 3 or higher TEAEs were seen in 54.0% of patients in the paclitaxel arm vs 89.5% in the combination arm. The most common grade 3 or higher TEAEs were anemia (11.5% in the paclitaxel arm vs 20.9% in the combination arm), fatigue (4.6% vs 11.6%), neutropenia (3.4% vs 11.6%), hypophosphatemia (1.1% vs 11.6%), and pulmonary embolism (3.4% vs 10.5%).

While these findings may not be conclusively in support of adding sapanisertib to paclitaxel treatment, the investigation of new agents in combination with standard-of-care immunotherapy could prove to be a new path forward in treating endometrial cancer.

1. Han SN, Oza A, Colombo N, et al. A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer. Gynecol Oncol. 2023;178:110-118. doi:10.1016/j.ygyno.2023.09.013
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