Endometrial Cancer Enters Immunotherapy Age

Martee L. Hensley, MD

The tumor-site agnostic FDA approval of the PD-1 inhibitor pembrolizumab (Keytruda) for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors has helped propel endometrial cancer into the immunotherapy age, according to Martee L. Hensley, MD.

Research into mismatch repair deficiency across tumor types has shown that, “About 17% to 18% of [patients with] endometrial cancer may be good candidates for immunotherapy when they have advanced disease, and other treatments are no longer working,” Hensley, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a discussion at the 35th annual CFS^®.

The pembrolizumab approval, which is specifically for patients who have progressed after prior treatment and have no satisfactory alternative treatment options, was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. The study included 14 patients with endometrial cancer, which was the largest representation among tumor types other than colorectal cancer.

The overall objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses and 48 (32.2%) partial responses. The median duration of response (DOR) was not yet reached (range, 1.6+ months to 22.7+ months). In the patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.

Among the 14 patients with endometrial cancer, there were 5 responses, for an ORR of 36% (95% CI, 13%-65%). The DOR ranged from 4.2+ to 17.3+ months.

Data from the KEYNOTE-028 multicohort, open-label, phase Ib basket trial published in the Journal of Clinical Oncology (Ott PA, et al. doi: 10.1200/JCO.2017.72.5952) also demonstrated the efficacy of pembrolizumab in endometrial cancer. Among 24 women with advanced PD-L1—positive endometrial cancer, the ORR was 13% (95% CI, 2.8-33.6). The 3 responses were all partial responses in patients with endometrioid adenocarcinoma. The median DOR was 6 months and the 6-month progression-free survival rate was 40.4%.

Twenty-two patients had received prior treatment for recurrent or metastatic disease. The remaining 2 patients had undergone prior adjuvant radiotherapy. Median age was 67 years (range, 34-87) and 17 patients (70.8%) had endometrioid adenocarcinoma. Other histologies included other adenocarcinomas (12.5%), high-grade serous carcinoma (8.3%), and carcinosarcoma (4.2%).

In addition to the 3 partial responses, 3 patients (13%) had stable disease. Median time to response was 8.1 weeks (range, 7.6-8.1). Thirteen patients (56.5%) had experienced progressive disease, and 3 patients (13.0%) had no assessment conducted at the time of the February 2016 data cutoff.

Tumors in 5 of 20 evaluable patients showed decrease from baseline in target lesion, and researchers said this decrease was durable in the patients exhibiting partial response. The response was ongoing in 2 of these patients; 1 had a DOR of 63.7+ weeks and the other had a DOR of 64.7+ weeks. DOR for the third patient who had partial response was 64.3 weeks. Median duration of stable disease was 24.6 weeks (range, 13.1-24.6).

Given this potential to use immunotherapy in the management of endometrial cancer, Hensley reviewed available diagnostic tools and opportunities for the application of microsatellite testing.

She said that histopathology should be used in all patients for diagnosis and prognosis and immunohistochemistry (IHC) is useful for all patients in terms of identifying Lynch Syndrome. IHC can also be used in tandem with MSI to identify patients with recurrent or advanced disease who are candidates for anti—PD-1 therapy.

Hensley also noted that somatic genomic profiling “has really turned from interesting for endometrial cancer to potentially having therapeutic utility. One of the reasons you might do it is to look for a somatic mutation of Lynch-like tumors—they have loss of MMR, but no germline mutation. So, your somatic testing may help elucidate why that’s happening.”

Somatic testing could also be used for TCGA-like classification for prognostic reasons and for mutational analyses to generate an MSI score, said Hensley. The MSI score could then be used to make a decision about immunotherapy in advanced disease, with some of the MSI-high tumors being appropriate for anti—PD-1 therapy.

The next step with immunotherapy in endometrial cancer, said Hensley, is a phase III trial being launched by the Gynecologic Oncology Group examining whether the addition of pembrolizumab to frontline paclitaxel/carboplatin can improve survival in patients with advanced disease. All patients’ MSI status will be determined and used as a stratification factor at the time of randomization.