Pembrolizumab Continues to Show Robust Antitumor Activity in MSI-H/dMMR Endometrial Cancer

Updated results of the phase 2 KEYNOTE-158 study (NCT02628067) reconfirm the robust and durable antitumor activity of pembrolizumab (Keytruda) in patients with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) advanced endometrial cancer.¹

Encouraging survival outcomes were also seen with an objective response rate (ORR) of 50% (95% CI, 39.5-60.5), and a median progression-free survival (PFS) of 13.1 months (95% CI, 4.3-25.7). Responses were seen across all prior treatment lines.

Findings were reported in a poster session at the 2022 European Society of Oncology (ESMO) Annual Congress by David O'Malley, MD, focusing on cohorts D and K, which enrolled patients with MSI-H/dMMR advanced endometrial cancer.

“We published the results in Journal of Clinical Oncology which showed approximately 50% overall response rates with patients doing very well long-term and continuing the duration of response. That trial contributed to extending the approval of pembrolizumab, specifically to endometrial cancer for pembrolizumab in patients with MSI-H/dMMR endometrial cancer,” said O’Malley, a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and the director of the Division of Gynecologic Oncology at the OSUCCC–James, in an interview with Targeted Oncology^TM.

In the phase 2 KEYNOTE-158 study, 94 patients aged 18 years and older with histologically or cytologically-documented, advanced solid tumors were enrolled in order to evaluate pembrolizumab in this patient population.²

Patients enrolled were administered pembrolizumab at 200 mg intravenously (IV) on day 1 of each 3-week cycle for up to 35 administrations. Patients with any advanced solid tumor that had failed at least 1 line of therapy and was tumor-mutational burden-high (TMB-H), excluding those with dMMR/MSI-H tumors were administered 400 mg every 6 weeks for up to 18 times.

Enrollment in the trial was open to patients with progression of tumor or intolerance to therapies known to provide clinical benefit, radiologically-measurable disease, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and adequate organ function.

The primary end point of the trial was ORR with secondary end points including duration of response, PFS, overall survival (OS), and safety.

The analysis presented at ESMO examined the enrolled patients who had a substantially longer follow-up. This included cohorts D and K of KEYNOTE-158 of previously treated patients with MSI-H/dMMR advanced endometrial cancer.

MSI-H/dMMR status was determined retrospectively by PCR at a central lab in cohort D and prospectively by PCR and/or IHC at a local lab in cohort K. In both cohorts, patients received pembrolizumab at 200 mg once every 3 weeks for up to 35 cycles until disease progression, unacceptable toxicity, or for up to 24 months.

Updated efficacy and safety outcomes of these cohorts showed that the objective response rate was 50% (95% CI, 39.5-60.5) with responses seen across all prior treatment lines. Median progression-free survival (PFS) was 13.1 months (95% CI, 4.3-25.7) and the median OS was 65.4 months (29.5-not reached). Then, 4-year PFS and OS rates were 37% and 59%, respectively

Sixteen patients (15%) had a complete response, 34 (32%) had a partial response, and 18 (17%) had stable disease. Additionally, the median duration of response was 63.2 months (range, 2.9-63.2). The duration of response beyond 1 year was 87%, beyond 2 years was 71%, and beyond 3 or 4 years was 66%, respectively.

Regarding safety, 71 patients (76%) had 1 or more treatment-related adverse event (TEAE) of which 13 patients (14%) had grades 3 or 4 TEAEs. There were no fatal or grade 5 TEAEs reported in the trial.

Overall, pembrolizumab elicited robust and durable antitumor activity in patients with previously treated, advanced MSI-H/dMMR tumors.

“If patients responded, the chance that they extended beyond 4 years or more was 66%. We are talking about potentially curing women with recurrent ovarian cancer who are MMR deficient or MSI-high,” added O’Malley.

References:

1. O'Malley D, Bariani G.M., Cassier P.A., et al. Pembrolizumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced endometrial cancer: Long-term follow-up results from KEYNOTE-158. Annals of Oncology 2022;33(suppl7:546P. doi:10.1016/annonc/annonc1054

2. Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-158/KEYNOTE-158). ClinicalTrials.gov. Updated July 14, 2022. Accessed September 14, 2022. https://www.clinicaltrials.gov/ct2/show/NCT02628067