Pembrolizumab Earns EU Approval in 2 New Indications for Endometrial and Cervical Cancer

The European Commission has approved pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel for the first-line treatment of adult patients with primary advanced or recurrent endometrial carcinoma who are candidates for systemic therapy; and in combination with chemoradiotherapy for the treatment of adult patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to IVA locally advanced cervical cancer who have not received prior definitive therapy.¹

The 2 new indications for pembrolizumab in endometrial carcinoma and cervical cancer were supported by data from the phase 3 KEYNOTE-868 (NCT03914612) and KEYNOTE-A18 (NCT04221945) trials, respectively.

In KEYNOTE-868, findings showed that at a median follow-up of 12 months in the mismatch repair–deficient (dMMR) cohort, patients treated with pembrolizumab plus chemotherapy (n = 112) experienced a median progression-free survival (PFS) that was not reached (NR; 95% CI, 30.6-NR) compared with 7.6 months (95% CI, 6.4-9.9) for those given placebo plus chemotherapy (n = 113; HR, 0.30; 95% CI, 0.19-0.48; P < .001).2 The estimated 12-month PFS rates were 74% and 38%, respectively.

At a median follow-up of 7.9 months for the mismatch repair–proficient (pMMR) cohort, the median PFS was 13.1 months (95% CI, 10.5-18.8) in the pembrolizumab arm (n = 290) vs 8.7 months (95% CI, 8.4-10.7) in the placebo arm (n = 292; HR, 0.54; 95% CI, 0.41-0.71; P < .001).

Data from KEYNOTE-A18 showed that at a median follow-up of 17.9 months (IQR, 11.3-22.3), the median PFS was NR in both the pembrolizumab plus chemoradiotherapy (n = 529) arm and placebo plus chemoradiotherapy arm (n = 531; HR, 0.70; 95% CI, 0.55-0.89; P = .0020).3 The 24-month PFS rates were 68% for the pembrolizumab arm vs 57% for the placebo arm.

The median overall survival (OS) was NR in both groups, and data did not cross the boundary for statistical significance at data cutoff (HR, 0.73; 95% CI, 0.49-1.07). The 24-month OS rates were 87% in the pembrolizumab group and 81% in the placebo group.

“These [pembrolizumab]-based regimens have the potential to change the treatment paradigm for people with endometrial and cervical cancer, 2 of the most commonly diagnosed cancers among women in Europe,” Gursel Aktan, MD, PhD, vice president ofglobal clinical development at Merck Research Laboratories, stated in a news release.1 “These approvals underscore the continued expansion of the use of [pembrolizumab] in diverse patient populations and treatment settings with utility of [pembrolizumab] ranging from earlier lines of therapy to treating advanced disease.”

In January 2024, the FDA approved pembrolizumab plus chemoradiation for patients with FIGO 2014 stage III to IVA cervical cancer, based on data from KEYNOTE-A18.4 In June 2024, the regulatory agency also approved pembrolizumab in combination with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma, based on data from KEYNOTE-868.⁵

KEYNOTE-868

During the double-blind, placebo-controlled, randomized KEYNOTE-868 trial, investigators enrolled patients at least 18 years of age with confirmed metastatic or recurrent endometrial cancer of any histologic subtype other than carcinosarcoma.² Patients needed to have newly diagnosed stage III or IVA endometrial cancer with measurable disease per RECIST 1.1 criteria; or recurrent or stage IVB endometrial cancer with or without measurable disease. Prior adjuvant chemotherapy was allowed if patients had a chemotherapy-free interval of at least 12 months. Known MMR status (except for patients in Japan) and an ECOG performance status of 0 to 2 were required.

Patients were randomly assigned 1:1 to receive 200 mg of pembrolizumab or placebo once every 3 weeks plus 175 mg/m2 of paclitaxel plus carboplatin at area under the curve 5 mg for up to 6 cycles. Pembrolizumab at 400 mg or placebo were then continued as monotherapy once every 6 weeks for up to 14 cycles.

Stratification factors included MMR status (dMMR vs pMMR), ECOG performance status (0 or 1 vs 2), and prior adjuvant chemotherapy (yes vs no).

Investigator-assessed PFS per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points comprised OS, safety, and quality of life.

Safety data were comparable between the pMMR and dMMR cohorts, and the safety profile of pembrolizumab plus chemotherapy was consistent with the expected adverse effects (AEs) for the agents.

KEYNOTE-A18

The randomized, double-blind, placebo-controlled study included patients at least 18 years of age with newly diagnosed, high-risk, FIGO 2014 stage IB2 to IIB with node-positive disease or stage III to IVA disease irrespective of nodal status, locally advanced, histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.³ No prior systemic therapy, immunotherapy, definitive surgery, or radiation was allowed. Other key inclusion criteria consisted of an ECOG performance status of 0 or 1, evaluable disease per RECIST 1.1 criteria, and adequate organ function.

Investigators randomly assigned patients in a 1:1 fashion to receive pembrolizumab at 200 mg or placebo once every 3 weeks in combination with cisplatin at 40 mg/m2 once per week plus external beam radiotherapy followed by brachytherapy for up to 5 cycles. A sixth cycle of chemoradiotherapy was allowed at investigator discretion. Following the completion of chemoradiotherapy, patients continued with pembrolizumab at 400 mg or placebo once every 6 weeks for up to 15 cycles.

Investigator-assessed PFS per RECIST 1.1 criteria and OS were the trial’s dual primary end points. Secondary end points included PFS per blinded independent central review; 24-month PFS rate; PFS and OS by PD-L1 status; time to subsequent disease progression, objective response rate; 12-week complete response rate; patient-reported outcomes; and safety.

Treatment-emergent AEs (TEAEs) of any grade were reported in 99% of patients in the pembrolizumab arm and 99% of patients in the control arm. The respective rates of grade 3 or higher TEAEs were 75% and 69%.

References

1. Merck’s Keytruda (pembrolizumab) receives 30th approval from European Commission with two new indications in gynecologic cancers. News release. Merck. October 24, 2024. Accessed October 24, 2024. https://www.merck.com/news/mercks-keytruda-pembrolizumab-receives-30th-approval-from-european-commission-with-two-new-indications-in-gynecologic-cancers/
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312
3. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024;403(10434):1341-1350. doi:10.1016/S0140-6736(24)00317-9
4. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed October 24, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer
5. FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma. FDA. June 17, 2024. Accessed October 24, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma