Pembrolizumab-Based Regimens Earn Positive CHMP Opinion in Endometrial and Cervical Cancers

Gursel Aktan, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued positive opinions recommending the approval of pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel, followed by pembrolizumab monotherapy, for the first-line treatment of adult patients with primary advanced or recurrent endometrial carcinoma who are candidates for systemic therapy, and pembrolizumab in combination with chemoradiotherapy for the treatment of adult patients with International Federation of Gynecology and Obstetrics (FIGO) stage III to IVA locally advanced cervical cancer who have not received prior definitive therapy.¹

The recommendation for pembrolizumab plus chemotherapy for patients with primary advanced or recurrent endometrial carcinoma is based on data from the phase 3 NRG GY018/KEYNOTE-868 trial (NCT03914612). The recommendation for pembrolizumab plus chemoradiotherapy for patients with locally advanced cervical cancer stems from findings from the phase 3 KEYNOTE-A18 trial (NCT04221945).

The European Commission (EC) will review both recommendations from the CHMP, and final decisions regarding approvals are anticipated in the fourth quarter of 2024.

“At Merck, we are deeply committed to expanding the role of [pembrolizumab] to improve outcomes for more patients facing difficult-to-treat gynecologic cancers as we work to address the impact of women’s cancers around the world,” Gursel Aktan, MD, PhD, vice president of global clinical development at Merck Research Laboratories, stated in a news release. “These positive CHMP opinions bring us one step closer to providing new immunotherapy-based regimens to more patients with endometrial and cervical cancer in the European Union who may benefit. We look forward to the EC’s decisions.”

KEYNOTE-868

Findings from the randomized, blinded, placebo-controlled KEYNOTE-868 trial were presented at the 2023 SGO Annual Meeting and published in the New England Journal of Medicine. Data showed that at a median follow-up of 7.9 months, patients with mismatch repair–proficient (pMMR) endometrial carcinoma treated with pembrolizumab plus carboplatin and paclitaxel (n = 290) experienced a median progression-free survival (PFS) of 13.1 months (95% CI, 10.5-18.8) compared with 8.7 months (95% CI, 8.4-10.7) for those given placebo plus carboplatin and paclitaxel (n = 292; HR, 0.54; 95% CI, 0.41-0.71; P < .001).²

At a median follow-up of 12 months for patients with MMR-deficient (dMMR) endometrial carcinoma, pembrolizumab plus chemotherapy (n = 112) elicited a median PFS that was not reached (NR; 95% CI, 30.6 months-NR) compared with 7.6 months (95% CI, 6.4-9.9) for placebo plus chemotherapy (n = 113; HR, 0.30; 95% CI, 0.19-0.48; P < .001).

Investigators enrolled patients at least 18 years of age with confirmed stage III to IVB, metastatic or recurrent endometrial cancer of any histologic subtype, other than carcinosarcoma. Patients had either newly diagnosed stage III or IVA endometrial cancer with measurable disease per RECIST 1.1 criteria or stage IVB or recurrent endometrial cancer with or without measurable disease. Prior adjuvant chemotherapy was allowed if patients had a chemotherapy-free interval of at least 12 months.

Patients were randomly assigned 1:1 to receive 200 mg of pembrolizumab or placebo once every 3 weeks plus carboplatin and paclitaxel for up to 6 cycles, followed by 400 mg of pembrolizumab or placebo alone as maintenance once every 6 weeks for up to 14 cycles. Patients who had measurable disease and had stable disease or a partial response per RECIST 1.1 criteria following 6 cycles of chemotherapy were allowed to receive paclitaxel plus carboplatin in combination with pembrolizumab or placebo for up to 10 cycles, per investigator discretion.

PFS per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included safety, overall survival (OS), and health-related quality of life.

Additional data presented at the 2024 SGO Annual Meeting showed that the median OS was 27.96 months (95% CI, 21.42-NR) in the pembrolizumab arm vs 27.37 months (95% CI, 19.52-NR) in the placebo arm for the pMMR population (HR, 0.79; 95% CI, 0.53-1.17; P = .1157). In the dMMR population, the median OS was NR in both arms (HR, 0.55; 95% CI, 0.25-1.19; P = .0617).³

Regarding safety, the adverse effects (AEs) reported in the experimental arm were consistent with the expected toxicities for pembrolizumab in combination with chemotherapy.²

KEYNOTE-A18

Data from the randomized, double-blind, placebo-controlled trial presented at the 2024 ESMO Congress and published in The Lancet showed that at a median follow-up of 17.9 months (interquartile range, 11.3-22.3), the median PFS was NR in both the pembrolizumab plus chemoradiotherapy arm (n = 529) and the placebo plus chemoradiotherapy arm (n = 531; HR, 0.70; 95% CI, 0.55-0.89; P = .0020).⁴ The estimated 24-month PFS rates were 68% (95% CI, 62%-73%) in the experimental arm and 57% (95% CI, 51%-63%) in the placebo arm.

The median OS was NR in both arms (HR, 0.73; 95% CI, 0.49-1.07). The estimated 24-month OS rates were 87% (95% CI, 82%-91%) for the pembrolizumab arm and 81% (95% CI, 75%-86%) for the placebo arm.

The study included patients at least 18 years of age with newly diagnosed, high-risk, locally advanced, histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients needed to have FIGO 2014 stage IB2 to IIB, node-positive disease or stage III to IVA, node-positive or -negative disease. No prior systemic therapy, immunotherapy, definitive surgery, or radiation was permitted. 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.

Patients were randomly assigned 1:1 to receive 5 cycles of pembrolizumab at 200 mg or placebo once every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab at 400 mg or placebo once every 6 weeks. Chemoradiotherapy, which was allowed to be given as a sixth cycle at investigator discretion, consisted of cisplatin at 40 mg/m² once per week plus external beam radiotherapy followed by brachytherapy.

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 assessment; 24-month PFS and OS; PFS and OS by PD-L1 status; time to second progression; objective response rate; 12-week complete response rate; patient-reported outcomes; and safety.

Regarding safety, grade 3 or higher AEs occurred in 75% of patients treated in the pembrolizumab arm vs 69% of patients in the placebo arm.

References

1. Merck receives positive EU CHMP opinions for Keytruda (pembrolizumab) regimens as treatment for patients with two types of gynecologic cancers. News release. September 20, 2024. Accessed September 20, 2024. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinions-for-keytruda-pembrolizumab-regimens-as-treatment-for-patients-with-two-types-of-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. Eskander RN, Sill M, Miller A, et al. Overall survival, progression-free survival by PD-L1 status, and blinded independent central review results with pembrolizumab plus carboplatin/paclitaxel (CP) versus placebo plus CP in patients with endometrial cancer: results from the NRG GY018 trial. Presented at: 2024 SGO Annual Meeting for Women's Cancer; March 15-18, 2024; San Diego, CA.
4. 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