Pembrolizumab Plus Lenvatinib Improves Survival in dMMR Endometrial Cancer

Vicky Makker, MD

The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) led to a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in patients with mismatch repair deficient (dMMR) advanced endometrial cancer following platinum-based chemotherapy, according to findings from a prespecified exploratory analysis of the phase 3 KEYNOTE-775 trial (NCT03517449) that was presented during the 2021 International Gynecologic Cancer Society Annual Global Meeting.¹

In the dMMR cohort, the median OS was not reached ([NR]; 95% CI, NR-NR) in the pembrolizumab/lenvatinib arm (n = 65) vs 8.6 months (95% CI, 5.5-12.9) in the physician’s choice of treatment arm (n = 65; HR, 0.37; 95% CI, 0.22-0.62; P <.0001).

The median PFS was 10.7 months (95% CI, 5.6-NR) vs 3.7 months (95% CI, 3.1-4.4), respectively (HR, 0.36; 95% CI, 0.23-0.57; P <.0001).

“Efficacy in the dMMR population of patients with advanced endometrial cancer appeared to improve with pembrolizumab plus lenvatinib, at least consistent with that of patients in both the pMMR and all-comers populations previously reported,” lead study author Vicky Makker, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a virtual presentation of the data.

There is no standard second-line therapy for patients with advanced endometrial cancer following platinum-based chemotherapy, creating a high unmet need for effective treatments.

However, checkpoint inhibitors have shown benefit in patients with microsatellite instability–high (MSI-H) and dMMR tumors. In prior findings from the KEYNOTE-775 trial, pembrolizumab plus lenvatinib led to a statistically significant improvement in OS, PFS, and objective response rate (ORR) vs physician’s choice of treatment in mismatch repair proficient (pMMR) and all-comer populations with advanced endometrial cancer following platinum-based chemotherapy.²

On July 21, 2021, the FDA granted a full approval to pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation based on data from the KEYNOTE-775 trial.³

However, around 16% to 31% of endometrial cancers are MSI-H/dMMR. To better understand the effects of the combination in this population, investigators evaluated the outcomes of patients with MSI-H/dMMR tumors enrolled in KEYNOTE-775. 

In the trial, patients with advanced, metastatic, or recurrent endometrial cancer with measurable disease following platinum-based chemotherapy were randomized to 20 mg of oral lenvatinib once daily plus 200 mg of intravenous (IV) pembrolizumab every 3 weeks, or 60 mg/m2 of IV doxorubicin every 3 weeks or 80 mg/m2 of IV paclitaxel for 3 consecutive weeks followed by 1 week off.

The study comprised 660 patients with pMMR tumors and 120 patients with dMMR tumors.

In the present analysis, exploratory end points included PFS, OS, ORR, duration of response (DOR), and safety.

Regarding baseline characteristics in the dMMR cohort, 52.3% of patients in both arms had an ECOG performance status of 0, most patients in both arms (58.4%) were White, approximately 85% of patients in both arms had endometrioid histology, and nearly 90% of patients in both arms received 1 line of prior platinum-based chemotherapy.

A total of 41.5% of patients in the pembrolizumab/lenvatinib arm received prior neoadjuvant and or adjuvant therapy vs 49.2% of patients in the physician’s choice treatment arm.

Additional results showed that the ORR in the dMMR cohort was 40.0% (95% CI, 28.0%-52.9%) in the pembrolizumab/lenvatinib arm vs 12.3% (95% CI, 5.5%-22.8%) in the physician’s choice treatment arm.

Moreover, the complete response rate was 13.8% vs 3.1%, respectively. The partial response rate was 26.2% vs 9.2%, respectively.

Twice as many patients experienced progressive disease on treatment of physician’s choice (23.1%) vs pembrolizumab/lenvatinib (10.8%).

The median DOR was NR with pembrolizumab/lenvatinib vs 4.1 months with treatment of physician’s choice. The disease control rate was 73.8% vs 47.7%, respectively.

Regarding safety, the median duration of treatment was 335.5 days (range, 2.0-762.0) in the pembrolizumab/lenvatinib arm vs 86.0 days (range, 1.0-331.0) in the physician’s choice treatment arm.

All patients in the pembrolizumab/lenvatinib arm had a treatment-emergent adverse effect (TEAE) vs 98.4% of patients in the physician’s choice treatment arm; 95.3% vs 73.0% of these TEAEs were grade 3 or higher, respectively.

TEAEs leading to dose reductions occurred in 64.1% of patients in the pembrolizumab/lenvatinib arm vs 12.7% of patients in the physician’s choice treatment arm. Any-grade TEAEs leading to dose interruption occurred in 71.9% vs 22.2% of patients, respectively. Any-grade TEAEs leading to dose discontinuation occurred in 43.8% vs 6.3% of patients, respectively.

TEAEs that occurred in at least 25% of patients in the pembrolizumab/lenvatinib vs treatment of physician’s choice arm, respectively, included hypothyroidism (68.8% vs 0%), hypertension (56.3% vs 4.8%), diarrhea (51.6% vs 22.2%), nausea (50.0% vs 39.7%), decreased appetite (48.4% vs 23.8%), vomiting (37.5% vs 22.2%), anemia (35.9% vs 47.6%), fatigue (32.8% vs 23.8%), weight decrease (32.8% vs 6.3%), dysphonia (29.7% vs 0%), proteinuria (28.1% vs 1.6%), asthenia (26.6% vs 27.0%), arthralgia (25.0% vs 4.8%), and neutropenia (10.9% vs 31.7%).

“Pembrolizumab plus lenvatinib had a manageable safety profile in the dMMR population and was generally consistent with that observed in the all-comers population and the established safety profiles of the individual monotherapies,” concluded Makker.

References

1. Makker V, Colombo N, Casado Herraez A, et al. Randomized phase 3 study of lenvatinib plus pembrolizumab for advanced endometrial cancer: subgroup analysis of patients with DNA mismatch repair-deficient tumors. Presented at: 2021 IGCS Annual Global Meeting; August 30-September 2, 2021; virtual. Plenary 1.
2. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-26, 2021; virtual.
3. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA. July 22, 2021. Accessed September 6, 2021. https://bit.ly/3wRB9Sw