Pembrolizumab/Lenvatinib Approaches EU Approval for Select RCC and Endometrial Carcinoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion regarding approval of the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for 2 indications: select patients with renal cell carcinoma (RCC) and select patients with endometrial carcinoma, according to an announcement from Merck.¹

The first positive opinion is for use of the doublet in the frontline treatment of adult patients with advanced RCC based on data from the phase 3 CLEAR/KEYNOTE-581 trial (NCT02811861). Pembrolizumab plus lenvatinib was found to result in a 34% reduction in the risk of death compared with sunitinib (Sutent) in this population (HR, 0.66; 95% CI, 0.49-0.88; P = .0049).

The doublet also improved median progression-free survival over sunitinib, at 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0), respectively (HR, 0.39; 95% CI, 0.32-0.49; P < .0001). The confirmed objective response rate (ORR) also proved to be higher with the combination vs the monotherapy, at 71% (95% CI, 66%-76%) and 36% (95% CI, 31%-41%), respectively.

The second opinion is supporting the use of pembrolizumab plus lenvatinib in the treatment of adult patients with advanced or recurrent endometrial carcinoma who experienced disease progression on, or following, previous treatment with a platinum-containing therapy in any setting and who are not eligible for curative surgery or radiation. The opinion is based on findings from the phase 3 KEYNOTE-775 trial (NCT03517449) in this population.

Specifically, the doublet resulted in a 38% reduction in the risk of death vs investigator’s choice of chemotherapy, which was either doxorubicin or paclitaxel. The median OS in the investigative arm was 18.3 months vs 11.4 months in the control arm (HR, 0.62; 95% CI, 0.51-0.75; P < .0001). Pembrolizumab plus lenvatinib also reduced the risk of disease progression or death by 44% compared with chemotherapy. The median PFS in the investigative and control arms was 7.2 months vs 3.8 months, respectively (HR, 0.56; 95% CI, 0.47-0.66; P < .0001).

“[Pembrolizumab] plus [lenvatinib] demonstrated a survival benefit for advanced RCC in the first-line setting and represents an important potential new treatment option for these patients. Additionally, [pembrolizumab] plus [lenvatinib] is the first anti–PD-1 and TKI combination to demonstrate a survival benefit in [patients with] advanced endometrial carcinoma, and the benefit was shown regardless of mismatch repair status,” Gregory Lubiniecki, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “We are pleased that the CHMP has recognized the important role of the combination therapy in these difficult-to-treat cancers.”

The multicenter, open-label, phase 3 CLEAR trial enrolled 1069 patients with advanced RCC. Patients were able to enroll regardless of PD-L1 tumor expression status. However, those with autoimmune disease or a condition that required immunosuppression were excluded.²

Stratification factors included geographic region (North American and Western Europe vs rest of the world) and Memorial Sloan Kettering Cancer Center prognostic risk groups (favorable vs intermediate vs poor risk).

Study participants were randomized 1:1:1 to oral lenvatinib at a daily dose of 20 mg plus intravenous (IV) pembrolizumab at 200 mg given every 3 weeks for up to 24 months; lenvatinib at a daily dose of 18 mg plus oral everolimus (Afinitor) at a daily dose of 5 mg, or oral sunitinib at a daily dose of 50 mg for 4 weeks on treatment followed by 2 weeks off treatment.

Treatment was administered until unacceptable toxicity or disease progression. The immunotherapy was given for a maximum of 24 months and patients had the option to continue lenvatinib beyond that time point.

Major efficacy measures were PFS per independent review committee (IRC) and RECIST v1.1 criteria, and OS. Investigators also evaluated IRC-assessed ORR.

KEYNOTE-775 enrolled patients with advanced, metastatic, or recurrent endometrial cancer with measurable disease after platinum-based chemotherapy.³ Participants were randomized to receive oral lenvatinib at a daily dose of 20 mg plus IV pembrolizumab at 200 mg given every 3 weeks, or 60 mg/m² of IV doxorubicin given every 3 weeks or 80 mg/m² of IV paclitaxel for 3 consecutive weeks followed by 1 week off.

A total of 660 patients with mismatch repair proficient tumors and 120 patients with mismatch repair deficient tumors (dMMR) were enrolled to the trial. Exploratory end points for the trial included PFS, OS, ORR, duration of response (DOR), and safety.

Data presented during the 2021 International Gynecologic Cancer Society Annual Global Meeting showed that the median OS was not reached (NR) with the doublet (n = 65) in the dMMR cohort vs 8.6 months (95% CI, 5.5-12.9) with chemotherapy (n = 65; HR, 0.37; 95% CI, 0.22-0.62; P < .0001). The median PFS in the investigative and control arms 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).

The ORR in the dMMR cohort was 40.0% (95% CI, 28.0%-52.9%) with pembrolizumab plus lenvatinib vs 12.3% (95% CI, 5.5%-22.8%) with chemotherapy; the complete response rates were 13.8% and 3.1%, respectively, and the partial response rates were 26.2% and 9.2%, respectively. The median DOR was NR vs 4.1 months, respectively. The disease control rates in the investigative and control arms were 73.8% and 47.7%, respectively.

The safety of pembrolizumab plus axitinib (Inlyta) or lenvatinib in patients with advanced RCC, or in combination with lenvatinib in endometrial carcinoma, was examined in 1456 patients. In these populations the most common toxicities reported included diarrhea (58%), hypertension (54%), hypothyroidism (46%), fatigue (41%), decreased appetite (40%), nausea (40%), arthralgia (30%), vomiting (28%), weight decreased (28%), dysphonia (28%), and abdominal pain (28%).

Other adverse effects included proteinuria (27%), palmar plantar erythrodysesthesia syndrome (26%), rash (26%), stomatitis (25%), constipation (25%), musculoskeletal pain (23%), headache (23%), and cough (21%).

References

1. Merck and Eisai receive positive EU CHMP opinions for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) in two different types of cancer. News release. Merck. October 15, 2021. Accessed October 15, 2021. https://bit.ly/3FJR5Ma
2. FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). News release. Merck. August 11, 2021. Accessed October 15, 2021. https://bwnews.pr/3fXk8Rj
3. 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.