Pembrolizumab/Lenvatinib Approved in Japan for Endometrial Cancer Following Progression on Chemo

The Japanese Ministry of Health, Labour, and Welfare has approved the combination of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for use in patients with unresectable, advanced, or recurrent endometrial carcinoma that has progressed on chemotherapy.¹

The regulatory decision is supported by findings from the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449), in which treatment with the doublet resulted in a significant 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.51-0.75; P < .0001) compared with investigator’s choice of doxorubicin or paclitaxel.^2,3 The median overall survival (OS) was 18.3 months (95% CI, 15.2-20.5) with pembrolizumab plus lenvatinib vs 11.4 months (95% CI, 10.5-12.9) with chemotherapy.

The doublet also resulted in a statistically significant improvement in progression-free survival (PFS) over chemotherapy, at 7.2 months (95% CI, 5.7-7.6) vs 3.8 months (95% CI, 3.6-4.2), respectively (HR, 0.56; 95% CI, 0.47-0.66; P < .0001), translating to a 44% reduction.

“This is the first approval of the [pembrolizumab] plus [lenvatinib] combination in Japan,” Terushige Iike, president of Eisai Japan at Eisai, stated in a press release. “We thank the patients, families, and healthcare providers who made this approval possible. By delivering this combination therapy, we are proud to provide patients with advanced or recurrent endometrial cancer an additional treatment option.”

The multicenter, open-label, randomized, active-controlled, phase 3 KEYNOTE-775 trial enrolled a total of 827 patients with advanced endometrial carcinoma who had received prior treatment with at least 1 platinum-based chemotherapy regimen in any setting; this included 104 Japanese patients.

Patients were able to have received up to 2 platinum-containing therapies, if 1 was given in the neoadjuvant or adjuvant setting. Patients could not have endometrial sarcoma, carcinosarcoma, pre-existing grade 3 or higher fistula, uncontrolled blood pressure (>150/90 mmHg), or significant cardiovascular impairment or event within the past year. Patients also could not have active autoimmune disease or a medical condition that required immunosuppression.

Study participants were randomized 1:1 to receive intravenous pembrolizumab at a dose of 200 mg every 3 weeks in combination with oral lenvatinib at a dose of 20 mg, or investigator’s choice of chemotherapy, which could be doxorubicin at 60 mg/m² every 3 weeks or paclitaxel at a weekly dose of 80 mg/m² on a 3-weeks-on/1-week-off schedule.

Treatment was administered until progressive disease per RECIST v1.1 criteria, which was verified by blinded independent central review (BICR) or intolerable toxicity. The immunotherapy agent was given for a maximum of 2 years.

Notably, if the treating investigator found that the patient was deriving clinical benefit from the combination with acceptable tolerability, the regimen could be administered beyond disease progression. Of the 411 patients who received the doublet, 29% (n = 121) continued the study therapy beyond RECIST-defined disease progression. The median duration of post-progression therapy was 2.8 months. Investigators performed tumor assessments every 8 weeks.

The primary end points of the trial were OS and PFS per BICR. A key secondary end point was BICR-assessed objective response rate (ORR).

Additional data from the trial showed that pembrolizumab plus lenvatinib elicited an ORR of 32% (95% CI, 27%-37%) vs 15% (95% CI, 11%-18%) with chemotherapy (P < .0001). In the investigative arm, the complete response (CR) rate was 7% and the partial response (PR) rate was 25%; these rates were 3% and 12%, respectively, in the control arm.

Regarding safety, the Japanese package inserts for pembrolizumab and lenvatinib note that in the trial, 97.3% of patients (n = 395/406) experienced adverse reactions with the doublet; this included 51 of 52 Japanese patients.

The most frequently reported toxicities included hypertension (61.3%), hypothyroidism (54.7%), diarrhea (42.1%), nausea (38.9%), decreased appetite (37.2%), fatigue (27.8%), proteinuria (25.9%), vomiting (24.1%), weight decrease (22.4%), arthralgia (21.4%), and palmar-plantar erythrodysesthesia (20.7%).

“Rates of endometrial carcinoma have been steadily increasing in Japan each year, and there are limited options for patients who are diagnosed at an advanced stage or find their disease has returned,” Gregory Lubiniecki, MD, vice president of clinical research at Merck Research Laboratories, added in the press release. “With [this] approval, patients in Japan with unresectable, advanced, or recurrent endometrial carcinoma now have the option of the first immunotherapy and TKI combination that has significantly improved OS and PFS compared with chemotherapy.”

In November 2021, the European Commission granted an approval to pembrolizumab/lenvatinib for use in patients with advanced or recurrent endometrial carcinoma who have progressive disease on, or following, prior platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation.⁴ The decision was based on data from KEYNOTE-775.

Prior to that, in July 2021, the FDA granted a regular approval to pembrolizumab and lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression after prior systemic therapy in any setting, and who are not eligible for curative surgery or radiation.²

In September 2019, the combination was granted an accelerated approval in for use in patients with advanced endometrial carcinoma.5 At the time, the decision was based on data from 94 patients with endometrial carcinoma who were not MSI-H or dMMR. In these patients, the combination elicited an ORR of 38.3%; this included a CR rate of 10.6% (n = 10) and a PR rate of 27.7% (n = 26). Moreover, a duration of response of 6 months or longer was reported in 69% (n = 25) of patients.

References

1. KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) approved in Japan for patients with unresectable, advanced or recurrent endometrial carcinoma that progressed after cancer chemotherapy. News release. Merck; December 27, 2021. Accessed January 3, 2022. https://bit.ly/3zk9I6L
2. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. News release. FDA; July 22, 2021. Accessed January 3, 2022. https://bit.ly/3wRB9Sw
3. FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for patients with certain types of advanced endometrial carcinoma. News release. Merck; July 22, 2021. Accessed January 3, 2022. https://bwnews.pr/3y0k5ee
4. European Commission approves Keytruda (pembrolizumab) Plus Lenvima (lenvatinib) for patients with certain types of endometrial carcinoma. News release. Merck; November 29, 2021. Accessed January 3, 2022. https://bit.ly/31aqcBG
5. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. News release. FDA; September 17, 2019. Accessed January 3, 2022. https://bit.ly/3izkxcZ