Combined use of pembrolizumab and lenvatinib: A review

Abstract

Objective

The purpose of this article is to review the pharmacology, safety, evidence for current use, and potential futures uses for combination therapy with pembrolizumab and lenvatinib.

Data Sources

A literature review was carried out through PubMed to identify ongoing trials evaluating use, efficacy, and safety of combination pembrolizumab and lenvatinib. NCCN guidelines were utilized to identify current approved uses in therapy and medication package inserts were used to identify pharmacology and preparation requirements.

Data Summary

A total of five completed clinical trials and two ongoing trials were evaluated for use and safety of pembrolizumab with lenvatinib. Data suggests that combination therapy with pembrolizumab and lenvatinib can be used first line for clear cell renal carcinoma in patients with favorable risk or intermediate/poor risk and in endometrial carcinoma as a preferred second-line regimen for recurrent or metastatic disease for biomarker-directed systemic therapy in non-MSI-H/non-dMMR tumors. This combination may have potential for use in unresectable hepatocellular carcinoma and gastric cancer.

Conclusions

Use of non-chemotherapy containing regimens spare patients from extended durations of myelosuppression and reduce the risk of infection. Additionally, pembrolizumab with lenvatinib demonstrates efficacy as first line treatment in clear cell renal carcinoma, second line in endometrial carcinoma, and several potential uses on the horizon.

Introduction

Traditionally, pembrolizumab and lenvatinib have been used individually or with chemotherapy to treat multiple malignancies.^1,2 Pembrolizumab has been used to treat melanoma and lymphoma or in combination with traditional chemotherapy to treat non-small cell lung cancer. ¹ Lenvatinib has been used to treat thyroid and hepatocellular carcinoma. ² However, treatment with single agents often lead to short-lived responses and relapse; demonstrating a need for continued innovation and new treatments. Combination chemotherapy regimens containing cytotoxic agents are limited by their significant adverse event profiles. Combination therapy utilizing two novel mechanisms, such as tyrosine kinase inhibitors (TKIs) and immunotherapy, introduces a paradigm shift in the approach to cancer treatment. Pembrolizumab/lenvatinib is one of the first chemotherapy free combinations approved to provide effective treatment with two Food and Drug Administration (FDA) approved uses and numerous studies ongoing.

Pembrolizumab/lenvatinib was granted a Breakthrough Designation by the FDA based on the absence of a clearly recommended second-line option for endometrial carcinoma. ³ This is the first treatment approved for use in endometrial carcinoma patients who progress after systemic therapy and do not have MSI-H/dMMR tumors.^3,4 Additionally, this combination has received approval for use as first-line therapy in clear cell renal cell carcinoma (ccRCC) due to dramatic improvement in patient outcomes. This review covers pharmacology, evidence for current use, and potential futures uses for this combination.

Pharmacology

Pembrolizumab

Pembrolizumab is an immune checkpoint inhibitor acting against PD-L1. T-cells act against tumor cells through proliferation and release of cytokines to decrease and prevent tumor growth. T-cells use a receptor, PD-1, to detect cancer cells. Cancer cells are capable of developing PD-L1 on their surfaces, this interacts with PD-1 to downregulate both T-cell activity and tumor surveillance. This allows for uninhibited tumor growth. Pembrolizumab is a monoclonal antibody that binds to PD-1 to prevent T-cell inactivation by PD-L1 on the tumor cells.

When pembrolizumab is administered every 3 weeks at a dose of 200 mg the steady state concentrations were reached at week 16. ¹ Distribution at steady state was found to be 6.0 L; the half-life was 22 d; clearance was found to be lower at steady state than after the initial first dose was given. ¹ However, this decrease of clearance (23%) is considered clinically insignificant. ¹ Elimination was not impacted by renal impairment or mild hepatic impairment. Effects of moderate/severe hepatic impairment on pembrolizumab are unknown.

Lenvatinib

Lenvatinib is a tyrosine kinase inhibitor affecting multiple receptors. Inhibited receptors include: vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4); fibroblast growth factor (FGF) receptors FGRF 1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. ² Inhibition of all these pathways decrease angiogenesis and growth of tumors. When combined with anti-PD-1 monoclonal antibodies, an increase of cytotoxic T cells and decrease in tumor-associated macrophages were observed compared to when either agent was used alone.

Lenvatinib is taken orally and has a Tmax of between 1 and 4 h with an average concentration max at 2 h. ² Absorption is unaffected by coadministration with food; however, the average Tmax was delayed to 4 h. ² Distribution is independent of concentration and not impacted by renal or hepatic function. ² This drug is heavily protein bound, 97%–99%; the half-life is approximately 28 h and is mainly metabolized by CYP3A and aldehyde oxidase and other non-enzymatic processes. ² CYP3A and P-gp inhibitors increase drug concentrations and CYP3A and P-gp inducers decrease the AUC of lenvatinib but have no effect on Cmax. ²

Administration

Pembrolizumab

Before administration, pembrolizumab is diluted in NS or D5 W to a final concentration of 1–10 mg/mL. When mixing, the solution should not be shaken and requires a 0.2–5 micron add-on/in-line filter for administration. This preparation can be stored for up to 6H at room temperature once pembrolizumab is mixed into the diluent, this includes the infusion time of 30 minutes for administration. Doses studied include 200 mg every 3 weeks and 400 mg every 6 weeks for treatment of ccRCC and endometrial carcinoma. However, weight-based dosing, 1–2 mg/kg may also be used.

Lenvatinib

Lenvatinib is available in a range of strengths ranging from 4 to 24 mg capsules. These must be stored at room temperature. The treatment dose for ccRCC and endometrial carcinoma is 20 mg by mouth daily; however, this dose may be decreased depending on side effects or renal insufficiency. These capsules may be taken without regard to food or dissolved in water for administration. Adherence to oral chemotherapy regimens is extremely important for optimal patient outcomes.

Therapeutic use

Pembrolizumab/lenvatinib is the first approved treatment for use in endometrial carcinoma in women with recurrent or metastatic disease who have previously undergone treatment with carboplatin/paclitaxel. ³ There are no compelling second-line options due to limited data and trials. Pembrolizumab/lenvatinib use in women with non-MSHI-H/dMMR tumors have numerous studies showing efficacy and improvement. ⁴ Worldwide, uterine corpus cancer was the sixth most diagnosed cancer in women in 2020, with 417,000 new cases and 97,000 deaths. ⁵ The highest incidence being observed in North America, Europe, Micronesia/Polynesia, and Oceana. ⁵

Regarding ccRCC, there were 431,288 new cases in 2020 and 179,368 deaths. ⁵ Around 70% of kidney cancer are RCC; additionally, RCC makes of 4.1% of all newly diagnosed cancer. ⁶ Pembrolizumab/lenvatinib is approved for use in ccRCC and is a preferred, first-line treatment regimen for favorable and poor/intermediate risk patients. This combination may also be used in subsequent lines of therapy. ⁶

ccRCC treatment

CLEAR trial ⁷

Pembrolizumab/lenvatinib was studied as a first line treatment in the CLEAR trial. This was a multicenter, open-label, randomized, phase 3 trial comparing lenvatinib/pembrolizumab, or lenvatinib/everolimus with sunitinib alone in previously untreated patients with advanced renal cell carcinoma (RCC). Patients were randomized 1:1:1 to each arm of the study. Arm A consisted of patients on lenvatinib 18 mg daily plus everolimus 5 mg daily (n  =  357); Arm B consisted of lenvatinib 20 mg daily plus pembrolizumab 200 mg IV every 3 weeks (n  =  355); Arm C consisted of patients taking sunitinib 50 mg daily for 4 weeks followed by 2 weeks off (n  =  357). All patients needed to have at least one measurable lesion according to RECIST 1.1 criteria, Karnofsky performance-status of 70, and controlled blood pressure. Key exclusion criteria include previous systemic anticancer therapy for RCC, any CNS metastases, and active malignancy besides RCC. Progression free survival (PFS) for the lenvatinib/pembrolizumab group was 23.9 months compared to sunitinib which had a PFS of 9.2 months with a hazard ratio (HR) for disease progression or death of 0.39. Overall survival (OS) was 79.2% for combination therapy and 70.4% for the sunitinib group. Lenvatinib/pembrolizumab showed significantly longer survival compared to sunitinib (p  =  0.005) and all subgroups demonstrated improvement in the combination therapy group vs sunitinib. Duration of response (DOR) to treatment was 25.8 months when using combination therapy compared to sunitinib which had a duration of 14.6 months. When considering safety of this combination, higher incidence of serious side effects was seen in the intervention group compared to sunitinib. The relative risk (RR) was 1.97 and adverse events grade 3 or higher occurred in 82.4% of patients taking combination therapy compared to 71.8% of patients taking sunitinib alone. Commonly observed adverse events include diarrhea, hypertension and hypothyroidism.

CLEAR
	Lenvatinib/Pembro	Sunitinib	HR
PFS	23.9 mos	9.2 mos	0.39
OS	79.2%	70.4%
Grade > 3	82.4%	71.8%
RR	1.97
Inclusion	At least one measurable lesion according to RECIST 1.1 criteria, Karnofsky performance-status of 70, and controlled blood pressure
Exclusion	Previous Systemic Anticancer Therapy For RCC, Any CNS Metastases, And Active Malignancy Besides RCC

Endometrial carcinoma

Pembrolizumab/lenvatinib is also FDA-approved for advanced endometrial cancer. There have been two clinical trials to determine efficacy of pembrolizumab/lenvatinib in this population, 309-KEYNOTE-775 and 111-KEYNOTE-146. Currently there is a third onging trial, ENGOT-en9/LEAP-001, which is set to end in April 2023.

111-KEYNOTE-146 ⁸

Efficacy of pembrolizumab/lenvatinib in endometrial carcinoma was first studied in a phase 1b/2 multinational, open-label, single-arm study. Patients must have had at least one trial of platinum-based therapy to be eligible for this study; additional inclusion criteria include: no history of exposure to VEGF or PD-1 targeting regimens, at least one measurable lesion based on RECIST 1.1, and an ECOG score of 1 or 0. Key exclusion criteria include any CNS metastases, active autoimmune disease, and females pregnant or breastfeeding. Participants were given lenvatinib 20 mg PO daily and pembrolizumab 200 mg IV every 3 weeks. Results of this trial led to development of an ongoing study, ENGOT-en9/LEAp-001, which is comparing efficacy and safety of first-line pembrolizumab/lenvatinib therapy to paclitaxel plus carboplatin in newly diagnosed stage III/IV or recurrent endometrial cancer. In this study the most benefit was seen in patients with MSI-H/dMMR tumors. Median PFS for all participants, MSS/pMMR, and MSI-H/dMMR were 7.4, 7.4, and 18.9 months, respectively. Overall response rate (ORR) for each group was 38.0% for all participants, 36.2% in MSS/pMMR patients, and 63.6% for MSI-H/dMMR tumors and DOR was 16.7 months, 16.4 months, and not estimable for each group. When considering ADEs, 88% of patients had a Grade 3 or 4 reaction; the most common were hypertension (31.5%), fatigue (7.3%), and diarrhea (6.5%).

111-KEYNOTE-146
	All Participants	MSS/pMMR	MSI-H/dMMR
Median PFS	7.4 mos	7.4 mos	18.9 mos
ORR at 24 wks	38.0%	36.2%	63.6%
DOR	21.2 mos	NE	21.2 mos
OS	16.7 mos	16.4 mos	NE (not estimable)
Grade ≥ 3	66.9%
Inclusion	At least one trial of platinum-based therapy to be eligible for this study; additional inclusion criteria include: no history of exposure to vascular endothelial growth factor or PD-1 targeting regimens, at least one measurable lesion based on RECIST 1.1, and an ECOG score of 1 or 0
Exclusion	CNS metastases, active autoimmune disease, and females pregnant or breastfeeding

309-KEYNOTE-775 ⁹

In the 309-KEYNOTE-775 trial pembrolizumab/lenvatinib was compared to patients receiving the physicians choice (PC) of either doxorubicin or paclitaxel. Inclusion and exclusion criteria mirrored the protocol outlined in 111-KEYNOTE-146. Eligible participants were divided 1:1 between Arm A (pembrolizumab 200 mg IV every 3 weeks plus lenvatinib 20 mg by mouth daily [n  =  411]) and PC mediations (doxorubicin 60 mg/m² every 3 weeks or paclitaxel 80 mg/m² weekly [n  =  416]). The median PFS was 6.6 and 3.8 months for combination therapy and PC respectively with an HR of 0.39. OS for each group was 18.3 and 11.4 months for combination therapy and PC with an HR of 0.62. A greater number of serious adverse events were seen in the pembrolizumab/lenvatinib group compared to PC therapy; 88.9% of patients in the combination therapy group had a grade 3 or higher reaction while 72.2% of the PC group had grade 3 or higher reaction. The most common ADEs were hypertension, hypothyroidism, and diarrhea.

309-KEYNOTE-775
	Lenva & Pembro	PC	HR
PFS All Patients	7.2 mos	3.8 mos	0.56
PFS pMMR Patients	6.6 mos	3.8 mos	0.6
OS All Patients	18.3 mos	11.4 mos	0.62
OS pMMR Patients	17.4 mos	12.0 mos	0.68
Objective Response All Patients	31% of patients	14.7% of patients
Objective Response pMMR	30.3% of patients	15.1% of patients
Objective Response dMMR	40% of patients	12% of patients
Inclusion	At least one trial of platinum-based therapy to be eligible for this study; additional inclusion criteria include: no history of exposure to vascular endothelial growth factor or PD-1 targeting regimens, at least one measurable lesion based on RECIST 1.1, and an ECOG score of 1 or 0
Exclusion	CNS metastases, active autoimmune disease, and females pregnant or breastfeeding

ENGOT-en9/LEAP-001 ⁸

This is an ongoing trial based of results of KEYNOTE-775 and the results of a phase 1b/2 trial (111-KEYNOTE-146). ENGOT-en9/LEAp-001 was designed to determine efficacy and safety of first-line pembrolizumab/lenvatinib compared to paclitaxel plus carboplatin in newly diagnosed stage III/IV or recurrent endometrial cancer. This is a phase 3, randomized, open-label, active-controlled trial set to end in April of 2023 (NCT04865289).

Unresectable hepatocellular carcinoma (uHCC)

Studies are underway to evaluate lenvatinb/pembrolizumab in uHCC; however, this is not an FDA approved indication for use of this combination at this time.

Study 116 ⁹

Study 116 is phase 1b multicenter open-label trial. This study consisted of two phases, the first phase, referred to as the dose-limiting toxicity (DLT) phase was used to start patients on treatment. If no ADEs were observed they were moved on to the second phase, the expansion phase, where the recommended dose from the DLT phase was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. Patients were eligible if HCC was confirmed by histology, cytology, or using the American Association for the Study of Liver Disease criteria; were stage B or C based on Barcelona Clinic Liver Cancer staging; had at least 1 measurable lesion based on mRECIST; Child-Pugh class A; and ECOG of 0 or 1. Exclusion criteria included invasion of bile duct or portal vein with Vp4; prior blood enhancing treatment or use of any anti-PD-L1/PD-1/PD-L2 inhibitors, and imaging showing HCC ≥ 50% liver occupation. Patients less than 60 kg received lenvatinib 8 mg daily; patients weighing greater than 60 kg received a 12 mg dose taken daily; pembrolizumab 200 mg IV was administered on day 1 of a 21 day cycle. This regimen was continued for up to 2 years after cycle 1 day 1. Results based on mRECIST criteria were found to be ORR of 46%, DOR of 8.6 months, and PFS of 9.3 months. When utilizing RECIST v 1.1 ORR was 36%, DOR 12.6 months, and PFS 8.6 months. OS for this study was 22 months. Grade 3 or 4 events occurred in 67% of patients; the most common ADEs were hypertension, diarrhea, fatigue, decreased appetite, and hypothyroidism.

Study 116
	Investigator Review (mRECIST)	Independent Imaging Review (IIR)(mRECIST)	RECIST v 1.1 per IIR
ORR	41%	46%	36%
DOR	12.6 months	8.6 months	12.6 months
PFS		9.3 months	8.6 months
OS	22 months
Grade ≥ 3	67%
Inclusion	Histologically/cytologically confirmed HCC, or clinically confirmed HCC using the American Association for the Study of Liver Diseases criteria; Stage B or C based on Barcelona Clinic Liver Cancer staging system; and at least 1 measurable lesion based on mRECIST; Child-Pugh class A; ECOG of 0 or 1.
Exclusion	Clear invasion of bile duct; portal vein invasion with Vp4; prior blood enhancing treatment (transfusions, blood products, agents that stimulate blood cell production) within 28 days of first dose of study; prior tx w lenvatininb or any anti-PD-L1/PD-1/PD-L2 agents; and imaging of HCC ≥ 50% liver occupation; and prior systemic therapy for uHCC

Future Studies of uHCC

There is an ongoing phase III multicenter, randomized, double-blinded, active-controlled study measuring the safety and efficacy of Lenvatinib combined with pembrolizumab in advanced hepatocellular carcinoma set to complete on Dec 31, 2023 (NCT03713593), this study was based on results of the afore mentioned uHCC phase 1b study.

HCC- TACE with lenvatinib and pembrolizumab

In addition to being studied for uHCC, combination therapy is also being considered as part of transarterial chemoembolization (TACE). This is another a non-FDA approved use of combination therapy currently being studied.

LEAP-012 Study ¹⁰

LEAP-012 is a prospective, double-blind randomized phase 3 study designed to compare transarterial chemoembolization (TACE) with and without the addition of pembrolizumab/lenvatinib. This study is ongoing, the primary endpoint is set to December 2024 (NCT04246177). Primary outcomes include PFS per RECIST 1.1 and OS. Secondary outcomes will look at PFS via mRECIST criteria, ORR, disease control rate, DOR, time to progression, and percentage of patients to experience ADEs. Participants will be split between two comparator arms, one group will not receive combination therapy with TACE, the other group will receive combination therapy with lenvatinib 12 mg daily if weight is ≥60 kg, or 8 mg daily if weight is <60 kg; with 400 mg of pembrolizumab administered every 6 weeks. Eligible participants must have confirmed HCC localized to the liver without portal vein thrombosis not amenable to curative treatment, at least one measurable tumor based on RECIST v 1.1, ECOG of 0 or 1, Child-Pugh class A, and no history of treatment with systemic treatment for HCC. Exclusion criteria included extrahepatic disease, eligibility for liver transplant, HCC tumor ≥ 10 cm, or gastric variceal bleeding in the past 6 months, and use of past systemic or locoregional chemotherapy.

Advanced gastric cancer—phase 2 trial

EPOC1706 ¹¹

The last indication under investigation for pembrolizumab/lenvatinib therapy is gastric cancer. EPOC1706 was an open-label, single-arm phase 2 trial done at the National Cancer Center Hospital East in China and Japan. The primary endpoint was objective response rate based on RECIST v 1.1 in all participants who received protocol treatment at least once. Patients received levatinib 20 mg by mouth daily and pembrolizumab 200 mg IV every 3 weeks until disease progression. First line treatment was received in 48% (n  =  14) and as second line treatment in 52% (n  =  15) of patients. Participants must be at least 20 years old, have histologically/cytologically confirmed metastatic or recurrent adenocarcinoma of the stomach or gastro-esophageal junction, ECOG of 0–1, and measurable lesion based on RECIST v. 1.1. Key exclusion criteria included previous chemotherapy, surgery, or radiotherapy within 2 weeks of enrollment, history of previous treatment with an anti-PD-L1/PD-1, active /history of chronic or recurrent autoimmune disease or presence of serious comorbidity (intestinal palsy, obstruction, pulmonary fibrosis, uncontrolled DM, HG, MI, UA, renal or liver failure, mental health disease, or CV disease. Objective response rate based on RECIST and irRECIST was 69% (n  =  20) per each criteria, PFS was 7.1 months, and median OS was not reached in this study. Disease control was seen in all participants (n  =  29). Additionally, 8 of the 9 patients with stable disease showed initial tumor shrinkage. In terms of safety, no Grade 4 reactions were observed; however, the most common adverse events were hypertension, hypothyroidism, and decreased appetite. Hypertension caused the most dose reductions in lenvatinib, all patients in the study required a reduction to 14 mg versus the original 20 mg dose.

EPOC1706
	RECIST	irRECIST
Objective Response	69% (n  =  20)	69% (n  =  20)
PFS	7.1 months
OS	Median OS not reached
Two pts had MMR-deficient tumors and 27 had MMR-proficient tumors.	Disease control was seen in all 29 participants; 8 of 9 pts with stable disease showed initial tumor shrinkage. Of 20 pts with objective response, response was still ongoing in 8 of the pts.
Inclusion	Must be at least 20 years old, have histologically/cytologically confirmed metastatic or recurrent adenocarcinoma of the stomach or gastro-esophageal junction, ECOG of 0–1, and measurable lesion based on RECIST v. 1.1
Exclusion	Tried previous chemotherapy, surgery, or radiotherapy within 2 weeks of enrollment, history of previous treatment with an anti-PD-L1/PD-1, active /history of chronic or recurrent autoimmune disease or presence of serious comorbidity (intestinal palsy, obstruction, pulmonary fibrosis, uncontrolled DM, HG, MI, UA, renal or liver failure, mental health disease, or CV disease

Discussion

Chemotherapy-free regimens are a new horizon for cancer treatment providing unique mechanisms for targeted therapy. Unlike cytotoxic chemotherapy these agents avoid myelosuppression, neurotoxicity, and nephrotoxicity associated with several cytotoxic chemotherapy agents. However, targeted agents have their own collection of side effects that can be anticipated by using the drug target. These range from inducing hypertension, hypothyroidism, slowing wound healing, pneumonitis, colitis, and coagulopathies.

Pembrolizumab with lenvatinib is one of the first, but not the only, combinations being explored for alternatives to chemotherapy for patients. Small cell lung cancer patients have new third- and fourth-line options such as nivolumab or nivolumab with ipilimumab being studied in ongoing trials. ¹² Acute lymphoblastic lymphoma patients have new opportunities for use of blinatumomab with or without a TKI. ¹³ These examples illustrate the growing pool of targeted therapy combinations.

When considering combination therapy with pembrolizumab and lenvatinib their place in treatment has been established by the CLEAR trial, which demonstrated an impressive increase in PFS compared to sunitinib alone. This regimen has also found a place in endometrial carcinoma with the KEYNOTE-775 trial for patients without MSI-H/dMMR tumors. Previously this population had no treatment options if they progressed on first-line therapy; however, this combination has given these patients additional treatment options. The most prominent side effects observed when using this combination are hypertension, hypothyroidism, diarrhea, and fatigue. There are multiple ongoing studies determining future uses for this combination in addition to many other chemotherapy free regimens being studied.