Pembrolizumab + Lenvatinib for Gastric Cancer

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Cardiovascular impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: Approximately 71 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of two treatments, pembrolizumab and lenvatinib, to assess their effectiveness in fighting advanced gastric cancer that has spread or cannot be surgically removed. Pembrolizumab, an immunotherapy drug, helps the immune system attack cancer cells, while lenvatinib blocks enzymes that promote tumor growth. The study seeks participants with previously treated gastroesophageal adenocarcinoma that is advanced and unresponsive to other treatments. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or immunosuppressive therapy, you may need to stop these at least 7 days before starting the trial treatment.

Is there any evidence suggesting that pembrolizumab and lenvatinib are likely to be safe for humans?

Research has shown that the combination of pembrolizumab and lenvatinib has been studied before. In these studies, the safety of this combination matched earlier findings, with no unexpected side effects.

Pembrolizumab helps the immune system attack cancer cells, while lenvatinib blocks substances that cancer cells need to grow. Although generally well-tolerated, this treatment can have side effects. Safety data for this combination in stomach cancer indicates that patients experienced similar effects as in past studies with other cancer types.

As this is an early phase trial, the main goal is to understand the treatment's safety and how the body responds. Researchers closely monitor for any side effects. Prospective participants should discuss any concerns with the trial team, who can provide more details on what to expect. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about pembrolizumab and lenvatinib for gastric cancer because they bring a fresh approach to treatment. Pembrolizumab is an immunotherapy that helps the body's immune system recognize and attack cancer cells, which is different from traditional chemotherapy that directly kills cells. Lenvatinib is a targeted therapy that blocks proteins involved in cancer cell growth and blood vessel formation, offering a more precise attack on tumors. Together, these treatments offer a dual mechanism that might improve effectiveness and potentially reduce side effects compared to standard chemotherapy regimens.

What evidence suggests that pembrolizumab and lenvatinib might be an effective treatment for gastric cancer?

Research shows that combining pembrolizumab and lenvatinib has potential in treating certain cancers. This trial will evaluate the effectiveness of this combination for gastric cancer. Studies have found that it helps patients live longer without cancer progression and has been effective for advanced, inoperable cancers. Pembrolizumab aids the immune system in attacking cancer cells, while lenvatinib inhibits tumor growth by blocking specific enzymes. Although data for gastroesophageal adenocarcinoma is limited, this treatment has shown promise in similar conditions. ^{1 2 4 6 7}

Who Is on the Research Team?

Mariela Blum

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic gastroesophageal adenocarcinoma that's inoperable and hasn't responded to standard treatments. Participants must have acceptable organ function, controlled blood pressure, no major surgery within 3 weeks before the trial, not be pregnant or breastfeeding, and agree to use effective contraception.

Inclusion Criteria

Subject (or legally acceptable representative if applicable) provides written informed consent for the trial

Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or EPO dependency

AST and ALT =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases

Exclusion Criteria

Currently participating in or has participated in a study of an investigational agent or used an investigational device within 4 weeks prior to the first dose of study treatment

Known psychiatric or substance-abuse disorders that would interfere with cooperation with trial requirements

I have cancer that has spread to my brain or surrounding membranes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab intravenously on day 1 and lenvatinib orally once daily. Treatment repeats every 42 days for up to 17 cycles.

Approximately 71 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 12 weeks

1 visit at 30 days post-treatment, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lenvatinib
• Pembrolizumab

Trial Overview The study tests pembrolizumab (an immunotherapy drug) combined with lenvatinib (a drug blocking enzymes needed by cancer cells). It aims to see if this combination can better attack the cancer and halt its growth compared to current methods.

How Is the Trial Designed?

Group I: Treatment (pembrolizumab, lenvatinib) Experimental Treatment 2 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1 and lenvatinib PO QD, Treatment repeats every 42 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

Lenvatinib is already approved in United States, European Union for the following indications:

Approved in United States as Lenvima for:

• Differentiated Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Lenvima for:

• Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Kisplyx for:

• Renal Cell Carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

In a phase 2 trial involving 29 patients with advanced gastric cancer, the combination of lenvatinib and pembrolizumab resulted in a promising objective response rate of 69%, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with the most common grade 3 adverse events being manageable, such as hypertension and proteinuria, and no serious treatment-related complications or deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Kawazoe, A., Fukuoka, S., Nakamura, Y., et al.[2020]

In a phase 1b study involving 6 Japanese patients with metastatic solid tumors, the combination of lenvatinib and pembrolizumab was well-tolerated, with no dose-limiting toxicities reported.

The treatment showed promising antitumor activity, with an objective response rate of 33.3%, particularly in patients with urothelial cancer, indicating potential efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. Kitano, S., Fujiwara, Y., Shimizu, T., et al.[2022]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

Combination therapy with pembrolizumab and lenvatinib is effective as a first-line treatment for clear cell renal carcinoma and as a second-line option for recurrent or metastatic endometrial carcinoma, based on data from five completed clinical trials and two ongoing trials.

This non-chemotherapy regimen helps spare patients from prolonged myelosuppression and lowers the risk of infection, making it a safer alternative for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined use of pembrolizumab and lenvatinib: A review. Eisinger, C., Muluneh, B.[2023]

The combination of lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

In a phase 2 study involving 54 patients with advanced endometrial cancer, the combination of lenvatinib and pembrolizumab resulted in a 39.6% objective response rate at week 24, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with serious adverse events occurring in 30% of patients, including one treatment-related death; however, the safety profile was consistent with previous studies of the individual drugs, except for a higher incidence of hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Makker, V., Rasco, D., Vogelzang, NJ., et al.[2020]

The combination of pembrolizumab and lenvatinib demonstrated significantly higher objective response rates (ORRs) and progression-free survival (mPFS) compared to their individual therapies in solid cancers, with ORRs reaching up to 70% in renal cell carcinoma.

Despite a high incidence of adverse events (68.0% for the combination therapy), the toxicities were manageable and no unexpected safety issues were reported, indicating that the combination therapy is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. Mo, DC., Luo, PH., Huang, SX., et al.[2021]

In a phase 3 study involving 487 patients with advanced urothelial carcinoma, the combination of pembrolizumab and lenvatinib did not show improved progression-free survival (4.5 months) or overall survival (11.8 months) compared to pembrolizumab with placebo.

The combination treatment resulted in a higher rate of severe adverse events (51%) compared to the placebo group (27%), leading to the conclusion that the benefit-to-risk ratio was not favorable for using lenvatinib with pembrolizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Matsubara, N., de Wit, R., Balar, AV., et al.[2023]

In a study of 71 patients with unresectable hepatocellular carcinoma (uHCC), the combination of lenvatinib and pembrolizumab demonstrated a high disease control rate of 84.1% for first-line treatment, indicating its efficacy in managing this condition.

The treatment did not adversely affect liver function, as measured by the Albumin-Bilirubin (ALBI) score, and factors such as prior nivolumab failure and Child-Pugh class B were associated with poorer progression-free and overall survival, highlighting the need for further investigation in these subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. Wu, CJ., Lee, PC., Hung, YW., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00748

The Phase III, Randomized LEAP-015 Study Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or ...

2. merck.com merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-015-trial-evaluating-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-combination-with-chemotherapy-in-patients-with-certain-types-of-ga/

Merck and Eisai Provide Update on Phase 3 LEAP-015 ... The KEYTRUDA plus LENVIMA-based regimen demonstrated a statistically significant improvement in progression-free survival (PFS), one of the study's dual ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10540481/

Combined use of pembrolizumab and lenvatinib: A review Data suggests that combination therapy with pembrolizumab and lenvatinib can be used first line for clear cell renal carcinoma in patients with favorable risk.

4. eisai.com eisai.com/news/2025/news202505.html

Eisai and Merck & Co., Inc., Rahway, NJ, USA Provide ... The LENVIMA plus KEYTRUDA-based regimen demonstrated a statistically significant improvement in progression-free survival (PFS), one of the study's dual ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.4042

Phase II study of lenvatinib plus pembrolizumab for ... Lenvatinib combined with pembrolizumab was well tolerated, responses were seen, but the study did not meet the primary endpoint in ICI naïve AGC.

6. cancernetwork.com cancernetwork.com/view/pembrolizumab-combo-does-not-meet-os-end-point-in-advanced-gastric-cancer

Pembrolizumab Combo Does Not Meet OS End Point in ... Pembrolizumab plus lenvatinib showed a safety profile consistent with previous reports evaluating the combination.

7. clinicaloptions.com clinicaloptions.com/activity/ecase/downloadsectionfile/6B348255-9BB3-4047-8133-6EF5323EF80F

LEAP-015: Phase III Safety Run-in Data With ... LEAP-015: Phase III Safety Run-in Data With Pembrolizumab + Lenvatinib + Chemotherapy for Advanced Gastroesophageal Cancer. Supported by educational grants ...