Pembrolizumab + Lenvatinib for Pancreatic Cancer

Overseen By Brandon Smaglo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Steroids, others

Disqualifiers: Immunodeficiency, Autoimmune disease, 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: 6-12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether pembrolizumab (an immunotherapy drug) and lenvatinib (a targeted therapy), when used together, can help manage pancreatic ductal adenocarcinoma, a common type of pancreatic cancer. Participants will receive either lenvatinib pills daily or pembrolizumab through an IV every cycle. This trial is ideal for those with metastatic pancreatic adenocarcinoma who have already tried at least one treatment and experienced visible cancer progression.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or certain immunosuppressive treatments, you may need to stop them before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that the combination of lenvatinib and pembrolizumab showed promise in controlling pancreatic cancer. Lenvatinib is usually well-tolerated, but it can cause side effects like tiredness and high blood pressure. In one study, 1.9% of patients with liver cancer experienced stomach issues while taking lenvatinib.

Pembrolizumab, approved for treating skin cancer (melanoma), has been tested with other drugs for pancreatic cancer. One study found it to be safe and showed early signs of effectiveness against the cancer. However, its safety specifically for pancreatic cancer patients is still being confirmed.

Since this trial is in its early stages, researchers are still collecting safety information. Previous studies provide some insight into what patients might expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pembrolizumab and lenvatinib for pancreatic cancer because they bring a novel approach to treatment. Unlike standard treatments like chemotherapy, pembrolizumab is an immunotherapy drug that helps the immune system recognize and fight cancer cells more effectively. Lenvatinib, on the other hand, is a targeted therapy that inhibits proteins involved in tumor growth. This combination has the potential to enhance treatment effectiveness by using both the body's immune response and targeted action against cancer cells, offering a promising alternative to traditional therapies.

What evidence suggests that pembrolizumab and lenvatinib could be effective for pancreatic cancer?

Research has shown that lenvatinib, one of the treatments in this trial, may help treat advanced pancreatic cancer. In studies, lenvatinib allowed patients to live without their cancer worsening for an average of 15.7 months and maintained disease stability in many cases. In this trial, some participants will receive lenvatinib alone, while others will receive pembrolizumab, another treatment option. Previous studies combining lenvatinib with pembrolizumab resulted in a positive response in 66% of patients. Pembrolizumab aids the immune system in fighting cancer and has shown some success in rare cases of pancreatic cancer, with patients living without disease progression for an average of 12 months. However, when used alone, pembrolizumab typically has low success rates in treating pancreatic cancer. Combining these treatments might be beneficial because they attack the cancer in different ways. ^{4 6 7 8 9}

Who Is on the Research Team?

Brandon Smaglo, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced pancreatic ductal adenocarcinoma who've had one prior treatment for metastatic disease. They must be able to consent, have controlled blood pressure, a life expectancy over 3 months, adequate organ function, and can swallow pills. Excluded are those with certain serious health issues like fluid accumulation needing drainage or active infections, brain metastases, recent major surgery or therapy that could affect the trial's outcome.

Inclusion Criteria

My blood pressure is ≤150/90 mm Hg and stable for the last week.

My pancreatic cancer diagnosis is confirmed by lab tests.

I am a man and agree to use contraception if I am taking lenvatinib.

Exclusion Criteria

Patient has known psychiatric- or substance-abuse disorders that would interfere with cooperation with trial requirements

Patient has a left ventricular ejection fraction below the institutional normal range

Patient has urine protein ≥1 g/24 hours

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab by vein on Day 1 of each cycle and lenvatinib capsules daily

6-12 weeks

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lenvatinib
• Pembrolizumab

Trial Overview The study tests pembrolizumab combined with lenvatinib in controlling advanced pancreatic cancer after first-line treatment failure. Participants will provide tissue samples from their tumors and undergo imaging based on RECIST 1.1 criteria to measure the effects of these drugs.

How Is the Trial Designed?

Group I: Pembrolizumab Experimental Treatment 2 Interventions

by vein over about 30 minutes on Day 1 of each cycle.

Group II: Lenvatinib Experimental Treatment 2 Interventions

2 lenvatinib capsules at the same time by mouth every day while on study.

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+

STRATEGIC ALLIANCE: Merck

Collaborator

Trials

1

Recruited

10+

Published Research Related to This Trial

In a study of 41 pancreas cancer patients treated with pembrolizumab, the median overall survival was 7.2 months, which is considered favorable compared to the benchmark of over 4 months.

Patients with specific genetic markers (dMMR, MSI-H, TMB-H, or Lynch syndrome) had a significantly lower risk of death, indicating that these biomarkers may help identify patients who could benefit more from pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. Storandt, MH., Tran, N., Martin, N., et al.[2023]

In a phase II trial involving 46 patients with advanced pancreatic ductal adenocarcinoma, the combination of selumetinib (a MEK inhibitor) and erlotinib showed modest antitumor activity, with 41% of patients experiencing stable disease for at least 6 weeks and a median overall survival of 7.3 months.

Patients with tumors that had a high level of E-cadherin expression were more likely to respond to the treatment, suggesting that specific molecular subtypes may benefit more from this dual-targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. Ko, AH., Bekaii-Saab, T., Van Ziffle, J., et al.[2021]

In a phase Ib trial involving 22 patients with metastatic pancreatic ductal adenocarcinoma, combinations of avelumab or talazoparib with binimetinib showed higher-than-expected rates of dose-limiting toxicity (DLT), particularly at the 45 mg dose, leading to dose adjustments.

Despite the safety concerns, the overall safety profiles of the combinations were consistent with those of the individual drugs, but no objective tumor responses were observed in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. Rodon Ahnert, J., Tan, DS., Garrido-Laguna, I., et al.[2023]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

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 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]

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 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]

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 the CLEAR study involving 352 patients, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common adverse reactions including fatigue (63.1%), diarrhea (61.9%), and hypertension (56.3%).

Most adverse reactions occurred within approximately 5 months of starting treatment, and effective management strategies such as monitoring and dose modifications were identified to ensure patient safety and support ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. Motzer, R., George, S., Merchan, JR., et al.[2023]

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

In a phase 2 study involving 38 patients with pleural mesothelioma, the combination of pembrolizumab and lenvatinib resulted in a promising objective response rate of 58%, indicating significant anti-tumor activity after prior chemotherapy.

However, the treatment was associated with considerable toxicity, with 26% of patients experiencing serious treatment-related adverse events, including one death, highlighting the need for careful monitoring and supportive care during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. Douma, LH., Lalezari, F., van der Noort, V., et al.[2023]

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]

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