Lenvatinib + Pembrolizumab for Neuroendocrine Cancer

Overseen By Phu Lam

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: Immunosuppressants, QT prolonging drugs

Disqualifiers: Poorly differentiated NEC, Cardiovascular disease, Active infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

29 Participants Needed

Trial Summary

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, certain medications, especially those that might interact with the trial drugs or affect the QT interval, may need to be adjusted or stopped. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Lenvatinib and Pembrolizumab for treating neuroendocrine cancer?

Research shows that Pembrolizumab, one of the drugs in the combination, has been studied for its effects on neuroendocrine tumors. In some studies, it has shown limited activity, with a few patients experiencing stable disease or partial response, suggesting potential benefits in certain cases. ^{1 2 3 4 5}

Is the combination of lenvatinib and pembrolizumab safe for humans?

The combination of lenvatinib and pembrolizumab has been studied in various cancers and generally shows a manageable safety profile. Common side effects include high blood pressure, low thyroid hormone levels, diarrhea, nausea, vomiting, loss of appetite, tiredness, and weight loss. ^{6 7 8 9 10}

What makes the drug combination of lenvatinib and pembrolizumab unique for treating neuroendocrine cancer?

The combination of lenvatinib and pembrolizumab is unique because it targets both the blood vessels that supply the tumor and the immune system's ability to fight cancer, potentially offering a new option for neuroendocrine cancer, which currently has limited treatment choices. ^{7 11 12 13 14}

What is the purpose of this trial?

This is the first study to be done in a newly described class of neuroendocrine tumors known as well-differentiated grade 3 neuroendocrine tumors (WD G3 NET). First described in the pancreas in 2017, the classification was broadened to include gastrointestinal tract tumors in 2019. Recent data suggest an equivalent subtype exists in the lungs (NEC with carcinoid morphology). WD G3 NETs can occur de novo as well as the result of grade progression over time. This is a single arm, multi-site, Phase II study in biomarker "unselected" participants. This study will also incorporate serial blood samples, tumor biopsies, and special imaging to better understand the impact of therapy on the tumor and microenvironment. Hyperpolarized (HP) 13C-pyruvate magnetic resonance imaging (MRI) - a novel non-radioactive imaging modality able to provide in vivo measurements of the pyruvate-to-lactate conversion rate (kpl).

Research Team

Emily Bergsland, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults with well-differentiated grade 3 neuroendocrine tumors (WD G3 NET), including those in the pancreas, gastrointestinal tract, or lungs with specific characteristics. Participants must have a life expectancy over 3 months and at least one measurable lesion. They should be able to undergo MRI imaging if at UCSF, have good organ function, controlled blood pressure, and agree to use contraception.

Inclusion Criteria

At least 1 measurable target lesion according to RECIST 1.1

My cancer progressed after treatment and my Ki67 score is below 30%.

Tumors with ambiguous histology and/or Ki67 >/=55% must be reviewed at the participating site to confirm that they are not poorly differentiated

Exclusion Criteria

I have not had coughing up blood or tumor bleeding in the last 3 weeks.

Pregnant women

I don't have any health issues that could affect the study's results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 20 mg once daily of lenvatinib plus 400 mg of pembrolizumab every 6 weeks for up to 18 doses

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse event monitoring for 30 days and serious adverse events for 90 days

3 months

Long-term Follow-up

Participants are followed for disease status until disease progression, initiation of non-study cancer treatment, or withdrawal of consent

Until disease progression or end of study

Treatment Details

Interventions

• Lenvatinib
• Pembrolizumab

Trial Overview The study tests Lenvatinib combined with Pembrolizumab on patients with WD G3 NETs. It's a Phase II trial across multiple sites without selection based on biomarkers. The effects of treatment are monitored through blood samples, tumor biopsies, and Hyperpolarized 13C-Pyruvate MRI scans that measure changes in the tumor environment.

Participant Groups

Group I: Lenvatinib Plus Pembrolizumab Experimental Treatment 3 Interventions

Participants will receive 20 mg once daily of lenvatinib plus 400 mg of pembrolizumab every 6 weeks for up to 18 doses. Eligible participants may also receive a Hyperpolarized 13C-pyruvate (HP 13C) magnetic resonance imaging (MRI) scan

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?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In the KEYNOTE-028 study, pembrolizumab showed antitumor activity in patients with well-differentiated or moderately-differentiated neuroendocrine tumors (NETs), with objective response rates of 12% for carcinoid tumors and 6.3% for pancreatic NETs after a median follow-up of 20 to 21 months.

The treatment was generally well-tolerated, with 68% to 69% of patients experiencing treatment-related adverse events, the most common being diarrhea and fatigue, indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Mehnert, JM., Bergsland, E., O'Neil, BH., et al.[2021]

In a study involving 29 patients with metastatic high-grade neuroendocrine neoplasms (G3NENs), Pembrolizumab showed limited efficacy as only 3.4% of patients had an objective response, and the overall disease control rate was 24.1%.

Pembrolizumab was well tolerated, with only 9 instances of grade 3 adverse events and no grade 4 events, indicating it can be safely administered to this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Vijayvergia, N., Dasari, A., Deng, M., et al.[2021]

In a study of 107 patients with advanced well-differentiated neuroendocrine tumors (NETs), pembrolizumab showed limited efficacy, with an objective response rate of only 3.7%, indicating that it may not be a highly effective treatment for this specific cancer type.

Despite the low response rate, pembrolizumab was associated with manageable safety, as 75.7% of patients experienced treatment-related adverse events, with only 21.5% classified as severe (grade 3-5).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Strosberg, J., Mizuno, N., Doi, T., et al.[2021]

In a study of 21 patients with metastatic extra-pulmonary high-grade neuroendocrine neoplasms treated with pembrolizumab, only one patient showed a partial response, indicating limited efficacy of this treatment for this aggressive tumor type.

Longer progression-free survival (median 59 days) was associated with higher pre-treatment peripheral T-cell counts and lower activation of naïve T cells, suggesting that immune profile characteristics may help predict treatment outcomes and support the need for combination therapies to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of pembrolizumab therapy on immune phenotype in patients with high-grade neuroendocrine neoplasms. MacFarlane, AW., Yeung, HM., Alpaugh, RK., et al.[2022]

In a phase II trial involving 7 women with recurrent small cell neuroendocrine tumors of the lower genital tract, pembrolizumab showed minimal efficacy, with no patients remaining progression-free at 27 weeks.

The treatment was generally well tolerated, with only 29% of patients experiencing severe treatment-related adverse events, indicating a relatively low risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract. Frumovitz, M., Westin, SN., Salvo, G., et al.[2023]

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]

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 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]

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 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]

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 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]

The combination of pembrolizumab and lenvatinib has shown promising efficacy in treating advanced endometrial cancer, with previous trials indicating improved objective response rates and survival outcomes compared to standard chemotherapy.

This ongoing phase 3 trial aims to determine if pembrolizumab plus lenvatinib is superior to the chemotherapy regimen of paclitaxel plus carboplatin in newly diagnosed patients, with a target enrollment of about 875 participants and results expected in 2022.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Marth, C., Tarnawski, R., Tyulyandina, A., et al.[2022]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Impacts of pembrolizumab therapy on immune phenotype in patients with high-grade neuroendocrine neoplasms. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]

8. Switzerland 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. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. [2022]

11. England 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. [2020]

12. England 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. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. [2022]

14. Germany pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. [2022]