Tepotinib + Ramucirumab for Lung Cancer

Recruiting at 245 trial locations

Overseen By SWOG P Department

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: SWOG Cancer Research Network

Must not be taking: MET inhibitors, Angiogenesis inhibitors

Disqualifiers: Leptomeningeal disease, Brain metastases, others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase II Expanded Lung-MAP treatment trial tests tepotinib with or without ramucirumab for the treatment of patients with advanced non-small cell lung cancer that has spread from where it first started (primary site) to other places in the body (stage IV) or that has come back after a period of improvement (recurrent). Tepotinib is used in patients whose cancer has a mutated (changed) form of a gene called MET. It is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal MET protein that signals tumor cells to multiply. This helps slow or stop the spread of tumor cells. Ramucirumab is a monoclonal antibody that may prevent the growth of new blood vessels that tumors need to grow. Giving tepotinib with ramucirumab may lower the chance of the cancer from growing or spreading in patients with stage IV or recurrent non-small cell lung cancer.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must not have received any systemic therapy, including chemotherapy or immunotherapy, within 21 days before joining the study, and you cannot receive any concurrent cancer treatments while participating.

What data supports the effectiveness of the drug combination of Tepotinib and Ramucirumab for lung cancer?

Research shows that Tepotinib, when combined with other drugs, can help overcome resistance in certain types of lung cancer, and Ramucirumab has been shown to improve outcomes in patients with specific lung cancer mutations. This suggests that the combination of Tepotinib and Ramucirumab might be effective for treating lung cancer. ^{1 2 3 4 5}

Is the combination of Tepotinib and Ramucirumab safe for humans?

Safety data for Ramucirumab shows it has been used safely in combination with other drugs like erlotinib and afatinib in lung cancer patients, with safety profiles consistent with what is already known about these drugs. Tepotinib has also been evaluated for safety in combination with gefitinib in lung cancer patients, indicating it is generally safe in humans. ^{1 5 6 7 8}

What makes the drug combination of Tepotinib and Ramucirumab unique for lung cancer treatment?

The combination of Tepotinib and Ramucirumab is unique because Tepotinib is a highly selective oral MET inhibitor, which targets specific genetic changes in lung cancer cells, while Ramucirumab is a VEGFR inhibitor that helps block blood supply to tumors. This combination targets both the cancer cells and their blood supply, offering a novel approach for patients with specific genetic profiles in non-small cell lung cancer. ^{1 3 4 5 9}

Research Team

Paul K Paik

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer that has spread or returned, and have a specific gene change (MET Exon 14 skipping). They must have had at least one prior treatment, measurable disease by CT or MRI, no other major actionable mutations, and be stable after any brain metastases treatments. Participants need to show progression after the last therapy and can't have unresolved severe side effects from previous treatments.

Inclusion Criteria

My cancer has worsened after the latest treatment.

I have had at least one treatment for stage IV or recurrent non-small cell lung cancer.

My cancer can be seen and measured on a CT or MRI scan taken recently.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tepotinib with or without ramucirumab. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle, ongoing until progression or toxicity

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 12 weeks until progression, then every 6 months for 2 years, and at the end of 3 years.

Up to 3 years

Every 12 weeks, then every 6 months

Treatment Details

Interventions

• Ramucirumab (Monoclonal Antibody)
• Tepotinib (Kinase Inhibitor)

Trial Overview The study tests tepotinib alone or combined with ramucirumab in patients. Tepotinib is a kinase inhibitor targeting abnormal MET protein to slow tumor growth; ramucirumab aims to stop tumors from growing new blood vessels. The combination's effectiveness against stage IV or recurrent lung cancer is being evaluated.

Participant Groups

Group I: Arm A: (Ramucirumab and tepotinib) Experimental Treatment 6 Interventions

Patients receive ramucirumab IV over 30-60 minutes on day 1 of each cycle and tepotinib PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo lymphoscintigraphy scan and CT scan and/or MRI throughout the trial. Patients also undergo blood sample collection while on study.

Group II: Arm B: (Tepotinib) Active Control 5 Interventions

Patients receive tepotinib PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo lymphoscintigraphy scan and CT scan and/or MRI throughout the trial. Patients also undergo blood sample collection while on study.

Tepotinib is already approved in Japan for the following indications:

Approved in Japan as Tepmetko for:

• Non-small cell lung cancer (NSCLC) with MET alterations

Who Is Running the Clinical Trial?

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

EMD Serono

Industry Sponsor

Trials

147

Recruited

27,800+

Dr. Shepard

EMD Serono

Chief Medical Officer since 2021

MD from University of Cincinnati Medical School, Fellowships in Hematology and Oncology at University of Chicago Hospitals and Clinics

Miguel Fernández Alcalde

EMD Serono

Chief Executive Officer

Bachelor's Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master's Degree in Management from IESE Business School

Findings from Research

In a study involving 73 patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC), the combination of tepotinib and gefitinib showed promising efficacy, particularly in patients with high MET overexpression or MET amplification, leading to longer progression-free survival (PFS) compared to standard chemotherapy.

The treatment was generally well-tolerated, with no dose-limiting toxicities observed, although some patients experienced grade 3 or worse adverse events, such as increased amylase and lipase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Wu, YL., Cheng, Y., Zhou, J., et al.[2020]

Tepotinib, a selective c-Met inhibitor, shows promise in overcoming resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), particularly in models with high c-Met expression.

In various xenograft models, tepotinib combined with EGFR TKIs not only delayed tumor regrowth but also achieved complete tumor regression in certain cases, suggesting its potential as a treatment strategy for patients with acquired resistance to EGFR TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The selective c-Met inhibitor tepotinib can overcome epidermal growth factor receptor inhibitor resistance mediated by aberrant c-Met activation in NSCLC models. Friese-Hamim, M., Bladt, F., Locatelli, G., et al.[2022]

Tepotinib, an oral MET inhibitor approved for treating metastatic non-small cell lung cancer, generally causes mild to moderate adverse events (AEs) such as peripheral edema, nausea, and diarrhea, which are manageable with proper care.

Proactive monitoring and early intervention, including treatment interruptions for severe AEs, are essential for effective nursing management of patients on tepotinib, ensuring better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tepotinib: Management of Adverse Events in Patients With MET Exon 14 Skipping Non-Small Cell Lung Cancer. Ahn, L., Alexander, T., Vlassak, S., et al.[2023]

In the RELAY trial, patients with untreated, metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) showed improved progression-free survival (PFS) when treated with ramucirumab plus erlotinib (RAM+ERL), regardless of their TP53 mutation status.

TP53 mutations were found to be a negative prognostic factor, but the combination of RAM+ERL still provided significant benefits in clinical outcomes, indicating that this treatment is effective for patients with both mutant and wild-type TP53.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association Between TP53 Status and Clinical Outcome. Nishio, M., Paz-Ares, L., Reck, M., et al.[2023]

In a study involving six patients with EGFR-mutated lung adenocarcinoma, the combination of osimertinib and ramucirumab was found to be generally safe, with only one case of dose-limiting toxicity (grade 3 appetite loss) and no other severe adverse events reported.

Five out of six patients showed a partial response to the treatment, with a median progression-free survival of 9.2 months for those with the EGFR T790M mutation, suggesting promising efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. Akamatsu, H., Ozawa, Y., Oyanagi, J., et al.[2023]

In the phase 3 RELAY trial, the combination of ramucirumab and erlotinib significantly improved progression-free survival in patients with EGFR-mutated metastatic non-small cell lung cancer (NSCLC), with a median PFS of 19.4 months compared to 12.4 months for the placebo group.

Patient-reported outcomes indicated that overall quality of life and symptom burden were similar between the ramucirumab/erlotinib and placebo/erlotinib groups, although there was a notable increase in reports of blood in sputum for the ramucirumab group, suggesting a specific safety concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. Yoh, K., Atagi, S., Reck, M., et al.[2023]

In a study of 33 patients with EGFR-mutated metastatic non-small cell lung cancer (NSCLC), the combination of afatinib and ramucirumab showed a median progression-free survival (PFS) of 71 months, indicating a strong potential for long-term disease control.

The upfront combination of afatinib and ramucirumab resulted in a median overall survival (OS) of 30 months, suggesting that this treatment strategy may offer significant survival benefits, particularly for patients with uncommon EGFR mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non-small cell lung cancer. Huang, CY., Huang, HL., Lan, CC., et al.[2023]

The RELAY study is a phase Ib/III clinical trial designed to evaluate the safety and efficacy of combining ramucirumab with erlotinib in about 450 previously untreated patients with stage IV non-small-cell lung cancer and activating EGFR mutations.

The study aims to determine if adding ramucirumab, an antiangiogenic agent, can enhance the effectiveness of erlotinib, which is already a standard treatment for this type of cancer, with the primary focus on progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non-Small-Cell Lung Cancer. Garon, EB., Reck, M., Paz-Ares, L., et al.[2023]

In a study of patients with non-small cell lung cancer (NSCLC), the addition of ramucirumab to docetaxel did not significantly improve overall survival for patients with EGFR mutant disease compared to those receiving docetaxel alone, with overall survival times of 6.7 months and 4.9 months respectively.

The study found no significant differences in treatment duration or overall survival between patients with EGFR mutant and wild type disease receiving ramucirumab with docetaxel, suggesting that the expected benefits of ramucirumab may not apply to all patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of ramucirumab with docetaxel in epidermal growth factor receptor mutant and wild-type non-small cell lung cancer. Ellis-Caleo, T., Neal, JW.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. [2020]

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

The selective c-Met inhibitor tepotinib can overcome epidermal growth factor receptor inhibitor resistance mediated by aberrant c-Met activation in NSCLC models. [2022]

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

Tepotinib: Management of Adverse Events in Patients With MET Exon 14 Skipping Non-Small Cell Lung Cancer. [2023]

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

RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association Between TP53 Status and Clinical Outcome. [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes in RELAY, a phase 3 trial of ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small-cell lung cancer. [2023]

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

A real-world study of Afatinib plus ramucirumab in treatment-naïve, EGFR-mutated, non-small cell lung cancer. [2023]

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

Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non-Small-Cell Lung Cancer. [2023]

9. China pubmed.ncbi.nlm.nih.gov

The role of ramucirumab with docetaxel in epidermal growth factor receptor mutant and wild-type non-small cell lung cancer. [2022]