Ramucirumab + Erlotinib for Lung Cancer

(RELAY Trial)

Not currently recruiting at 198 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Eli Lilly and Company

Must be taking: Erlotinib

Must not be taking: CYP3A4 inducers

Disqualifiers: T790M mutation, Brain metastases, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of different medication combinations for treating non-small cell lung cancer (NSCLC) with an EGFR mutation. Researchers compare the drug ramucirumab (Cyramza), combined with either erlotinib (Tarceva), gefitinib, or osimertinib, to erlotinib with a placebo. The trial targets individuals with stage IV NSCLC who have not received prior treatment and have a tumor with an EGFR mutation. Participants must have a stage IV lung cancer diagnosis and should not have certain other health conditions, such as serious bleeding disorders or brain metastases. As a Phase 3 trial, this study is the final step before FDA approval, offering participants the chance to contribute to potentially groundbreaking treatment advancements.

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

The trial does not specify if you need to stop all current medications, but you cannot be on ongoing treatment with CYP3A4 inducers or strong inhibitors, or nonsteroidal anti-inflammatory drugs for more than 2 months.

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

Research has shown that combining ramucirumab with erlotinib is generally easy for patients to handle. In a study, patients taking these drugs experienced a significant improvement in progression-free survival, meaning their cancer did not worsen for a longer period. This suggests the drugs did not cause side effects that were too difficult to manage.

Similarly, ramucirumab with gefitinib proved safe for East Asian patients with a specific type of lung cancer, indicating most people managed the treatment well without serious problems.

For ramucirumab combined with osimertinib, studies indicate it is safe and tolerable. Patients generally followed the treatment plan well, meaning they could continue without too many issues.

In all combinations, the treatments showed promising safety results, suggesting they are manageable for most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ramucirumab with erlotinib, gefitinib, or osimertinib for lung cancer because ramucirumab introduces a unique mechanism by targeting the blood vessels that supply tumors. Unlike most treatments that focus solely on the cancer cells themselves, ramucirumab works by inhibiting angiogenesis, which may effectively starve the tumor of nutrients and oxygen. This approach, when combined with erlotinib, gefitinib, or osimertinib, which are known for targeting specific mutations in cancer cells, offers a dual-action strategy that could enhance treatment effectiveness and potentially overcome resistance seen with standard therapies.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Studies have shown that combining ramucirumab and erlotinib, one of the treatment arms in this trial, can significantly extend the time patients with EGFR-mutated non-small cell lung cancer live without disease progression. On average, patients experienced 19.4 months without progression compared to 12.4 months for those taking a placebo with erlotinib. This combination has also been linked to some patients living longer overall, with some exceeding 50 months.

Another treatment arm in this trial involves ramucirumab with either gefitinib or osimertinib. Research on ramucirumab with gefitinib found that 59% of patients had no disease progression at 6 months, and 55% experienced a noticeable reduction in tumor size. Additionally, the combination of ramucirumab and osimertinib has significantly extended the time without disease progression in patients not previously treated with tyrosine kinase inhibitors. These findings suggest that ramucirumab, when used with these medications, can effectively slow lung cancer in patients with specific genetic mutations. ^{1 3 6 7 8}

Who Is on the Research Team?

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Are You a Good Fit for This Trial?

This trial is for people with a specific type of advanced lung cancer (Stage IV NSCLC) that has not been treated before and has certain EGFR mutations. Participants must have a life expectancy of at least 3 months, one measurable lesion, and provide tissue samples. It's not for those with certain medical conditions like significant bleeding disorders or recent major blood vessel invasion by cancer.

Inclusion Criteria

You are expected to live for at least 3 more months.

You are able to receive erlotinib as your first treatment if your tumor has certain mutations in the EGFR gene.

You need to provide tissue samples from your lung cancer. If you don't have stage IV lung cancer, other tissue samples may be accepted.

Exclusion Criteria

You have been taking nonsteroidal anti-inflammatory drugs for more than 2 months.

You have a history of coughing up a lot of blood.

There are visible holes inside the tumor on the imaging tests.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Safety and tolerability of ramucirumab in combination with erlotinib are assessed

Up to 37 months

Every 2 weeks (in-person)

Treatment Part B

Participants receive ramucirumab or placebo in combination with erlotinib

Up to 37 months

Every 2 weeks (in-person)

Treatment Part C

Efficacy and safety of ramucirumab in combination with gefitinib or osimertinib are assessed

Up to 37 months

Every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 37 months

What Are the Treatments Tested in This Trial?

Interventions

• Erlotinib
• Gefitinib
• Osimertinib
• Placebo
• Ramucirumab

Trial Overview The study tests the effectiveness and safety of Ramucirumab combined with Erlotinib versus placebo combined with Erlotinib in treating lung cancer. Part C extends to test Ramucirumab with Gefitinib or Osimertinib in East Asian participants based on disease progression and mutation status.

How Is the Trial Designed?

Group I: Ramucirumab + Gefitinib or Osimertinib Experimental Treatment 3 Interventions

Part C: 10 mg/kg ramucirumab administered every 2 weeks intravenously (IV) + 250 mg Gefitinib or 80 mg Osimertinib daily orally. * Ramucirumab and gefitinib administered during period 1. * Ramucirumab and osimertinib administered during period 2.

Group II: Ramucirumab + Erlotinib Experimental Treatment 2 Interventions

Part A: 10 milligrams per kilogram (mg/kg) ramucirumab administered every 2 weeks intravenously (IV) in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met. Part B: 10 mg/kg ramucirumab administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

Group III: Placebo + Erlotinib Placebo Group 2 Interventions

Part B: Placebo administered every 2 weeks IV in combination with 150 mg erlotinib daily orally. Participants may continue to receive treatment until discontinuation criteria are met.

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

Approved in European Union as Tarceva for:

• Non-small cell lung cancer
• Pancreatic cancer

Approved in United States as Tarceva for:

• Non-small cell lung cancer
• Pancreatic cancer

Approved in Canada as Tarceva for:

• Non-small cell lung cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead 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

Published Research Related to This Trial

Osimertinib significantly improves progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, showing a median PFS of 10.1 months compared to 4.4 months with chemotherapy in a trial of 419 patients.

The safety profile of osimertinib is favorable compared to other EGFR tyrosine kinase inhibitors and chemotherapy, with common side effects including diarrhea and rash, making it a viable treatment option for patients who have progressed on previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. Odogwu, L., Mathieu, L., Goldberg, KB., et al.[2022]

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]

Osimertinib showed a high overall objective response rate (ORR) of 77% in treatment-naïve patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC), indicating its efficacy as a first-line treatment.

The median progression-free survival (PFS) was approximately 20.5 months across doses, and no acquired EGFR T790M mutations were detected in post-progression samples, suggesting that osimertinib may effectively manage resistance mechanisms in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. Ramalingam, SS., Yang, JC., Lee, CK., et al.[2022]

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 a phase 1b study involving 6 patients with untreated EGFR-mutated non-small cell lung cancer and asymptomatic brain metastases, ramucirumab combined with erlotinib or osimertinib was found to be safe, with no dose-limiting toxicities or serious adverse events related to central nervous system hemorrhage.

The treatment resulted in an objective systemic response in 5 out of 6 patients, and one patient showed a confirmed partial response in the brain, indicating potential efficacy in this challenging patient subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of ramucirumab in combination with erlotinib or osimertinib for untreated EGFR-mutated non-small cell lung cancer patients with asymptomatic brain metastases. Kaneda, H., Sawa, K., Daga, H., et al.[2023]

In the ADAURA study, adjuvant osimertinib significantly improved disease-free survival in patients with resected stage IB to IIIA EGFR-mutated non-small cell lung cancer (NSCLC) compared to placebo, with a median treatment duration of 35.8 months for osimertinib versus 25.1 months for placebo.

After three years of treatment, osimertinib showed no new safety concerns, and patients maintained their health-related quality of life, indicating that osimertinib is both effective and tolerable for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Year Safety, Tolerability, and Health-Related Quality of Life Outcomes of Adjuvant Osimertinib in Patients With Resected Stage IB to IIIA EGFR-Mutated NSCLC: Updated Analysis From the Phase 3 ADAURA Trial. John, T., Grohé, C., Goldman, JW., et al.[2023]

In a study of 240 advanced non-small-cell lung cancer (NSCLC) patients with acquired resistance to EGFR TKIs, 52.9% had the T790M mutation after rebiopsy, highlighting the mutation's prevalence in treatment resistance.

Patients with the T790M mutation who had previously used osimertinib experienced significantly longer post-progression survival (42.6 months) compared to those without osimertinib (18.0 months) or without the mutation (18.8 months), suggesting osimertinib's effectiveness as a standard treatment for T790M-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. Chiang, CL., Huang, HC., Shen, CI., et al.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2666364325000359

Final Survival Outcomes With Ramucirumab Plus Erlotinib ... The Japanese subset reported that RAM plus ERL improved PFS, and a mOS greater than 50 months was achieved. OS differed by EGFR mutation type.

2. jons-online.com jons-online.com/web-exclusives/combination-cyramza-and-tarceva-approved-for-first-line-treatment-of-metastatic-nsclc-with-egfr-mutation

Combination Cyramza and Tarceva Approved for First-Line ... The ramucirumab plus erlotinib arm had a median PFS of 19.4 months, compared with 12.4 months in the placebo plus erlotinib arm (hazard ratio [HR], 0.59; 95% ...

3. jto.org jto.org/article/S1556-0864(24)02495-X/fulltext

RELAY: Final Overall Survival for Erlotinib Plus ... At data cutoff, 297 deaths were reported (overall event rate = 66%), with a median follow-up of 45.1 months (interquartile range: 26.7–71.2), an OS HR of 0.98 ( ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40535732/

Ramucirumab and erlotinib combination as first-line ... Objectives: To evaluate the therapeutic efficacy and safety of RAM + ERL as a first-line treatment for advanced or recurrent NSCLC harboring the ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4165478/

A Phase II, Open-Label Study of Ramucirumab in ... Results: The 6-month PFS rate was 59.0% and the objective response rate was 55.0%. The most common treatment-related adverse events were fatigue ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40458541/

Final Survival Outcomes With Ramucirumab Plus Erlotinib ... The Japanese subset reported that RAM plus ERL improved PFS, and a mOS greater than 50 months was achieved. OS differed by EGFR mutation type.

7. tandfonline.com tandfonline.com/doi/full/10.1080/14796694.2025.2560225

RELAY: safety and efficacy of ramucirumab plus erlotinib in ... These results suggest that RAM+ERL may be a suitable first-line treatment option for elderly patients with EGFR-mutated NSCLC. Clinical trial registration. www.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39622410/

Final Overall Survival for Erlotinib Plus Ramucirumab or ... RELAY, a global double-blind, placebo-controlled phase 3 study (NCT02411448) found statistically significant improvement in progression-free survival (primary ...