Fianlimab + Cemiplimab for Melanoma

Recruiting at 110 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Regeneron Pharmaceuticals

Must not be taking: Immunosuppressants

Disqualifiers: Uveal melanoma, Autoimmune disease, HIV, others

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

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: Unknown

Duration: Up to 72 months

560 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for melanoma, a type of skin cancer. It combines two immunotherapy drugs, fianlimab and cemiplimab, to assess their safety and effectiveness compared to the approved treatment, Opdualag™. Researchers aim to learn about potential side effects, how the drugs behave in the body, and whether the body produces antibodies against them, which might impact their effectiveness. The trial seeks participants with melanoma that cannot be surgically removed or has spread and who have not received prior treatment for these conditions. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received prior systemic therapy for melanoma and should not be on systemic immune suppression. It's best to discuss your current medications with the trial team.

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

Research shows that the combination of fianlimab and cemiplimab is generally well-tolerated. Studies indicate its safety is similar to other treatments targeting PD-1, a type of immune therapy. Patients usually experience side effects similar to those of other immune-based cancer treatments. However, more reports of adrenal issues have emerged with this combination. Adrenal issues can affect hormone levels and might require attention from healthcare providers.

The other combination in the trial, relatlimab and nivolumab (known as Opdualag™), is already approved for treating melanoma in adults and children. This approval suggests it is safe enough for wider use, though, like any treatment, it may have side effects.

Both combinations aim to boost the body's immune response to fight melanoma. Participants should discuss potential side effects and benefits with their healthcare provider to make informed decisions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about fianlimab combined with cemiplimab for melanoma because this combination represents a new approach to boosting the immune system against cancer. Most treatments for melanoma, like nivolumab and relatlimab, focus on blocking immune checkpoints to enhance immune response. However, fianlimab targets a different immune checkpoint, LAG-3, which works alongside cemiplimab to potentially offer a stronger and more sustained immune attack on melanoma cells. This dual approach aims to improve the effectiveness and durability of responses compared to existing treatments.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that the combination of fianlimab and cemiplimab, which participants in this trial may receive, holds promise for treating melanoma, a type of skin cancer. Studies have found that this combination led to tumor shrinkage in 56% to 63% of patients with advanced melanoma, indicating a reduction in tumor size for many patients. The treatment has been effective regardless of specific tumor characteristics. Fianlimab aids the immune system in attacking cancer cells by blocking a protein called LAG-3. Cemiplimab is already known to be effective against certain skin cancers, making this combination a hopeful option for people with melanoma. Another treatment option in this trial is the combination of relatlimab and nivolumab, which serves as an active comparator. ^{1 6 7 8 9}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic melanoma who haven't had systemic therapy for this condition. They should have a performance status indicating they can carry out light activity, and their major organs must be functioning well.

Inclusion Criteria

My blood, liver, and kidney tests are normal.

My melanoma is at an advanced stage and cannot be surgically removed.

I have not had systemic therapy for my advanced melanoma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either fianlimab and cemiplimab or relatlimab and nivolumab to assess safety and effectiveness in treating melanoma

Up to 72 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of laboratory abnormalities

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cemiplimab
• Fianlimab
• Relatlimab+Nivolumab

Trial Overview The study compares the safety and effectiveness of two treatments: fianlimab combined with cemiplimab versus relatlimab plus nivolumab (Opdualag™). It also examines side effects, drug levels in blood over time, and potential immune responses to the drugs.

How Is the Trial Designed?

Group I: fianlimab+cemiplimab Experimental Treatment 2 Interventions

Randomized 1:1

Group II: relatlimab+nivolumab Active Control 1 Intervention

Randomized 1:1

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

Approved in European Union as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in United States as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Basal cell carcinoma (BCC)
• Non-small cell lung cancer (NSCLC)

Approved in Canada as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)
• Non-small cell lung cancer (NSCLC)

Approved in Brazil as Libtayo for:

• Cutaneous squamous cell carcinoma (CSCC)

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Published Research Related to This Trial

Interferon (IFN)-alpha-2b has been established as an effective adjuvant therapy for patients with localized melanoma at high risk for relapse, showing improved relapse-free and overall survival in three large randomized trials.

Recombinant interleukin-2 (rIL-2) has been approved for metastatic melanoma, demonstrating a 15-20% overall response rate and the potential for complete remissions in about 6% of patients, although ongoing trials are needed to confirm the benefits of combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving survival in patients with high-risk and metastatic melanoma: immunotherapy leads the way. Agarwala, S.[2018]

In a study of 945 patients with untreated metastatic melanoma, the combination of nivolumab and ipilimumab significantly improved progression-free survival to a median of 11.5 months compared to just 2.9 months with ipilimumab alone.

For patients with PD-L1-negative tumors, the combination therapy was particularly effective, showing a progression-free survival of 11.2 months compared to 5.3 months with nivolumab alone, highlighting the potential of dual checkpoint inhibition in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

The combination of bempegaldesleukin (BEMPEG) and nivolumab has shown promising clinical activity and good tolerability as a first-line treatment for metastatic melanoma in the Phase I/II PIVOT-02 trial.

The ongoing Phase III PIVOT IO 001 trial aims to compare the effectiveness of this combination therapy against nivolumab alone, focusing on key outcomes like objective response rate and overall survival in patients with untreated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. Khushalani, NI., Diab, A., Ascierto, PA., et al.[2021]

Tremelimumab, a monoclonal antibody, has shown the ability to induce durable tumor regressions in 7% to 10% of patients with metastatic melanoma, with effects lasting up to 8 years, primarily through the activation of cytotoxic T lymphocytes.

While tremelimumab can lead to significant tumor responses, it also carries a risk of severe toxicities (20% to 25% of patients), mainly due to inflammatory or autoimmune reactions from its mechanism of action, which involves inhibiting CTLA-4 to enhance immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of the anti-CTLA-4 antibody tremelimumab. Ribas, A.[2021]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Ipilimumab, an immune checkpoint inhibitor approved in 2011, has shown the potential to induce deep and durable remissions in up to 20% of metastatic melanoma patients by enhancing T-cell activation against tumors.

While ipilimumab can cause significant immune-related adverse events (irAEs), such as uveitis and nephritis, these can be effectively managed, and patients can still achieve remarkable outcomes, as demonstrated by a case where a patient had a complete response after treatment despite experiencing severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Full Spectrum: Efficacy and Toxicity of Immunotherapy in Metastatic Melanoma Zibelman, M., Olszanski, AJ.[2019]

In a study of 747 patients receiving immune checkpoint inhibitor therapy for advanced melanoma, 31.6% developed cutaneous immune-related adverse events (cirAEs), which were linked to improved survival rates overall (HR = 0.76).

Patients with acral melanoma were less likely to develop cirAEs compared to those with nonacral cutaneous melanoma (HR = 0.41), and they exhibited the worst survival outcomes, suggesting that lower cirAE incidence may indicate poorer immunotherapy response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy. Nguyen, N., Wan, G., Ugwu-Dike, P., et al.[2023]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

Regorafenib and NU7441 were identified as promising therapies that can enhance T-cell immunotherapy for melanoma by modifying immunomodulatory proteins and increasing melanoma antigens, which may improve treatment outcomes.

In mouse models, regorafenib not only suppressed melanoma progression but also positively influenced T-cell behavior, leading to increased proliferation and cytokine production, suggesting a synergistic effect when combined with other immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies. Tsai, AK., Khan, AY., Worgo, CE., et al.[2018]

In a study of 93 Chinese patients with advanced melanoma treated with PD-1 inhibitors, those who developed immune-related adverse events (irAEs) had significantly higher overall response rates (ORR) and disease control rates (DCR) compared to those without irAEs.

Patients experiencing three or more irAEs showed even better clinical outcomes, including longer progression-free survival and overall survival, suggesting that the presence of irAEs may indicate a more effective immune response to PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma. Zhao, JJ., Wen, XZ., Ding, Y., et al.[2021]

In a study of 249 melanoma patients, immune-related adverse events (irAEs) were observed in 74.6% of patients, with a notable correlation between the occurrence of irAEs and improved treatment outcomes in the non-adjuvant setting.

The frequency of irAEs was high in both treatment settings, but in the adjuvant setting, they did not correlate with disease relapse, suggesting that while irAEs may indicate better efficacy in some cases, they do not universally predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequency, Treatment and Outcome of Immune-Related Toxicities in Patients with Immune-Checkpoint Inhibitors for Advanced Melanoma: Results from an Institutional Database Analysis. Dimitriou, F., Staeger, R., Ak, M., et al.[2021]

Pembrolizumab and nivolumab are effective PD-1 inhibitors for treating metastatic melanoma, showing objective response rates of 26-38% and 31-40% respectively in patients who did not respond to previous treatments.

Both therapies have an acceptable safety profile, with most treatment-related side effects being mild (grade 1 or 2) and manageable, making them viable options for patients with treatment-refractory melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and nivolumab: PD-1 inhibitors for advanced melanoma. Ivashko, IN., Kolesar, JM.[2022]

In a phase II study involving 41 patients with untreated stage III/IV metastatic melanoma, the combination of bempegaldesleukin (BEMPEG) and nivolumab (NIVO) showed a promising objective response rate of 52.6%, with 34.2% achieving complete responses.

The treatment was well-tolerated, with only 17.1% of patients experiencing grade 3 or 4 adverse events, and it resulted in a median progression-free survival of 30.9 months, indicating its potential as an effective first-line therapy for metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. Diab, A., Tykodi, SS., Daniels, GA., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05352672

NCT05352672 | Clinical Study of Fianlimab in Combination ... The study is focused on patients with a type of skin cancer known as melanoma. The aims of the study are to see how effective the combination of fianlimab and ...

2. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/fianlimab-lag-3-inhibitor-combined-libtayor-cemiplimab-shows

Fianlimab (LAG-3 inhibitor) Combined with Libtayo® ... Data demonstrate objective response rates from 56% to 63% across three independent cohorts of advanced melanoma patients.

3. onclive.com onclive.com/view/fianlimab-cemiplimab-demonstrates-persistent-activity-in-advanced-melanoma-independent-of-lag-3-and-pd-l1-status

Fianlimab/Cemiplimab Demonstrates Persistent Activity in ... Fianlimab combined with cemiplimab-rwlc (Libtayo) demonstrated persistent and significant clinical activity in patients with advanced melanoma, irrespective of ...

4. curemelanoma.org curemelanoma.org/blog/clinical-trials-testing-combination-immunotherapy-for-high-risk-and-advanced-melanoma-regenerons-lag-3-program

Clinical Trials Testing Combination Immunotherapy for ... The phase 3 Harmony Melanoma trial (NCT05352672) is assessing how well the combination of fianlimab + cemiplimab works compared to pembrolizumab ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11647203/

First-in-Human Dose-Escalation Study of Fianlimab, an ... Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02172

Phase I Study of Fianlimab, a Human Lymphocyte ... We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38900987/

Phase I Study of Fianlimab, a Human Lymphocyte ... We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06246916

NCT06246916 | A Study With Combinations of Anti-LAG-3 ... The aim of the study is to see how safe and effective the combination of fianlimab and cemiplimab is in treating melanoma, in comparison with the combination ...

9. yalemedicine.org yalemedicine.org/clinical-trials/a-study-with-combinations-of-anti-lag-3-and-anti-pd-1-antibodies-in-adult-participants-with-advanced

R3767-ONC-22122: A Phase 3 Study of Fixed Dose ... The aim of the study is to see how safe and effective the combination of fianlimab and cemiplimab is in treating melanoma, in comparison with ...