Naporafenib + Trametinib for Melanoma

Recruiting at 58 trial locations

Overseen By Erasca Clinical Team

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Erasca, Inc.

Must be taking: Anti-PD-1/L1

Must not be taking: ERK-, MEK-, RAF-, RAS-inhibitors

Disqualifiers: Uveal melanoma, GI disease, 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

470 Participants Needed

Trial Summary

What is the purpose of this trial?

Stage 1: To select the optimal dose of naporafenib + trametinib to be studied in Stage 2. Stage 2: To compare progression free survival (PFS) and overall survival (OS) for patients with NRAS-mutant (NRASm) melanoma who are randomized to receive the combination of naporafenib + trametinib to that of patients who are randomized to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take herbal medicines known to cause liver toxicity starting 7 days before the trial and during the study.

What data supports the effectiveness of the drug combination Naporafenib + Trametinib for melanoma?

Research shows that a similar drug combination, dabrafenib plus trametinib, is effective for treating metastatic melanoma with a specific mutation (BRAF V600). This combination has been shown to improve survival and allow for surgical removal of tumors in some cases. ^{1 2 3 4 5}

Is the combination of Naporafenib and Trametinib safe for humans?

The combination of dabrafenib and trametinib, similar to Naporafenib and Trametinib, has been studied for safety in melanoma patients. Most side effects are mild to moderate and manageable, with common ones including fever, increased liver enzymes, and swelling. These findings suggest that the combination is generally safe for human use. ^{6 7 8 9 10}

What makes the drug combination of Naporafenib and Trametinib unique for treating melanoma?

The combination of Naporafenib and Trametinib is unique because it targets two different pathways involved in melanoma growth, potentially offering a more comprehensive approach to treatment compared to using a single drug. While Trametinib is a MEK inhibitor, Naporafenib's role in this combination is still being explored, which could provide new insights into treating melanoma. ^{1 7 9 11 12}

Research Team

Joyce Antal

Principal Investigator

Clinical Development

Eligibility Criteria

This trial is for adults over 18 with unresectable or metastatic cutaneous melanoma, including acral type, that has an NRAS mutation. Participants must have progressed on anti-PD-1/L1 therapy within the last 6 months and be able to take oral medication. They need at least one measurable lesion and a performance status of 0, 1, or 2.

Inclusion Criteria

I can care for myself and am up and about more than 50% of my waking hours.

My melanoma cannot be removed by surgery and may have spread.

Presence of at least 1 measurable lesion according to RECIST v1.1

Exclusion Criteria

I am not on drugs that strongly affect liver enzymes.

I have been treated with drugs targeting ERK, MEK, RAF, or RAS.

I do not have severe GI issues that could affect medication absorption.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Optimization (Stage 1)

To select the optimal dose of naporafenib + trametinib to be studied in Stage 2

4 weeks

Multiple visits for dose adjustment and monitoring

Treatment (Stage 2)

Participants receive either naporafenib + trametinib or physician's choice of therapy

24 months

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Naporafenib
• Trametinib

Trial Overview The study is in two stages: first to find the best dose of naporafenib plus trametinib; second to see if this combo improves survival compared to standard treatments (dacarbazine, temozolomide, or just trametinib) in patients with NRAS-mutant melanoma.

Participant Groups

Group I: Stage 2 Arm A Experimental Treatment 2 Interventions

Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1

Group II: Stage 1 Dose selection Lead-in Arm 2 Experimental Treatment 2 Interventions

Naporafenib + Trametinib Naporafenib (ERAS-254) 400 mg administered orally twice daily (BID) Trametinib 0.5 mg once daily (QD)

Group III: Stage 1 Dose selection Lead-in Arm 1 Experimental Treatment 2 Interventions

Naporafenib + Trametinib Naporafenib (ERAS-254) 100 mg administered orally twice daily (BID) Trametinib 1 mg once daily (QD)

Group IV: Stage 2 Arm B - Physician's Choice Active Control 3 Interventions

* Dacarbazine 1000 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle OR * Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle OR * Trametinib monotherapy, 2 mg PO QD

Group V: Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy Active Control 1 Intervention

Trametinib 2 mg once daily (QD)

Who Is Running the Clinical Trial?

Erasca, Inc.

Lead Sponsor

Trials

8

Recruited

1,200+

Findings from Research

In a long-term study of 60 Chinese patients with unresectable or metastatic BRAF V600-mutant melanoma, the combination of dabrafenib and trametinib resulted in a high objective response rate of 71.7% and a median duration of response of 7.5 months.

The 3-year overall survival rate was 28.8%, with better outcomes observed in patients with acral melanoma (35.7%), and factors like normal lactic dehydrogenase levels and fewer metastatic sites were linked to improved survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival of Patients With Unresectable or Metastatic BRAF V600-Mutant Acral/Cutaneous Melanoma Administered Dabrafenib Plus Trametinib: Long-Term Follow-Up of a Multicenter, Single-Arm Phase IIa Trial. Mao, L., Ding, Y., Bai, X., et al.[2022]

In a study of 66 patients with metastatic BRAF-mutated melanoma treated with dabrafenib and trametinib, 15 patients achieved a complete response (CR), indicating a significant survival benefit from this treatment.

The likelihood of achieving a complete response was higher in patients with smaller lesions (39.3% CR rate) compared to those with larger lesions (10.5% CR rate), suggesting that lesion size and the number of metastatic sites are important factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. Ribero, S., Malavenda, O., Fava, P., et al.[2019]

In a phase II trial involving 21 patients with unresectable locally advanced melanoma, neoadjuvant treatment with dabrafenib and trametinib enabled radical surgical resection in 86% of participants, with 81% achieving complete (R0) resection.

The median recurrence-free survival for patients who underwent surgery was 9.9 months, indicating that this combination therapy is a promising option for patients with previously inoperable melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial. Blankenstein, SA., Rohaan, MW., Klop, WMC., et al.[2021]

Combination therapy with dabrafenib and trametinib for BRAF-mutated metastatic melanoma showed a high overall response rate, with 64.6% of patients achieving a partial response and 6.2% achieving a complete response, indicating its efficacy in treating this condition.

The treatment was found to be relatively safe, with only 8.3% of patients experiencing severe adverse events, and 62.5% of patients remained on treatment, suggesting good tolerability in a real-life clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience. Cavalieri, S., Di Guardo, L., Cimminiello, C., et al.[2017]

In a study of 78 BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma treated with dabrafenib and trametinib, the median overall survival was over 2 years, with 72% of patients alive at 1 year and 47% at 3 years.

Approximately 20% of patients were progression-free at 3 years, with better outcomes associated with having fewer than three organ metastases and lower baseline lactate dehydrogenase levels, suggesting these factors may help predict durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. Long, GV., Weber, JS., Infante, JR., et al.[2022]

The combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib significantly improves outcomes for metastatic melanoma patients compared to single-agent therapies, with a manageable safety profile.

While 98% of patients experience at least one adverse event during combination therapy, these events are mostly mild to moderate and can be effectively managed, highlighting the importance of addressing even minor side effects to maintain patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Knispel, S., Zimmer, L., Kanaki, T., et al.[2017]

In a study of 77 East Asian patients with advanced BRAF V600-mutant cutaneous melanoma, the combination of dabrafenib and trametinib showed a high objective response rate of 61%, indicating significant efficacy in treating this patient population.

The treatment was generally well-tolerated, with the most common adverse event being pyrexia (fever) occurring in 56% of patients, and serious adverse events were reported in 38%, suggesting that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. Si, L., Zhang, X., Shin, SJ., et al.[2020]

The combination of dabrafenib and trametinib showed promising antitumor activity in Japanese patients with BRAF V600E/K mutant melanoma, with an overall response rate of 83% in both phase 1 and phase 2 of the study involving 12 patients.

The treatment was generally well-tolerated, with common adverse events including fever (75%) and increased liver enzymes (67%), indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. Yamazaki, N., Tsutsumida, A., Takahashi, A., et al.[2018]

The combination of dabrafenib and trametinib significantly improves progression-free survival and overall survival in patients with unresectable or metastatic melanoma with a BRAF (V600E/K) mutation, compared to monotherapy with dabrafenib or vemurafenib, based on results from two large phase III studies.

This combination therapy is well-tolerated, showing no increase in overall toxicity compared to monotherapy, and results in fewer skin-related adverse events, likely due to reduced activation of the MAPK pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. Dhillon, S.[2022]

In a study involving 112 Japanese patients with unresectable and metastatic melanoma, the combination therapy of dabrafenib and trametinib showed a significant objective response rate of 55.45%, indicating its efficacy in treating BRAF V600 mutation-positive melanoma.

The safety profile of the combination therapy was consistent with previous trials, with 75% of patients experiencing adverse drug reactions, the most common being pyrexia and hepatic function abnormalities, but no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation. Teshima, Y., Kizaki, M., Kurihara, R., et al.[2022]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

In a phase 3 trial involving 870 patients with resected stage III melanoma and BRAF V600 mutations, the combination of dabrafenib and trametinib significantly improved relapse-free survival, with a 3-year rate of 58% compared to 39% for the placebo group.

The combination therapy also showed a higher overall survival rate of 86% versus 77% in the placebo group, indicating its efficacy without introducing new safety concerns, as the safety profile was consistent with previous studies in metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long, GV., Hauschild, A., Santinami, M., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Overall Survival of Patients With Unresectable or Metastatic BRAF V600-Mutant Acral/Cutaneous Melanoma Administered Dabrafenib Plus Trametinib: Long-Term Follow-Up of a Multicenter, Single-Arm Phase IIa Trial. [2022]

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

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. [2019]

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

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial. [2021]

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

Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience. [2017]

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

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. [2022]

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

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. [2017]

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

Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. [2018]

9. France pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation. [2022]

11. France pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

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

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. [2023]