Oncological Adjuvant Trials in Melanoma

5 Key Points

These major adjuvant oncological trials in melanoma, which were based on the previous AJCC 7th Edition for Staging Melanoma, showed a significant survival benefit in patients with completely resected stage III disease. This can be summarised in 5-Key Points.

1. EORT 18,201 showed a significant survival benefit with adjuvant ipilimumab.
2. CheckMate 238 showed a significant survival benefit of adjuvant nivolumab over ipilimumab.
3. Combi-AD showed a significant survival benefit of adjuvant dabrafenib + trametinib in BRAF+ disease.
4. EORTC 1325/KeyNote 054 showed a significant survival benefit of adjuvant Pembrolizumab.
5. BRIM-8^​ showed a modest survival benefit of adjuvant vemurafenib in Stage 2C-3C disease.

EORTC 18,701

Eggermont et al^​1​ phase 3 trial in 2016 showed significant survival benefit at 5-years for adjuvant ipilimumab (checkpoint inhibitor) in Stage 3A-3C disease.

Background

• A phase 3 study following up from the data of a phase 2 trial( ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram)
• This phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.

Methods

• Patients had undergone complete resection of stage III cutaneous melanoma
• Random assignment to ipilimumab (475 patients) or placebo (476) medication.
• For up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred.
• Primary Endpoint: Recurrence-free survival.
• Secondary Endpoints: overall survival, distant metastasis–free survival, and safety.

Results

• Median follow-up of 5.3 years,
• Recurrence-free survival: Ipilimumab was 40.8%, placebo was 30.3%.
• Overall survival: Ipilimumab was 65.4%, placebo was 54.4%.
• Rate of distant metastasis: Ipilimumab was 48.3%, placebo was 38.9%.
• 1.1% treatment related death in the Ipilimumab group.

Conclusion

Ipilimumab adjuvant therapy results in significantly higher rates of

• Recurrence-free survival
• Overall survival
• Distant metastasis–free survival.

There were more immune-related adverse events with ipilimumab than with placebo.

CheckMate 238

Webster et al^​2​ in 2018 showed a significant relapse-free survival benefit of nivolumab over ipilimumab in resected Stage 3b-4 disease.

Methods

• Patients were ≥15 yrs with complete resection of stage IIIB/C or IV melanoma,
• 906 patients were randomised to treat nivolumab over ipilimumab.
• Primary endpoint was relapse free survival.

Results

• 24-month follow-up
• Relapse-Free Survival: NIVO 171/453, IPI 221/453
• Distant Metastasis-Free Survival: NIVO 70.5% and IPI 63.7%

Conclusion

• NIVO demonstrated a sustained efficacy benefit vs IPI in pts with resected stage III/IV melanoma at high risk of recurrence, regardless of disease stage, PD-L1 expression, or BRAF mutation status.
• Adjuvant Nivolumab is approved by the EMA and by NICE for patients with resected 3A-4 disease.

Combi-AD

The Combi-AD study^​3​ showed a 47% reduction in risk of developing metastasis, or death in the group treated with dabrafenib + trametinib. This was adjuvant treatment for BRAF positive resected 3A-3C disease.

Background

• Combination therapy with BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in advanced BRAF+ melanoma.
• Aim is to determine if adjuvant dabrafenib+trametinib improve outcomes in resected, stage III BRAF+ melanoma

Methods

• Double-blind, placebo-controlled, phase 3 trial,
• Patients had completely resected, stage III melanoma with BRAF V600E or V600K mutations.
• Primary endpoint: relapse-free survival
• Secondary endpoints: overall survival, distant metastasis–free survival, freedom from relapse, and safety.

Results

• Median follow-up of 2.8 years with 840 randomised patients.
• 3-year relapse-free survival: 59% in combination therapy, 39% placebo
• 3-year overall survival: 86% in combination therapy, 77% placebo.
• Safety profile of dabrafenib plus trametinib was consistent with normal standards.

Conclusion

• Adjuvant use of dabrafenib + trametinib significantly lowers risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations.
• It was not associated with new toxic effects

EORTC 1325/KeyNote 054

This study^​4​ showed the role of Pembrolizumab (a PD-1 inhibitor) to increase relapse free survival in high-risk completely resected stage III melanoma patients.

Background

• Pembrolizumab (programmed death 1 (PD-1) inhibitor) prolongs progression-free and overall survival among patients with advanced melanoma.
• Aim to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma in a phase 3 double-blind trial.

Methods

• Patients with completely resected stage III melanoma were randomly assigned to pembrolizumab (514 patients) or placebo (505 patients)
• Primary endpoints: Recurrence-free survival

Results

• Median follow-up of 15 months,
• Recurrence-free survival: Pembrolizumab 75.4%, placebo 61%.
• 14.7% of the patients in the pembrolizumab group had adverse effects, with one treatment-related death due to myositis in the pembrolizumab group.

Conclusion

• As adjuvant therapy for high-risk stage III melanoma, pembrolizumab significantly increases recurrence-free survival than placebo, with no new toxic effects identified.

Brim-8 Study

The BRIM8 study^​5​ examined the role of the adjuvant vemurafenib in Stage 2C-3C disease. This showed a modest impact on RFS and is not being taken forward.

Background

• Hypothesis: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma.
• Aim: Evaluate adjuvant vemurafenib monotherapy in patients with resected, BRAF ^V600 mutation-positive melanoma.

Methods

• Phase 3, international, double-blind, randomised, placebo-controlled study
• 498 adults with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF ^V600 mutation-positive melanoma that was fully resected.
• Patients were randomly assigned to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles).
• Primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort.

Outcome

• The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival must be considered exploratory only.
• 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.

References

1. 1. Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. November 2016:1845-1855. doi:10.1056/nejmoa1611299
2. 2. Weber JS, Mandalà M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). JCO. May 2018:9502-9502. doi:10.1200/jco.2018.36.15_suppl.9502
3. 3. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage IIIBRAF-Mutated Melanoma. N Engl J Med. November 2017:1813-1823. doi:10.1056/nejmoa1708539
4. 4. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. May 2018:1789-1801. doi:10.1056/nejmoa1802357
5. 5. Maio M, Lewis K, Demidov L, et al. Adjuvant vemurafenib in resected, BRAF V600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. The Lancet Oncology. April 2018:510-520. doi:10.1016/s1470-2045(18)30106-2