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Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma
M Amini-Adle1, N Khanafer2, M Le-Bouar3
1Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon 1 University, 165 Chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France. mona.amini-adle@chu-lyon.fr.
Background:
Anti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as first-line treatments in advanced melanoma. To date, no prospective data are available to give the best sequence of treatment. The objective of this study was to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or chemotherapy failure.
Methods:
This was a single institution cohort analysis in patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy failure. Melanoma evolution after anti-PD-1 initiation was analyzed in BRAF-mutated and BRAF wild-type patients. The efficacy of treatment was evaluated by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).
Results:
Seventy-four patients were included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF mutated group (2 vs. 5 months and 7 vs. 20 months, p = 0.001). The hazard ratio for disease progression was of 2.3 (95%CI:1.3-3.9; p = 0.003) and 2.5 (95%CI:1.3-4.5; p = 0.005) for death. Thirty-nine percent of BRAF-mutated-patients died within 3 months after anti-PD-1 initiation. Rapid death (≤3 months) was significantly higher in BRAF-mutated patients (55.2% vs. 20.0%, p = 0.014).
Discussion:
This is the largest series of unselected patients treated in real-life with anti-PD-1 as second-or-higher line of treatment. Anti-PD-1 was less effective in BRAF-mutated cases as a majority of patients presented aggressive tumor evolution after BRAFi discontinuation. These data are consistent with previous studies suggesting a negative impact of BRAFi prior to immunotherapy.
Insights
Anti-PD-1 immunotherapy is less effective in advanced melanoma patients with BRAF mutations after BRAF-inhibitor treatment. This real-world study found BRAF-mutated patients had poorer outcomes with anti-PD-1 therapy.
Area of Science:
- Oncology
- Immunotherapy
- Melanoma Research
Background:
- Advanced melanoma treatment involves anti-PD-1 and BRAF-inhibitors (BRAFi).
- Optimal sequencing of these treatments remains unclear.
- Real-world data on anti-PD-1 efficacy after prior therapies are limited.
Purpose of the Study:
- To evaluate the real-world effectiveness of anti-PD-1 therapy in advanced melanoma patients following failure of BRAFi, ipilimumab, or chemotherapy.
- To compare outcomes between BRAF-mutated and BRAF wild-type melanoma patients receiving anti-PD-1 therapy.
- To analyze melanoma progression and survival after initiating anti-PD-1 treatment.
Main Methods:
- A single-institution cohort analysis of 74 advanced melanoma patients treated with anti-PD-1 after prior therapy failure.
- Analysis of melanoma evolution, Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).
- Stratification of patients based on BRAF mutation status (mutated vs. wild-type).
Main Results:
- Anti-PD-1 Objective Response Rate was significantly lower in BRAF-mutated patients (12.2%) compared to wild-type (45.5%).
- BRAF-mutated patients experienced significantly shorter median Progression-Free Survival (2 vs. 5 months) and Overall Survival (7 vs. 20 months).
- Higher rates of rapid death (≤3 months) were observed in BRAF-mutated patients (55.2%) compared to wild-type (20.0%).
Conclusions:
- Anti-PD-1 therapy demonstrates reduced efficacy in BRAF-mutated melanoma patients as a second-line or later treatment.
- BRAF-mutated patients often exhibit aggressive tumor evolution after BRAF-inhibitor discontinuation, impacting immunotherapy response.
- Findings suggest a potential negative impact of prior BRAF-inhibitor treatment on subsequent anti-PD-1 immunotherapy effectiveness in advanced melanoma.
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