Management of Disease Progression in BRAF V600E Melanoma Patient on Dabrafenib/Trametinib
For a patient with cutaneous melanoma with BRAF V600E mutation showing disease progression on dabrafenib and trametinib therapy, the recommended next step is to switch to an immune checkpoint inhibitor therapy, specifically pembrolizumab or nivolumab/relatlimab combination.
Assessment of Current Situation
The PET/CT findings show clear evidence of disease progression while on BRAF/MEK inhibitor therapy:
- Increased FDG uptake in right hilar region
- New focal intense FDG uptake in L5 midline body
- Increased intensity of prior focus in left sacrum near L5-S1
- New focus of intense uptake in posterior left 11th rib
These findings represent treatment failure on the current regimen of dabrafenib and trametinib, which were started approximately 1 year ago.
Rationale for Treatment Change
Evidence of Progression: The patient has clear radiographic evidence of disease progression on current BRAF/MEK inhibitor therapy 1.
Treatment Resistance: Despite initial effectiveness, approximately 50% of patients on BRAF/MEK inhibitor therapy experience disease progression within 6 months due to acquired resistance 2.
NCCN Guidelines: The NCCN guidelines recommend discontinuing systemic therapy in cases of disease progression and switching to a different class of therapy 1.
Recommended Treatment Algorithm
1. Confirm Progression
- Obtain tissue biopsy of one of the new lesions if clinically feasible to:
- Confirm melanoma progression
- Assess for potential mechanisms of resistance
- Evaluate PD-L1 status if considering immune checkpoint inhibitors
2. Switch to Immune Checkpoint Inhibitor Therapy
- First choice: Pembrolizumab (anti-PD-1) or nivolumab/relatlimab (anti-PD-1/anti-LAG-3) combination 1
- Rationale: Immune checkpoint inhibitors have shown efficacy in patients who have progressed on BRAF/MEK inhibitor therapy 3
3. Consider Brain Imaging
- Given the presence of multiple new metastatic sites, obtain brain MRI to rule out CNS involvement
- Patients with new CNS lesions have significantly shorter survival after progression (median 4.0 months) compared to those with non-CNS progression (median 10.0 months) 2
Special Considerations
Potential for Rechallenge
In select cases, rechallenge with dabrafenib/trametinib after a treatment-free interval may be considered, but this approach should be reserved for patients who:
- Had a prolonged initial response (>6 months)
- Have limited disease progression
- Have exhausted other treatment options 4
Radiation Therapy
- Consider stereotactic body radiation therapy (SBRT) for the L5 and sacral lesions if they are symptomatic or threatening spinal stability
- Radiation can be safely administered concurrently with immune checkpoint inhibitor therapy
Monitoring and Follow-up
- Repeat imaging in 8-12 weeks after initiating new therapy to assess response
- Monitor for immune-related adverse events if switching to checkpoint inhibitor therapy
Caveats and Pitfalls
Pseudoprogression: Rarely, apparent progression on imaging may represent pseudoprogression, particularly with immune checkpoint inhibitors. However, the multiple new lesions in this case strongly suggest true progression.
CNS Progression: Patients with melanoma who develop CNS metastases have poorer outcomes. The dabrafenib/trametinib combination has shown some intracranial activity (39% response rate in treatment-naïve patients) 5, but progression suggests the need for alternative approaches.
Cutaneous Toxicity Management: When switching therapy, be aware that cutaneous adverse effects from dabrafenib/trametinib (including papillomas, palmoplantar hyperkeratosis, and alopecia) may improve, but new immune-related dermatologic toxicities may develop 6.
Treatment Sequencing: While there are no definitive comparative trials on optimal sequencing of BRAF/MEK inhibitors and immunotherapy, the development of progression on targeted therapy necessitates a switch in treatment approach 1.