Can dabrafenib (BRAF inhibitor) or trametinib (MEK inhibitor) cause acute pancreatitis, and what is the recommended management if it occurs?

Acute Pancreatitis from Dabrafenib and Trametinib

Yes, both dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) can cause acute pancreatitis, though this is a rare but potentially life-threatening adverse event that requires immediate drug discontinuation. 1, 2

Evidence for Drug-Induced Pancreatitis

BRAF Inhibitors (Dabrafenib)

• BRAF inhibitors paradoxically activate RAS signaling in BRAF-wild-type cells, which may lead to rare adverse effects including pancreatitis. 1
• Dabrafenib-induced pancreatitis has been documented in case reports, with patients experiencing sudden deep abdominal pain and elevated serum lipase after several months of therapy. 2
• The mechanism involves paradoxical MAPK pathway activation in non-target cells, similar to the pathway that causes secondary cutaneous malignancies. 1

MEK Inhibitors (Trametinib)

• While the guideline evidence specifically mentions pancreatitis as a rare adverse effect of BRAF inhibitors, trametinib in combination with dabrafenib has also been implicated in drug-induced pancreatitis cases. 2
• The combination therapy may compound the risk through dual MAPK pathway effects. 2

Clinical Recognition and Diagnosis

Presenting Features

• Sudden onset of deep epigastric abdominal pain, often radiating to the back 2
• Elevated serum lipase (typically >3 times upper limit of normal) 2
• Radiological findings consistent with acute pancreatitis on CT or ultrasound 2
• Symptoms may include nausea, vomiting, and fever 2

Timing

• Pancreatitis can occur after several months of therapy (reported at 4 months in documented cases) 2
• Onset is typically acute and requires emergency evaluation 2

Management Algorithm

Immediate Actions

1. Permanently discontinue both dabrafenib and trametinib immediately upon diagnosis of acute pancreatitis. 2
2. Admit to hospital for supportive care including:
   • Analgesia for pain control 2
   • Intravenous fluids to maintain urine output >0.5 ml/kg body weight 1
   • Oxygen supplementation to maintain arterial saturation >95% 1
   • Antibiotics if infection is suspected 2
3. Rule out other causes of pancreatitis (gallstones, alcohol, hypertriglyceridemia, other medications) 2

Monitoring

• Serial lipase measurements 2
• Clinical assessment for resolution of abdominal pain 2
• Radiological follow-up to assess for complications (necrosis, pseudocyst, fluid collections) 2
• Monitor for signs of severe pancreatitis including persistent organ failure 1

Treatment Decisions

• Do not rechallenge with either dabrafenib or trametinib after drug-induced pancreatitis—permanent discontinuation is required. 2
• Consider alternative melanoma therapies such as immunotherapy (anti-PD-1 antibodies) if oncologic treatment must continue 2
• Most patients experience symptom improvement within days of drug discontinuation with appropriate supportive care 2

Important Caveats

Risk-Benefit Discussion

• A careful discussion of the risks and benefits of ongoing BRAF/MEK inhibitor treatment is warranted given the potential for rare but serious adverse effects. 1
• While these agents show robust clinical activity (69% response rate in some malignancies), the risk of life-threatening complications like pancreatitis must be weighed against oncologic benefit 3

Differential Diagnosis Pitfall

• Do not assume all abdominal pain in patients on targeted therapy is drug-related—systematically exclude other common causes of pancreatitis including biliary disease, alcohol, and hypertriglyceridemia 2
• Other serious adverse events from this drug combination include rhabdomyolysis, renal failure, and visual disturbances, which may present with overlapping symptoms 4

Severity Assessment

• Patients with persistent organ failure (>48 hours) have the highest mortality risk and require ICU admission 1
• Early aggressive fluid resuscitation and oxygen therapy should be initiated for all patients until disease severity is established 1