What is the recommended 3rd line Tyrosine Kinase Inhibitor (TKI) for a patient with Gastrointestinal Stromal Tumor (GIST) of the stomach who has progressed on imatinib (Gleevec) and sunitinib (Sutent)?

Third-Line TKI for GIST After Imatinib and Sunitinib

Regorafenib 160 mg orally once daily for 21 days of each 28-day cycle is the standard third-line therapy for gastric GIST patients who have progressed on both imatinib and sunitinib. 1

Dosing and Administration

• Standard dose: 160 mg (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle 2
• Take at the same time each day with a low-fat meal (less than 600 calories and less than 30% fat) 2
• Continue treatment until disease progression or unacceptable toxicity 1, 2

Evidence Supporting Regorafenib

The recommendation is based on Level I evidence from a prospective, placebo-controlled, randomized trial that demonstrated:

• Median progression-free survival: 4.8 months with regorafenib versus 0.9 months with placebo (P<0.0001) 1
• Disease control rate: 53% versus 9% for placebo 1
• PFS rates: 60% at 3 months and 38% at 6 months, compared to 11% and 0% respectively for placebo 1
• This carries an ESMO-MCBS v1.1 score of 3, indicating meaningful clinical benefit 1

Mechanism of Action

Regorafenib is a multikinase inhibitor with activity against:

• KIT (the primary driver mutation in GIST) 3, 4
• PDGFR (platelet-derived growth factor receptor) 3, 4
• VEGFR (vascular endothelial growth factor receptor) 3, 4
• Unlike sunitinib, regorafenib demonstrates activity against some KIT secondary mutations in exon 17 1

Toxicity Management

Most common Grade ≥3 adverse events that require proactive management:

• Hypertension (23%) 1
• Hand-foot skin reaction/palmar-plantar erythrodysesthesia (20%) 1, 4
• Diarrhea (5%) 1
• Hepatotoxicity (monitor liver function tests before and during treatment) 2

Dose reduction strategy when toxicities occur 2:

• Reduce in 40 mg increments (one tablet at a time)
• First reduction: 120 mg daily
• Second reduction: 80 mg daily (lowest recommended dose)
• Discontinue permanently if unable to tolerate 80 mg dose 2

Critical Safety Monitoring

Hepatotoxicity warning 2:

• Severe and sometimes fatal hepatotoxicity has occurred in clinical trials
• Most cases occur within the first 2 months of therapy with a hepatocellular pattern of injury 2
• Monitor AST/ALT and bilirubin prior to and during treatment 2
• Discontinue permanently if AST or ALT >20 times ULN, or if AST/ALT >3 times ULN with concurrent bilirubin >2 times ULN 2

Fourth-Line Option

If progression occurs on regorafenib, ripretinib 150 mg daily is the standard fourth-line treatment for patients who have progressed on or are intolerant to imatinib, sunitinib, and regorafenib (Level I evidence, ESMO-MCBS v1.1 score: 3) 1

Alternative Considerations

If regorafenib is not tolerated or unavailable, consider:

• Enrollment in clinical trials (strongly encouraged at this stage) 1
• Imatinib rechallenge may provide symptom palliation in select patients who previously responded, though benefits are modest 1
• Continuation of TKI therapy even with slow progression may be beneficial compared to stopping treatment entirely 1

Common Pitfall to Avoid

Do not use nilotinib as third-line therapy—a randomized Phase III trial showed that nilotinib PFS was not superior to best supportive care (109 vs 111 days; P=0.56) in the general population of patients resistant to imatinib and sunitinib 1. Regorafenib has demonstrated superior efficacy with Level I evidence specifically in this setting 1.