What is the role of maintenance Bevacizumab (bevacizumab) in patients with gastrointestinal (GI) cancer who have responded to initial chemotherapy and Bevacizumab (bevacizumab) treatment?

Maintenance Bevacizumab in Gastrointestinal Cancer

Maintenance therapy with bevacizumab plus a fluoropyrimidine (capecitabine or 5-FU) is recommended for patients with metastatic colorectal cancer who have achieved stable disease or better after first-line chemotherapy plus bevacizumab, as this approach significantly improves progression-free survival and shows a trend toward improved overall survival. 1

Evidence-Based Maintenance Strategy

Primary Recommendation: Combination Maintenance

The optimal maintenance approach is bevacizumab combined with a fluoropyrimidine rather than bevacizumab alone or observation. 1

• The CAIRO3 trial demonstrated that maintenance with capecitabine/bevacizumab versus observation significantly improved the primary endpoint of PFS2 (time to second progression): 11.7 vs 8.5 months (HR 0.67,95% CI 0.56-0.81, P<0.0001) 1
• Quality of life was not negatively affected by maintenance therapy, though 23% developed hand-foot syndrome 1
• A nonsignificant trend toward improved OS was observed (21.6 vs 18.1 months; HR 0.83,95% CI 0.68-1.01, P=0.06) 1

Bevacizumab Monotherapy as Maintenance

Single-agent bevacizumab maintenance is acceptable but inferior to combination therapy. 1

• The AIO 0207 trial showed that fluoropyrimidine/bevacizumab was superior to no maintenance (time to failure of strategy: 6.9 vs 6.4 months), while bevacizumab alone was noninferior to fluoropyrimidine/bevacizumab but not superior to observation 1
• The SAKK 41/06 trial failed to demonstrate noninferiority of bevacizumab maintenance versus treatment holidays (time to progression: 4.1 vs 2.9 months; HR 0.74,95% CI 0.58-0.96), with no OS difference 1
• A 2021 meta-analysis of individual patient data from three phase III trials (909 patients) showed bevacizumab maintenance improved PFS from induction start (9.6 vs 8.9 months; HR 0.78,95% CI 0.68-0.89, P<0.0001) but provided no OS benefit 2

RAS Status Matters for Bevacizumab Monotherapy

The benefit of single-agent bevacizumab maintenance is limited to RAS wild-type patients. 2

• Subgroup analysis demonstrated significant interaction according to RAS status (p=0.048), with maintenance benefit restricted to RAS wild-type patients 2
• For RAS-mutant patients, fluoropyrimidine-based maintenance is preferred over bevacizumab alone 2

Continuation Beyond First Progression

Bevacizumab should be continued with a different chemotherapy backbone after progression on first-line bevacizumab-containing therapy. 1, 3, 4

• The TML (ML18147) trial showed that continuing bevacizumab with second-line chemotherapy after progression on bevacizumab improved OS (11.2 vs 9.8 months; HR 0.81,95% CI 0.69-0.94, P=0.0062) 1, 3, 4
• The BEBYP trial confirmed these findings with improved PFS (6.7 vs 5.2 months; HR 0.66,95% CI 0.49-0.90, P=0.0072) 1
• Retrospective analysis from US Oncology showed bevacizumab beyond progression was associated with longer OS (HR 0.76,95% CI 0.61-0.95) and post-progression OS (HR 0.74,95% CI 0.60-0.93) 1
• The NCCN guidelines state bevacizumab may be added to any second-line regimen that does not contain an EGFR inhibitor or ziv-aflibercept 1

Practical Implementation Algorithm

Step 1: After First-Line Induction (4-6 months of chemotherapy + bevacizumab)

If stable disease or better:

• First choice: Continue bevacizumab 5 mg/kg IV every 2 weeks + capecitabine or 5-FU until progression 1, 3
• Second choice (if fluoropyrimidine intolerance or cumulative toxicity): Bevacizumab 5 mg/kg IV every 2 weeks alone, particularly if RAS wild-type 1, 2
• Not recommended: Complete treatment holiday (observation alone was inferior in multiple trials) 1

Step 2: At First Progression on Maintenance

Switch chemotherapy backbone while continuing bevacizumab: 1, 3

• If progressed on FOLFOX/bevacizumab → switch to FOLFIRI + bevacizumab 5 mg/kg every 2 weeks 3
• If progressed on FOLFIRI/bevacizumab → switch to FOLFOX + bevacizumab 1
• The appropriate bevacizumab dose in second-line is 5 mg/kg (EAGLE trial showed no difference between 5 and 10 mg/kg) 1

Step 3: At Second Progression

Third-line options include: 4

• Regorafenib 160 mg orally daily, days 1-21 of 28-day cycles 4
• Trifluridine/tipiracil 35 mg/m² twice daily, days 1-5 and 8-12 every 28 days, preferably with bevacizumab 4

Critical Pitfalls to Avoid

Do not use single-agent bevacizumab without chemotherapy in first-line or second-line settings (E3200 trial showed inferior efficacy compared to chemotherapy alone or chemotherapy plus bevacizumab) 1

Do not combine bevacizumab with EGFR inhibitors (cetuximab or panitumumab) as they should not be used together 1

Do not rechallenge with the same chemotherapy backbone that the patient has already progressed on 4

Do not use bevacizumab in adjuvant colon cancer as two large randomized trials (BO17920 and NSABP-C-08) demonstrated lack of efficacy and potential harm, with hazard ratios for OS of 1.31 and 0.96 respectively 5

Toxicity Considerations

Monitor for bevacizumab-specific adverse events during maintenance: 5

• Hypertension (most common, occurring in 12-28% depending on regimen) 5
• Proteinuria (7-20% incidence) 5
• Hemorrhage/epistaxis (3-27% incidence) 5
• Thromboembolic events (3-9% incidence) 5
• Hand-foot syndrome occurs in 23% when combined with capecitabine 1

Bevacizumab discontinuation rates due to adverse events range from 8-22% across studies, with maintenance therapy generally well-tolerated 5

Special Populations

For elderly patients or those with cumulative toxicity: Single-agent bevacizumab maintenance is acceptable, particularly in RAS wild-type patients, though combination therapy remains superior when tolerable 6, 2

For gastric cancer: Limited evidence exists for maintenance bevacizumab, though case reports suggest potential benefit when combined with low-dose S-1 in heavily pretreated patients 6