Immunotherapy in Advanced Gallbladder Cancer
Pembrolizumab combined with gemcitabine and cisplatin is the recommended first-line treatment for advanced gallbladder cancer, demonstrating a significant overall survival benefit (12.7 vs 10.9 months, HR 0.83) compared to chemotherapy alone. 1
First-Line Treatment Approach
For patients with previously untreated, unresectable, locally advanced or metastatic gallbladder cancer:
Pembrolizumab 200 mg IV every 3 weeks (maximum 35 cycles) combined with gemcitabine (1000 mg/m² IV on days 1 and 8 every 3 weeks) and cisplatin (25 mg/m² IV on days 1 and 8 every 3 weeks, maximum 8 cycles) is the standard of care 1
This regimen achieved a statistically significant and clinically meaningful improvement in overall survival with a hazard ratio of 0.83 (95% CI 0.72-0.95, p=0.0034) 1
The FDA approved durvalumab (a PD-L1 inhibitor) in combination with chemotherapy for adult patients with locally advanced or metastatic gallbladder cancer in September 2022, marking the first FDA approval for immunotherapy in biliary tract cancers 2
Role of PD-L1 Testing
PD-L1 expression serves as a predictive biomarker for immunotherapy response in gallbladder cancer:
High PD-L1 expression (≥50%) is associated with significantly better response rates to pembrolizumab: 56% overall response rate in high PD-L1 expressors versus 6% in low PD-L1 expressors (p=0.004) 3
Disease control rate is substantially higher in patients with high PD-L1 expression: 78% versus 35% (p=0.019) 3
Among biliary tract cancer patients, 71% show tumoral PD-L1 positivity (≥1%), making this a relevant biomarker for patient selection 3
Microsatellite instability-high (MSI-H) status is rare in gallbladder cancer (1.4% of patients), limiting its utility as a predictive biomarker 3
Second-Line and Beyond
For patients who have progressed on first-line chemotherapy:
PD-1 inhibitors (pembrolizumab, nivolumab, sintilimab, toripalimab) combined with chemotherapy demonstrate superior progression-free survival compared to chemotherapy alone: 5.8 months versus 3.2 months (HR 0.47,95% CI 0.29-0.76, p=0.004) 4
Objective response rate with PD-1 inhibitor plus chemotherapy is 21.7% with a disease control rate of 80.4% 4
For patients with advanced gallbladder cancer receiving PD-1 inhibitors, the median progression-free survival is 7 months and median overall survival is 12 months 5
Combination Strategies
PD-1 inhibitors combined with targeted therapy or chemotherapy are more effective than immunotherapy alone:
Camrelizumab plus apatinib (targeted therapy) achieved disease control rates of 90.9% at 3 months and 45.5% at 6 months (p=0.003) 5
Camrelizumab plus chemotherapy achieved disease control rates of 85.7% at 3 months and 71.4% at 6 months (p=0.450) 5
Both combination approaches demonstrated superior median progression-free survival (6 months and 9 months respectively) compared to camrelizumab monotherapy (3 months, p<0.001) 5
Median overall survival was also superior with combination therapy: 12 months and 13 months versus 8 months with monotherapy (p=0.019 and p<0.001 respectively) 5
Safety Profile
Immunotherapy combinations demonstrate manageable toxicity:
Grade 3-4 treatment-related adverse events occur in 70% of patients receiving pembrolizumab plus gemcitabine and cisplatin, similar to the 69% rate with chemotherapy alone 1
Treatment-related deaths occurred in 2% of patients receiving pembrolizumab combination versus 1% with chemotherapy alone 1
Common immune-related adverse events include hypothyroidism (6.5%), rash (4.2%), and hepatitis (2.2%) 4
Grade 3-4 leukopenia rates are comparable between immunotherapy combinations and chemotherapy alone (4.3% vs 6.5%) 4
Most adverse events are grade 1-2, with only 3 cases of grade 3 or higher adverse events reported in some series 5
Clinical Pitfalls
Important considerations when using immunotherapy for gallbladder cancer:
Immune checkpoint inhibitor monotherapy is associated with low objective response rates due to the immune-suppressed microenvironment characteristic of most biliary tract cancers 1
The benefit of immunotherapy is driven primarily by patients with higher PD-L1 expression, making biomarker testing essential for optimal patient selection 3
Targeted therapy combinations show more obvious early effects on disease control rate, while chemotherapy combinations achieve more sustained effects, suggesting potential for sequential therapy approaches 5