What is the role of immunotherapy, such as pembrolizumab (anti-PD-1 antibody), in the treatment of advanced gallbladder cancer?

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, p=0.0034) compared to chemotherapy alone. 1

First-Line Treatment Approach

For treatment-naïve patients with advanced gallbladder cancer, pembrolizumab 200 mg IV every 3 weeks should be added to standard gemcitabine (1000 mg/m² on days 1 and 8) plus cisplatin (25 mg/m² on days 1 and 8) chemotherapy. 1 This combination represents the only Level 1 evidence for immunotherapy in this disease and should be considered the standard of care regardless of PD-L1 status. 1

• The KEYNOTE-966 trial established this regimen with a median overall survival of 12.7 months versus 10.9 months for chemotherapy alone (HR 0.83,95% CI 0.72-0.95). 1
• Pembrolizumab can be continued for a maximum of 35 cycles (approximately 2 years), while gemcitabine has no maximum duration and cisplatin is limited to 8 cycles. 1
• The safety profile was manageable, with grade 3-4 adverse events occurring in 79% of pembrolizumab-treated patients versus 75% with chemotherapy alone. 1

Biomarker Testing Considerations

While the KEYNOTE-966 trial did not require PD-L1 testing for enrollment, PD-L1 expression levels can provide prognostic information for treatment response, particularly in the refractory setting. 2, 3

• PD-L1 tumor proportion score (TPS) ≥50% is associated with significantly higher response rates to pembrolizumab monotherapy (37.5% vs 6.5% for TPS <50%, p=0.049). 2
• In patients treated with pembrolizumab monotherapy after chemotherapy failure, high PD-L1 expression (≥50%) yielded an objective response rate of 56% compared to only 6% in low PD-L1 expressors (p=0.004). 3
• Microsatellite instability-high (MSI-H) status is rare in biliary tract cancers (approximately 1.4% prevalence) and should not be relied upon as a primary biomarker for treatment selection. 3

Second-Line and Beyond Treatment Options

For patients who have progressed on first-line gemcitabine-cisplatin chemotherapy, pembrolizumab monotherapy can be considered, with efficacy strongly dependent on PD-L1 expression levels. 2, 3

• In PD-L1-positive patients who progressed on gemcitabine-cisplatin, pembrolizumab 200 mg IV every 3 weeks achieved an objective response rate of 10-12.5% with a median duration of response of 6.3 months. 2
• Median progression-free survival was 1.5 months and overall survival was 4.3 months in heavily pretreated patients. 2
• Patients with high PD-L1 expression (TPS ≥50%) demonstrated substantially better outcomes and should be prioritized for pembrolizumab monotherapy. 2, 3

Alternative PD-1 Inhibitor Strategies

For patients unable to access pembrolizumab or in combination regimens, camrelizumab represents an alternative PD-1 inhibitor with demonstrated activity in gallbladder cancer. 4, 5

• Camrelizumab combined with apatinib (a VEGFR-2 inhibitor) achieved disease control rates of 90.9% at 3 months and 45.5% at 6 months in advanced gallbladder cancer. 4
• Camrelizumab plus chemotherapy showed disease control rates of 85.7% at 3 months and 71.4% at 6 months, with median progression-free survival of 9 months and overall survival of 13 months. 4
• Camrelizumab monotherapy has limited efficacy (median PFS 3 months, OS 8 months) and should be reserved for patients intolerant to combination therapy. 4, 5

Critical Safety Monitoring

Grade 3 or higher adverse events occur in approximately 79% of patients receiving pembrolizumab plus chemotherapy, requiring vigilant monitoring and management. 1

• Treatment-related deaths occurred in 2% of pembrolizumab-treated patients versus 1% with chemotherapy alone. 1
• Common adverse events include fatigue, musculoskeletal pain, and rash, with immune-related adverse events requiring prompt recognition and corticosteroid management. 1
• Grade 1-2 adverse events are manageable in most patients, with grade 3 or higher events occurring in approximately 6% of patients on pembrolizumab monotherapy. 2, 5

Important Clinical Caveats

Pseudoprogression can occur with immunotherapy, and patients showing initial progression may subsequently achieve complete response (5% of progressive disease cases). 2 This phenomenon necessitates careful clinical judgment before discontinuing therapy in patients with apparent radiographic progression who remain clinically stable.

The evidence base for immunotherapy in gallbladder cancer is substantially weaker than for gastroesophageal cancers, where PD-L1 stratification algorithms are well-established. 6 However, the KEYNOTE-966 trial provides the strongest evidence to date for first-line immunotherapy in biliary tract cancers, including gallbladder cancer. 1