What is the role of immunotherapy, including checkpoint inhibitors like pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of gallbladder cancer?

Immunotherapy in Gallbladder Cancer

For patients with advanced or metastatic gallbladder cancer, first-line treatment should be gemcitabine and cisplatin combined with either durvalumab or pembrolizumab, as this combination significantly improves overall survival compared to chemotherapy alone. 1

First-Line Treatment for Advanced/Metastatic Disease

The standard of care has evolved based on two landmark phase III trials demonstrating survival benefit with immune checkpoint inhibitors added to chemotherapy:

Durvalumab-Based Regimen

• The TOPAZ-1 trial established durvalumab plus gemcitabine/cisplatin as superior to chemotherapy alone 1
• For gallbladder cancer patients specifically (n=65 in treatment arm, n=66 in control), the hazard ratio for overall survival was 0.61 (95% CI 0.41-0.91), representing a substantial mortality reduction 1
• Median overall survival improved from 11.3 months to 12.9 months in the overall biliary tract cancer population 1
• This combination received FDA and EMA approval for locally advanced unresectable or metastatic biliary tract cancers, including gallbladder cancer 1, 2

Pembrolizumab-Based Regimen

• The KEYNOTE-966 trial demonstrated pembrolizumab plus gemcitabine/cisplatin improved overall survival with a hazard ratio of 0.83 (95% CI 0.72-0.95; p=0.0034) 1, 3
• Median overall survival was 12.7 months versus 10.9 months with chemotherapy alone 3
• However, the benefit in extrahepatic cholangiocarcinoma subgroup (which includes gallbladder cancer) showed HR 0.99 (95% CI 0.73-1.35), suggesting the benefit was primarily driven by intrahepatic cholangiocarcinoma patients 1
• Despite this, the combination received FDA and EMA approval for all biliary tract cancers 1

Treatment Selection Algorithm

Choose durvalumab over pembrolizumab for gallbladder cancer based on the stronger subgroup-specific data showing HR 0.61 for extrahepatic cholangiocarcinoma (which includes gallbladder cancer) versus HR 0.99 for pembrolizumab in the same population 1

Second-Line Treatment Options

After Progression on First-Line Therapy

• FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil) should be offered as the preferred second-line option based on the ABC-06 trial showing overall survival benefit (HR 0.69; 95% CI 0.50-0.97; p=0.031) 1
• For the gallbladder cancer subgroup in ABC-06, the hazard ratio was 0.84 (95% CI 0.45-1.57), showing a trend toward benefit 1
• Alternative irinotecan-based regimens can be considered based on phase II data, though evidence is less robust 1

Role of PD-L1 Testing

PD-L1 testing may help predict response but should not exclude patients from immunotherapy:

• High PD-L1 expression (≥50%) was associated with 56% response rate to pembrolizumab versus 6% in low expressors (p=0.004) in advanced biliary tract cancer 4
• Disease control rate was also superior in high PD-L1 expressors (78% vs. 35%, p=0.019) 4
• However, responses occurred across all PD-L1 expression levels in the TOPAZ-1 and KEYNOTE-966 trials, supporting treatment regardless of PD-L1 status 1, 3

Microsatellite Instability Testing

MSI-High/dMMR testing should be performed, though prevalence is extremely low:

• Only 1.4% of biliary tract cancers demonstrate MSI-High status 4
• Pembrolizumab is FDA-approved for MSI-High/dMMR solid tumors including gallbladder cancer, independent of PD-L1 expression 5
• This represents a rare but important subset that may derive substantial benefit 5

Safety Considerations

The safety profile of immunotherapy combinations is manageable:

• Grade 3-4 adverse events occurred in 79% with pembrolizumab combination versus 75% with chemotherapy alone 3
• Treatment-related deaths were 2% with pembrolizumab combination versus 1% with chemotherapy alone 3
• No new safety signals emerged beyond known immune-related adverse events 3

Important Clinical Caveats

• Nivolumab monotherapy has been investigated but lacks phase III data specifically for gallbladder cancer and should not be used outside clinical trials 6, 5
• The evidence base for immunotherapy in gallbladder cancer comes primarily from biliary tract cancer trials where gallbladder cancer represents a subset 1, 3
• Patients must have adequate liver function (typically Child-Pugh A) to receive systemic therapy 5
• Combination immunotherapy plus chemotherapy represents the only FDA-approved immunotherapy approach for gallbladder cancer—monotherapy is not standard of care 1, 2