Senthil Kumar: First-Line Treatment Strategies for Advanced/Metastatic Gallbladder Cancer

Senthil Kumar, Medical Oncologist at Red Hills Chennai, shared a post on X:

“First-Line Treatment Strategies for Advanced/Metastatic Gallbladder Cancer (GBC).

Principles

Molecular Testing

Comprehensive molecular profiling is recommended for all patients with advanced/metastatic GBC to guide therapy. Testing should include:

• MSI-High/dMMR
• TMB-High
• BRAF V600E Mutation
• FGFR2 Fusions
• IDH1 Mutations
• HER2 Amplifications
• RET Mutations

Limited Data: For KRAS G12C mutations, MET amplification, and ALK, RET, or ROS1 fusions in GBC.

Germline Testing

Recommended for young patients, those with a family history of cancer, or those with specific genetic alterations.

Obstructive Jaundice

Biliary drainage is recommended prior to starting chemotherapy.

Performance Status (PS)

PS 0–1: Eligible for combination chemotherapy ± immunotherapy.

PS 2+: Prefer single-agent therapy or modified doublets.

Chemotherapy Backbone

Standard and Alternative Regimens

1. Gemcitabine + Cisplatin (GC): Standard first-line regimen.

2. Gemcitabine + Oxaliplatin (GEMOX): Alternative to GC.

3. Gemcitabine + Nab-Paclitaxel (GCN): Emerging regimen.

4. Gemcitabine + Capecitabine (GemCape): Alternative regimen.

5. Gemcitabine + S-1 (GemS-1): Used in East Asia.

6. Gemcitabine + 5-FU/Leucovorin (Gem5-FU/LV): Another option.

7. Carboplatin + Gemcitabine (CarboGem): Higher rates of neutropenia.

8. CAPEOX (Capecitabine + Oxaliplatin) and FOLFOX (5-FU + Oxaliplatin).

Non-Preferred Regimens:

Cisplatin + 5-FU or Cisplatin + Capecitabine due to inferior efficacy.

Targeted and Immunotherapy Approaches

Immunotherapy (First-Line)

Durvalumab + GC (TOPAZ-1) → Standard of care.

Pembrolizumab + GC (KEYNOTE-966) → Alternative regimen.

MSI-H/dMMR or TMB-High tumors: Single-agent Pembrolizumab.

Targeted Therapy (Second-Line or Beyond)

FGFR2 Fusions: Pemigatinib, Futibatinib.

IDH1 Mutations: Ivosidenib.

HER2 Amplifications: Trastuzumab + Pertuzumab, zanidatamab, TDxd

BRAF V600E Mutations: Dabrafenib + Trametinib.

NTRK Fusions: Larotrectinib or Entrectinib.

Key Clinical Trials and Outcomes

ABC-02 Trial (2010)

Population: 36% had metastatic GBC.

Comparison: Gemcitabine + Cisplatin (GC) vs. Gemcitabine alone.

Median OS: 11.7 vs. 8.1 months

Median PFS: 8.0 vs. 5.0 months

ORR: 26% vs. 16%

TOPAZ-1 Trial (2022)

Population: 25% had metastatic GBC.

Comparison: Durvalumab + GC vs. GC alone.

Median OS: 12.9 vs. 11.3 months

Median PFS: 7.2 vs. 5.7 months

ORR: 27% vs. 18%

KEYNOTE-966 Trial (2023)

Population: 25% had metastatic GBC.

Comparison: Pembrolizumab + GC vs. GC alone.

Median OS: 12.7 vs. 10.9 months

Median PFS: 7.4 vs. 5.6 months

ORR: 29.4% vs. 18.9%

TOPAZ-1 vs. KEYNOTE-966:

TOPAZ-1: Simpler maintenance with Durvalumab every 28 days and no gemcitabine, enhancing patient compliance.

SWOG S1815 Trial (2023)

Comparison: Gemcitabine + Cisplatin + Nab-Paclitaxel (GCN) vs. GC.

Median OS: 14 months (numerically higher, but not statistically significant).

PFS: Benefit observed in the GBC subset.

Toxicity: Higher toxicity with the triplet regimen.

Final Insights

Best First-Line Regimens

1. Durvalumab + Gemcitabine + Cisplatin (TOPAZ-1):

Best for fit, non-jaundiced patients.

Simpler maintenance: No gemcitabine and Durvalumab every 28 days.

2. Pembrolizumab + Gemcitabine + Cisplatin (KEYNOTE-966):

Alternative to the TOPAZ regimen.

3. Gemcitabine + Cisplatin (GC):

Standard in patients ineligible or not affordable for immunotherapy.

4. Gemcitabine + Oxaliplatin (GEMOX):

Suitable for cisplatin-ineligible patients.

5. Other Doublets:

Gemcitabine + Capecitabine (GemCape)

Gemcitabine + S-1 (GemS-1)

Gemcitabine + 5-FU/Leucovorin (Gem5-FU/LV)

CAPEOX, FOLFOX

Gemcitabine + Nab-Paclitaxel (GCN).”