Second-Line Treatment for KRAS G12D Mutated Metastatic Biliary Cancer
For patients with KRAS G12D mutated metastatic biliary cancer who have progressed on first-line chemotherapy, FOLFOX (5-fluorouracil-leucovorin-oxaliplatin) is the recommended second-line treatment based on the ABC-06 trial, which demonstrated a modest but significant overall survival benefit (6.2 vs 5.3 months; HR 0.69, p=0.031). 1
Primary Second-Line Recommendation
FOLFOX should be offered as the standard second-line therapy after progression on first-line cisplatin-gemcitabine (with or without durvalumab/pembrolizumab), as it is the only regimen with Level 1 evidence from a randomized phase III trial in biliary tract cancer 1
The ABC-06 study included 45 patients with extrahepatic cholangiocarcinoma (eCCA) in the subgroup analysis, showing a trend toward OS benefit (HR 0.84; 95% CI 0.45-1.57), though the small sample size limits definitive conclusions 1
Alternative Second-Line Options
Liposomal irinotecan plus 5-fluorouracil (NalIRI+5FU) may be considered as an alternative, based on the Korean NIFTY phase II trial which showed improved OS (8.6 vs 5.3 months; HR 0.68, p=0.02) 1
However, the European NALIRICC study failed to replicate these survival benefits in Caucasian patients and showed increased toxicity, making this option less robust 1
The ESMO guideline notes that irinotecan-based therapies have limited evidence and should be considered on a case-by-case basis, particularly if there is evidence of irinotecan sensitivity 1
Critical Consideration: KRAS G12D Mutation Status
The KRAS G12D mutation is NOT currently targetable in biliary tract cancer, unlike in lung cancer where KRAS G12C inhibitors (sotorasib, adagrasib) have shown efficacy 1
KRAS G12C-specific inhibitors are only approved for KRAS G12C mutations (not G12D) and only in non-small cell lung cancer after prior chemotherapy and immunotherapy 1
A multicenter phase II study showed that KRAS mutations (including G12D) were present in 32% of biliary tract cancers and showed a marginal relationship with worse overall survival (p=0.07), indicating a more aggressive disease biology 2
Molecular Profiling for Other Targetable Alterations
Comprehensive molecular profiling should be performed (if not already done) to identify other actionable alterations that may be present alongside the KRAS G12D mutation 1
For IDH1 mutations (R132): Ivosidenib is FDA-approved and recommended after first-line therapy failure, showing improved PFS (HR 0.37, p<0.0001) and OS (HR 0.49 after crossover adjustment, p<0.001) in the ClarIDHy trial 1
For FGFR2 fusions/rearrangements: FGFR inhibitors (pemigatinib, infigratinib, futibatinib) are FDA/EMA approved with ORRs of 20-40% and median PFS of ~7 months 1
For HER2/ERBB2 amplification: Trastuzumab-based therapies may be considered in later lines 1
What NOT to Use
Anti-EGFR antibodies (cetuximab, panitumumab) should NOT be used as they are only effective in RAS wild-type colorectal cancer and have no established role in biliary tract cancer 1
KRAS G12C inhibitors (sotorasib, adagrasib) are NOT indicated for KRAS G12D mutations, as they are mutation-specific and only target the G12C variant 1
Capecitabine monotherapy, gemcitabine-based regimens (already failed), mitomycin, interferons, taxanes, methotrexate, pemetrexed, and targeted agents like sunitinib, sorafenib, or erlotinib have not shown efficacy in this setting 3, 4
Third-Line and Beyond
If the patient maintains good performance status after FOLFOX failure, consider enrollment in clinical trials as the priority 1
Retrospective data shows that only 30% of patients receive second-line therapy, and outcomes remain poor with median OS of 6-7 months across various regimens 5, 6, 7
Single-agent chemotherapy appears to have similar efficacy to doublet regimens in the second-line setting with better tolerability 5
Performance Status Requirements
Second-line chemotherapy should only be offered to patients with maintained good performance status (ECOG 0-2), as those with poor performance status are unlikely to benefit 1
The ABC-06 trial demonstrated that preserved performance status was a favorable prognostic factor for second-line therapy benefit 6
Monitoring During Treatment
Radiological evaluation should be performed every 8-12 weeks with CT or MRI 8, 3
CA19-9 levels should be monitored, as low levels are associated with better prognosis in second-line therapy 6
Common Pitfalls to Avoid
Do not assume KRAS G12D can be targeted like KRAS G12C—these are distinct mutations with different therapeutic implications 1
Do not use gemcitabine-based regimens in second-line after progression on first-line gemcitabine-cisplatin, as re-challenge has not shown benefit 4, 6
Do not delay molecular profiling—it should be performed before or during first-line therapy to identify targetable alterations for second-line options 1
Do not continue treatment beyond progression without evidence of clinical benefit, as biliary tract cancer has limited salvage options and quality of life should be prioritized 1, 7