What is the role of durvalumab (Immunotherapy) in the treatment of pancreatic cancer?

Role of Durvalumab and Immunotherapy in Pancreatic Cancer

Durvalumab and other immune checkpoint inhibitors have no established role in the treatment of pancreatic adenocarcinoma, with the sole exception of pembrolizumab for the rare subset (<1%) of patients with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) tumors. 1

Immunotherapy Efficacy in Pancreatic Cancer

Standard Treatment Remains Chemotherapy-Based

• Gemcitabine-based regimens or FOLFIRINOX remain the standard first-line treatments for metastatic pancreatic cancer, with no role for checkpoint inhibitors in unselected patients. 1, 2
• The 2018 ASCO guidelines explicitly state there is no evidence supporting the use of checkpoint inhibitors beyond the dMMR/MSI-H population 1
• Older ESMO guidelines (2009-2012) found no evidence supporting bevacizumab, cetuximab, or other biologics in pancreatic cancer 1

The Single Exception: dMMR/MSI-H Tumors

Pembrolizumab (a PD-1 inhibitor, not durvalumab) is FDA-approved and ASCO-recommended as second-line therapy exclusively for patients with confirmed dMMR or MSI-H pancreatic tumors. 1

• Among 8 pancreatic cancer patients with dMMR in the Le et al. study, 25% achieved complete radiographic response and 75% had disease control 1
• The overall response rate across all dMMR tumor types was 53%, with mostly low-grade adverse events (74% of patients) 1
• Critical limitation: Only approximately 0.8% of pancreatic cancers have dMMR 1
• Testing for dMMR/MSI-H status should be performed using PCR or immunohistochemistry 1

Evidence Against Durvalumab in Pancreatic Cancer

Failed Clinical Trial Data

The CCTG PA.7 phase II randomized trial directly tested durvalumab plus tremelimumab combined with gemcitabine/nab-paclitaxel in 180 patients with metastatic pancreatic cancer and showed no survival benefit. 3

• The primary endpoint of overall survival was negative (p = 0.72) 3
• The combination added no efficacy beyond chemotherapy alone in the unselected patient population 3
• Toxicity was limited to lymphocyte elevation (p = 0.02) 3
• This trial definitively demonstrates that adding dual checkpoint inhibition (durvalumab + tremelimumab) to standard chemotherapy does not improve outcomes 3

Why Immunotherapy Fails in Pancreatic Cancer

Pancreatic cancer possesses unique immunosuppressive features that render checkpoint inhibitors ineffective: 4, 5, 6

• Low tumor mutational burden results in few neoantigens for immune recognition 4, 6
• Dense desmoplastic stroma creates a physical and immunologic barrier 6
• Highly immunosuppressive tumor microenvironment dominated by myeloid-derived suppressor cells 4, 6
• Lack of antigen-experienced T effector cells within tumors 7

Durvalumab's Approved Indication

Durvalumab is FDA-approved exclusively for stage III non-small cell lung cancer (NSCLC) as consolidation therapy after chemoradiation, not for pancreatic cancer. 8

• The PACIFIC trial in NSCLC showed median OS of 47.5 months with durvalumab versus 29.1 months with placebo (HR 0.72) 8
• This lung cancer indication has no applicability to pancreatic adenocarcinoma 8
• NCCN guidelines explicitly recommend standard adjuvant chemotherapy (gemcitabine preferred) rather than immunotherapy for pancreatic cancer patients completing chemoradiation 8

Current Treatment Algorithm for Metastatic Pancreatic Cancer

First-Line Therapy

• FOLFIRINOX for patients ≤75 years with ECOG PS 0-1 and bilirubin ≤1.5 ULN 1, 2
• Gemcitabine plus nab-paclitaxel for patients not meeting FOLFIRINOX criteria 1
• Gemcitabine monotherapy for patients with poor performance status 2

Second-Line Therapy (After Progression)

• Test all patients for dMMR/MSI-H status 1
• If dMMR/MSI-H positive: Pembrolizumab (NOT durvalumab) 1
• If dMMR/MSI-H negative: Fluorouracil plus nanoliposomal irinotecan (preferred) or fluorouracil plus oxaliplatin 1, 2

Critical Pitfalls to Avoid

• Do not use durvalumab or other checkpoint inhibitors in pancreatic cancer outside of clinical trials, except pembrolizumab for confirmed dMMR/MSI-H tumors 1, 3
• Do not assume lung cancer immunotherapy data applies to pancreatic cancer—the tumor biology is fundamentally different 8, 4
• Do not delay effective chemotherapy to pursue immunotherapy in unselected patients 1
• Testing for tumor mutational burden alone (without dMMR/MSI-H confirmation) is insufficient to justify immunotherapy use 1

Future Directions

• Clinical trial enrollment should be strongly encouraged for all lines of therapy given the disappointing results of standard treatments 1
• Emerging combination strategies targeting the immunosuppressive myeloid compartment are under investigation but remain experimental 4, 6
• Vaccine-based approaches (such as GVAX) show promise in inducing tertiary lymphoid aggregates but require further validation 7