Senthil Kumar: First-Line Therapy for Metastatic Pancreatic Cancer

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

“First-Line Therapy for Metastatic Pancreatic Cancer.

Triplets: Standard Regimens.

FOLFIRINOX (Triplet)

Trial Name: PRODIGE 4/ACCORD 11.
Components: Oxaliplatin, irinotecan, leucovorin, 5-FU.
Efficacy:

• Median OS: ~11.1 months (vs. 6.8 months for single-agent Gemcitabine).
• Median PFS: ~6.4 months (vs. 3.3 months for Gemcitabine).

Toxicity: High rates of neutropenia (~47%), fatigue (~25%), diarrhea (~23%), neuropathy (~18%).
Patient Selection:

• Fit patients (ECOG 0-1).
• Non-jaundiced.
• No significant baseline neuropathy (e.g., diabetic neuropathy).

NALIRIFOX (Triplet)

Trial Name: NAPOLI-3
Components: Liposomal irinotecan, oxaliplatin, leucovorin, 5-FU.
Efficacy:

• Median OS: 11.1 months (vs. 9.2 months for GnP).
• Median PFS: 7.4 months (vs. 5.6 months for GnP).
• ORR: 42%.

Toxicity:

• More nausea, vomiting, and diarrhea.
• Less neuropathy and neutropenia compared to FOLFIRINOX.

Consideration: High cost may limit accessibility.

Gemcitabine + Nab-Paclitaxel (GnP)

Trial Name: MPACT.
Components: Gemcitabine and nab-paclitaxel.
Efficacy:

• Median OS: ~8.5 months (vs. 6.7 months for single-agent Gemcitabine).
• Median PFS: ~5.5 months (vs. 3.7 months for Gemcitabine).

Toxicity:

• Neutropenia (~28%), fatigue (~20%), peripheral neuropathy (~17%).
• Alternate Biweekly Regimen:
• Offers reduced toxicity while maintaining comparable efficacy.

Patient Selection:

• Moderate performance status (ECOG 1-2).
• Non-jaundiced.

Role of Biomarkers in Therapy

BRCA Mutations

Germline BRCA-Positive: Maintenance of Olaparib after 16 weeks of platinum-based therapy (e.g., FOLFIRINOX or cis-Gemcitabine) in nonprogressors.

POLO Trial Outcomes:

Median PFS:

• 7.4 months (vs. 3.8 months for placebo).
• No OS advantage.

Germline/Somatic BRCA or PALB2 Mutations: Rucaparib can be used post-platinum-based regimens (e.g., FOLFIRINOX, cis-Gemcitabine, Gem-Ox, FOLFOX).

HRD

• Responds well to platinum-based doublets.
• Tumor-Agnostic Markers
• May be treated with targeted therapy in first-line

MSI-High: Treated with Pembrolizumab or Nivolumab + Ipilimumab.
RET Fusion: Targeted by Selpercatinib.

NTRK Fusion: Treated with Larotrectinib, Entrectinib, or Repotrectinib.

BRAF V600E Mutation:

• Treated with Dabrafenib + Trametinib.
• DYPD Testing

Importance: Detects dihydropyrimidine dehydrogenase deficiency to reduce the risk of severe 5-FU-related toxicity by adjusting doses accordingly.

Final Insights

Fit, Non-Jaundiced Patients (ECOG 0-1):

Triplet Regimens: Choose between NALIRIFOX and FOLFIRINOX based on affordability and toxicity profile.

NALIRIFOX vs. FOLFIRINOX:

• More nausea, vomiting, and diarrhea.
• Less neuropathy and neutropenia.
• Slightly better ORR for NALIRIFOX
• Higher cost for NALIRIFOX.
• After an induction course of 4-6 cycles, transition to a maintenance doublet (e.g., FOLFIRI) to reduce neuropathy and overall toxicity.

Moderately Fit, Non-Jaundiced Patients (ECOG 1-2):

Gemcitabine + Nab-Paclitaxel (GnP): The standard regimen is effective.

Biweekly regimen: Equally effective and less toxic, making it a viable option.

Jaundiced Patients:

Biliary Drainage: Optimize biliary drainage before initiating systemic therapy.

If Drainage is Not Feasible: Consider FOLFOX or Gemcitabine at a reduced dose of 800 mg/m² to minimize toxicity while managing the disease.

Poor Performance Status (ECOG 3): Supportive care or single agents, with cautious use of doublets.

Very Poor Performance Status (ECOG 4): Best supportive care (BSC).

In the presence of tumor agnostic biomarkers like MSI – high, NTRK, RET, BRAF, the specific target therapies may be used.”

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