The Evolving Treatment Algorithm for Pancreatic Cancers
Key Points
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Platinum-based chemotherapy regimens are a cornerstone in the treatment algorithm for pancreatic cancer populations.
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Collaborating with a multidisciplinary team is crucial for optimizing chemotherapy, radiotherapy, surgery, and supportive care strategies.
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Next-generation sequencing (NGS) is necessary to inform treatment decisions in both resectable and unresectable or metastatic settings, and should be done early so there are no delays between treatment lines.
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Novel agents directed against KRAS mutations have shown promising data in early clinical trials for pancreatic cancer.
Treatment Algorithms for Pancreatic Cancer Populations
On the Oncology Brothers podcast, Shubham Pant, MD, a gastrointestinal medical oncologist at MD Anderson Cancer Center, joined cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss the current treatment algorithm for pancreatic cancer.
The doctors discussed the importance of NGS testing, the role of neoadjuvant therapy for resectable disease, and the growing list of targeted options available in the metastatic setting. Throughout the conversation, the doctors also emphasized the need for a multidisciplinary approach between medical oncologists, radiation oncologists, surgical oncologists, and supportive care for nutrition and pain management when treating patients with pancreatic cancer.
Standard Treatment of Resectable or Borderline Resectable Pancreatic Cancer
The treatment algorithm for resectable pancreatic cancer is surgery followed by adjuvant chemotherapy, typically with either mFOLFIRINOX (modified leucovorin [folinic acid], fluorouracil [5-FU], irinotecan, and oxaliplatin) or gemcitabine plus capecitabine. For borderline resectable patients, the treatment algorithm is to start neoadjuvant chemotherapy with or without radiotherapy, with the goal of bringing the patient to surgery. Standard chemotherapy regimens include mFOLFIRINOX or gemcitabine plus nab-paclitaxel. However, gemcitabine plus cisplatin is preferred for patients with germline BRCA1, BRCA2, or PALB2 mutations.
Notably, many oncologists have incorporated neoadjuvant chemotherapy for baseline resectable patients as well. The purpose of neoadjuvant treatment in this population is to control potential micrometastases and reduce the rate of early relapse within 6 months of surgery. In Dr. Pant’s center, the majority of fit patients with resectable or borderline resectable pancreatic cancer start on neoadjuvant mFOLFIRINOX and switch to gemcitabine plus nab-paclitaxel if Cancer Antigen19-9 or other markers don’t indicate a response.
Importantly, before starting regimens that include 5-FU or capecitabine, patients should be tested for DPYD variants that cause dihydropyrimidine dehydrogenase deficiency, which is associated with increased risk of serious, potentially fatal adverse events, according to the FDA.
Unresectable or Metastatic Pancreatic Cancer Treatment Algorithm
The treatment algorithm for metastatic pancreatic cancer typically involves upfront chemotherapy or targeted agents, followed by alternate chemotherapy or targeted agents in later lines. Frontline chemotherapy regimens include mFOLFIRINOX, NALIRIFOX (liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin), and gemcitabine plus nab-paclitaxel. Single-agent chemotherapy may also be considered in frail patients. Among the 5-FU–based regimens, NALIRIFOX may be slightly more tolerable compared with mFOLFIRINOX, potentially helping patients stay on oxaliplatin for longer, said Dr. Pant.
Frontline targeted options for metastatic pancreatic cancers include entrectinib or larotrectinib for NTRK fusions, selpercatinib for RET fusions, pembrolizumab for microsatellite instability-high (MSI-H) or tumor mutational burden (TMB)≥10, and dabrafenib or trametinib for BRAF V600E–mutated disease. In addition, frontline gemcitabine plus cisplatin, followed by maintenance with olaparib or rucaparib, is approved for specific BRCA–mutated or PALB2–mutated subpopulations.
Later Lines of Therapy in Metastatic Pancreatic Cancer
In subsequent lines of therapy, patients can switch between 5-FU–based regimens and gemcitabine–based regimens depending on their frontline treatment. Targeted therapies approved in later lines include trastuzumab deruxtecan for HER2–positive, dostarlimab for MSI-H, nivolumab plus ipilimumab for TMB≥10, and zenocutuzumab for NRG1 fusion pancreatic cancer. For patients who progress during maintenance olaparib or rucaparib, Dr. Pant prefers to sequence back to platinum–based chemotherapy, typically with gemcitabine plus cisplatin if the patient can tolerate the regimen, although he acknowledged this is largely a data-free zone.
Emerging Role of Therapies Targeting KRAS Mutations
The majority of pancreatic cancers harbor some type of KRAS mutation, but there are no approved targeted agents available for these patients. This may change in the near future, as adagrasib and sotorasib, both KRAS G12C inhibitors, were added to National Comprehensive Cancer Network guidelines for pancreatic cancer. Furthermore, data are forthcoming from several trials on the pan-RAS inhibitor daraxonrasib across treatment settings. Dr. Pant was cautiously optimistic that positive findings for these agents could open up new options in the treatment algorithm for pancreatic cancer.