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While pancreatic cancer remains one of the toughest cancers to treat and is predicted to become the second-leading cause of cancer-related death in the U.S. before 2030, research and treatment advances in 2024 give us hope. This past year we have four new drug approvals for pancreatic cancer (one in the first-line setting and three targeted agents for previously treated cancer), a randomized phase 3 clinical trial showing an overall survival benefit in unresectable, locally advanced pancreatic cancer, and the first phase 3 trial of a RAS inhibitor in pancreatic cancer started enrolling patient
2024 started with the good news of the announcement that the five-year relative survival rate is up again for the third year in a row, rising to 13%. While this is cause for celebration, we must remember that pancreatic cancer is the only major solid tumor with a five-year relative survival rate below 20% and is behind other major solid tumors like breast, lung, colorectal, and prostate cancer, each of which have approved screening tests.
While most patients with pancreatic cancer have pancreatic ductal adenocarcinoma (PDAC), which is the hardest type to treat, we’ve also learned that other less common and less aggressive types of pancreatic cancer called endocrine and solid pseudopapillary cancer may be on the rise in younger people. Since these are all often lumped together in cancer statistics, it will be important moving forward to make sure we understand where we are making advances in treatment and outcomes.
In February, Onivyde (liposomal irinotecan) received FDA approval as part of a treatment combination called NALIRIFOX for first-line therapy in patients with metastatic pancreatic cancer. NALIRIFOX includes Onivyde in combination with 5 fluorouracil (5-FU)/leucovorin and oxaliplatin. Onivyde was previously approved for second-line therapy in combination with 5-FU and leucovorin. This approval provides a new treatment option for patients with newly diagnosed metastatic pancreatic cancer.
While chemotherapy has been the mainstay of treatment for the most common type of pancreatic cancer, PDAC, targeted therapies are emerging as an important new way to target PDAC. Many cancers, including PDAC, are driven by mutations in the RAS family of oncogenes – genes that, when altered, promote cancer. Researchers have long sought drugs that target the actions of mutant RAS proteins made from these altered genes – it has been such a tough journey that RAS has long been considered “undruggable.” Thankfully that is changing, as evidenced by the momentum in the RAS field that was palpable at the Fifth RAS Initiative Symposium in October this year.
The advances in our understanding of RAS are important because over 90% of patients with PDAC have tumors carrying a mutation in a type of RAS gene, known as KRAS. While two KRAS-targeted therapies are already approved for lung and colorectal cancer, they both target a mutation which is only present in a small percentage of pancreatic tumors. I am particularly excited for people with pancreatic cancer because the first Phase 3 clinical trial of a RAS inhibitor in pancreatic cancer opened enrollment in October. The RASolute 302 trial is evaluating an investigational drug called RMC-6236 that targets RAS proteins in their “on” state. Other preclinical and earlier phase clinical studies are underway evaluating additional novel approaches to target KRAS in pancreatic tumors. I am hopeful that all this research activity will lead to a new era of targeted therapies for PDAC.
In addition to KRAS mutations in most PDAC tumors, there are small subsets of PDAC tumors that are driven by other alterations that can be therapeutically targetable. Patients and their healthcare teams can learn about potentially “actionable” alterations in their tumor through biomarker testing, which involves a biopsy of their tumor tissue being analyzed. We at PanCAN strongly recommend that all patients undergo biomarker testing and genetic testing for inherited mutations as soon as possible after diagnosis. This year brought two new “tumor-agnostic” drug approvals, which refer to cancer treatments that are specific for a certain molecular alteration in a solid tumor, regardless of where the tumor started in the body.
Enhertu® (fam-trastuzumab deruxtecan-nxki) received accelerated approval for the treatment of HER2-positive solid tumors in patients with unresectable (not surgically removable) or metastatic disease who had received prior systemic therapy. Approximately 1-7% of pancreatic cancers are HER2-positive.
In June, AugtyroTM (repotrectinib) received accelerated approval for patients with solid tumors with NTRK gene fusions with locally advanced or metastatic disease that progressed following treatment. NTRK fusions are thought to be very rare in pancreatic tumors – present in around 0.5% of cases.
The most recent development in December was the FDA accelerated approval of Bizengri® (zenocutuzumab-zbco) for people with previously-treated advanced, unresectable, or metastatic pancreatic adenocarcinoma whose tumor has an NRG1 fusion, which is present in roughly 3% of pancreatic cancers. This FDA approval of the first NRG1 fusion-targeted therapy in pancreatic (as well as in non-small cell lung) cancer marks a pivotal moment for precision medicine in drug development and pancreatic cancer treatment. This Bizengri drug approval is testament to the progress we are making to improve outcomes for patients with pancreatic cancer.
In early December, we learned that Tumor Treating Fields (TTFields) in combination with chemotherapy improved overall survival in the PANOVA-3 Phase 3 trial in unresectable, locally advanced pancreatic cancer. TTFields is a non-invasive therapy that uses low intensity alternating electrical fields to disrupt tumor cell division. TTFields already has FDA approval in glioblastoma and lung cancer, and this trial result in pancreatic cancer suggests that TTFields, if approved, could become a treatment option for patients with PDAC.
With more and more targeted therapies available for patients whose pancreatic tumors harbor the right molecular alteration, it is more important than ever that every patient with pancreatic cancer knows their tumor’s molecular profile through biomarker testing, so their doctors can help them choose the right treatment options, including clinical trials. While pancreatic cancer remains a challenge, 2024 has brought significant advancements in both treatment options and clinical research. The approvals of NALIFIROX for first-line therapy and three targeted therapies for pancreatic cancer patients with pretreated advanced disease, the promise of KRAS inhibitors, and encouraging results with TTFields are paving the way for more effective treatments. Ongoing clinical trials and new diagnostic techniques continue to fuel hope for improved outcomes, signaling a brighter future for patients with pancreatic cancer. Overall, while there is still much work left to do, 2024 has been a year of momentum for pancreatic cancer research and treatment.
