Adding nimotuzumab to gemcitabine increases survival in advanced pancreatic cancer patients with KRAS wild-type disease, in particular for patients who did not need surgery for obstruction of a pancreatic bile duct.
Median overall survival (OS) was longer for patients in the nimotuzumab-gemcitabine group (10.9 months) compared to those who received gemcitabine plus a placebo (8.5 months). The 1-year survival rate was 43.6 percent in the nimotuzumab-gemcitabine group versus 26.8 percent in the placebo-gemcitabine group, and 13.9 percent versus 2.7 percent for 3-year survival, respectively. The median progression-free survival (PFS) was also longer in the nimotuzumab-gemcitabine group (4.2 months) versus the placebo-gemcitabine group (3.6 months).
"The nimotuzumab plus gemcitabine regimen improved median OS compared with placebo plus gemcitabine, with a decrease of 50 percent mortality risk and improved median PFS, with a decrease of 44 percent disease progression risk," said co-lead author Shukui Qin, MD, Professor & Chief Physician of the Cancer Center for the Jinling Hospital at Nanjing University of Chinese Medicine, who presented the results of the study at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract LBA4011).
Pancreatic cancer is one of the most lethal malignant tumors, with nearly 500,000 new diagnosed cases and more than 450,000 deaths worldwide. "Current treatment regimens provide only 6-8 months of median OS. Locally advanced pancreatic cancer patients have 6-9 months of median OS, and metastatic pancreatic cancer only 3-5 months of median OS, with a 5-year survival rate of only 7-9 percent," Qin said.
KRAS mutations are commonly found in pancreatic cancer (in the U.S. in about 90 percent of patients and in China about 87 percent) and act as a driver gene, said Qin, adding that the 10-15 percent of pancreatic cancers with KRAS wild-type urgently need a breakthrough in treatment.
Nimotuzumab, a humanized monoclonal antibody that targets the epidermal growth factor receptor on a cell's surface, was developed as a joint Chinese-Cuban venture. It was approved by the Chinese National Medical Products Administration to be marketed in China in 2008 for the treatment of nasopharyngeal carcinoma. A series of clinical studies of nimotuzumab for head and neck, cervical, esophageal, and other cancers are ongoing in China. The drug has not been approved by the FDA.
Study Details
In the prospective, double-blind, Phase III NOTABLE clinical trial, 92 patients in China with locally advanced or metastatic pancreatic cancer were randomly assigned to receive either nimotuzumab (400 mg, every week) followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 4 weeks) (46 patients) or a placebo plus gemcitabine (46 patients) until progression or unacceptable toxicity. The researchers conducted subgroup analyses based on whether the patients needed surgery to remove bile duct obstructions prior to receiving chemotherapy. Patients without the need for surgery to repair obstructions have better liver function and no jaundice and, therefore, may better tolerate chemotherapy. The primary endpoint was OS and secondary endpoints included PFS, objective response rate, and safety.
The OS benefit in patients who did not need surgery to remove a biliary obstruction was 11.9 versus 8.5 months. For those who had no surgical history, it was 15.8 versus 6 months for the nimotuzumab-gemcitabine versus placebo-gemcitabine groups, respectively. PFS for those who had no surgical history for a biliary obstruction was 5.5 versus 3.4 months in the nimotuzumab-gemcitabine versus placebo-gemcitabine groups, respectively.
"Nimotuzumab plus gemcitabine reduced mortality risk up to 60 percent and reduced the risk of disease progression, especially for no surgery history," Qin noted.
The incidence of adverse events in the nimotuzumab-gemcitabine group was similar to the placebo-gemcitabine group. The most common adverse events for those who received nimotuzumab-gemcitabine were neutropenia (11.1%), leukopenia (8.9%), and thrombocytopenia (6.7%).
"We believe our NOTABLE trial will be a breakthrough in the field of pancreatic cancer. The outcomes in this trial may bring new hope to patients with KRAS wild-type pancreatic cancer," Qin stated.
The patients in the study continue to be followed for effects on OS and long-term safety endpoints. The investigators continue to recruit patients to enroll a population that is as representative of the real-world population of pancreatic cancer patients as possible.
Qin concluded: "Nimotuzumab combined with gemcitabine increases OS and PFS in patients with KRAS wild-type locally advanced or metastatic pancreatic cancer, with an obvious good safety profile. Notably, the study showed a breakthrough in treatment of advanced pancreatic cancer [and] enlightened a new era of target treatment of enriched pancreatic cancer population based on a biomarker. The addition of nimotuzumab to the current treatment regimen will provide benefit and great value to pancreatic cancer patients."
ASCO expert in gastrointestinal cancers Cathy Eng, MD, the David H. Johnson Chair in Surgical and Medical Oncology, Co-Leader of the Gastrointestinal Cancer Research Program, and Professor of Medicine (Hematology and Oncology) at the Vanderbilt-Ingram Cancer Center, commented: "To see any survival benefit in a trial for metastatic pancreatic cancer is of interest. The investigators have evaluated a subset of pancreatic cancer, KRAS wild-type, which is rarely investigated prospectively because this form of the cancer represents less than 10 percent of all pancreatic cancer patients. Additional studies in comparison with the combination of gemcitabine/nab-paclitaxel would be of interest. We should consider validating any potential advances to make a true difference in the lives of all patients with pancreatic cancer."
Mark L. Fuerst is a contributing writer.