In patients with locally advanced or metastatic pancreatic cancer and KRAS wild-type tumors, novel treatment with the monoclonal antibody nimotuzumab, which targets the epidermal growth factor receptor (EGFR), plus gemcitabine significantly improved overall survival and other outcomes over gemcitabine alone in the phase III NOTABLE trial, investigators from China reported at the 2022 ASCO Annual Meeting.1
In this prospective, randomized double-blind study, median overall survival in the full analysis set of patients was 10.9 months with nimotuzumab plus gemcitabine vs 8.5 months with gemcitabine plus placebo (hazard ratio [HR] = 0.50; P = .024). Median progression-free survival was 4.2 months and 3.6 months, respectively.
“Nimotuzumab plus gemcitabine improved median overall survival compared with placebo plus gemcitabine, with a 50% decrease in mortality risk and a 44% decrease in the risk of disease progression,” said Shukui Qin, MD, PhD, Professor and Chief Physician of the Cancer Center of Jinling Hospital, Nanjing University of Chinese Medicine. “We believe our trial will be a breakthrough in the field of pancreatic cancer…. The addition of nimotuzumab to current treatment regimens will provide benefit and be of great value to patients with pancreatic cancer,” he said.
Shukui Qin, MD, PhD
The benefits were most striking in patients who had not undergone treatment of biliary obstruction or prior surgery, he added. Dr. Qin noted that these patients may reflect a group with better underlying health, including better liver function, who may tolerate chemotherapy better.
Dr. Qin pointed out that with current treatment regimens, median overall survival in advanced pancreatic cancer is poor—6 to 9 months for locally advanced disease, dropping to 5 months or less for metastatic disease. Many patients (85%–90%) harbor KRAS mutations. The NOTABLE trial focused on the rare subset of patients with KRAS wild-type tumors, “who urgently need more attention and breakthrough treatments,” he said.
Nimotuzumab, developed as a joint Chinese-Cuban venture, has been approved for nasopharyngeal carcinoma in China but is not approved in the United States.
Key Study Findings
The study randomly assigned 90 Chinese patients with KRAS wild-type locally advanced or metastatic pancreatic cancer to receive nimotuzumab (400 mg every week) followed by gemcitabine (1,000 mg/m2 every 4 weeks) or placebo plus gemcitabine. The primary endpoint was overall survival.
The 1-year overall survival rate was 43.6% in the nimotuzumab/gemcitabine group vs 26.8% in the placebo/gemcitabine group; survival at 3 years was 13.9% vs 2.7%, respectively, in the full analysis set of patients. In the per-protocol analysis, median overall survival was 11.5 months vs 8.5 months, respectively (HR = 0.60; P = .039).
In addition to the survival benefit, median progression-free survival was also significantly improved, from 3.6 months in the placebo arm to 4.2 months with nimotuzumab/gemcitabine (HR = 0.56; P = .013), in the full analysis set. A trend toward benefit was also seen in the time to disease progression (HR = 0.67; P = .137).
Objective response rates did not significantly differ between the arms: 7.3% in the experimental arm and 9.8% in the control arm. The clinical benefit rate was slightly improved with nimotuzumab/gemcitabine, though not significantly so (39.3% vs 32.3%; P = .573).
In both sets of analyses, essentially all subgroups benefited from nimotuzumab/gemcitabine. As for overall survival, the most benefit was seen in two subsets: patients without treatment of biliary obstruction, who had a median overall survival of 11.9 months with the novel regimen vs 8.5 months with gemcitabine alone (HR = 0.54; 95% confidence interval [CI] = 0.33–0.88), and patients with no history of surgery, whose median overall survival was 15.8 months vs 6.0 months, respectively (HR = 0.40; 95% CI = 0.19–0.84).
The combination of nimotuzumab plus gemcitabine was reported to be well tolerated, with adverse events similar to those in the placebo arm: 68.9% vs 64.4%. The most common grade 3 treatment-emergent adverse events associated with nimotuzumab/gemcitabine were neutropenia (9%), leukopenia (11%), and thrombocytopenia (7%). No grade 4 adverse events were reported.
Future for Nimotuzumab?
As a drug that is developed and evaluated in China, it is not likely that nimotuzumab plus gemcitabine will replace the current standard of care in advanced pancreatic cancer in the United States, at least in the near future, ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO, told journalists at a press briefing.
“The findings are not going to change practice tomorrow,” Dr. Gralow said. The drug is approved and manufactured in China, and U.S. regulatory agencies would no doubt require multiregional studies in a population more reflective of patients with cancer in the United States, she noted. Also, nivolumab plus gemcitabine was compared with gemcitabine alone in the NOTABLE trial, although the standard of care is gemcitabine plus nab-paclitaxel. This should be the comparator in future studies, Dr. Gralow suggested.
“However,” she added, “this is proof of concept. We have other anti-EGFR antibodies we could test in this population, and there are many other novel approaches under investigation in this patient population.”
DISCLOSURE: The NOTABLE trial was conducted in China and sponsored by Biotech Pharmaceutical Co, Ltd. Dr. Qin reported no conflicts of interest. Dr. Gralow has served as a consultant or advisor to Genentech, AstraZeneca, Roche, Novartis, and Seagen.
1. Qin S, Bai Y, Wang Z, et al: Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer. 2022 ASCO Annual Meeting. Abstract LBA4011. Presented June 3, 2022.
Thomas Seufferlein, MD, Professor of Medicine at Ulm University Hospital in Germany, found the data from the NOTABLE trial1 encouraging and “clinically interesting.” However, he suggested the study’s design did not allow the EGFR inhibitor to be optimally tested.
The NOTABLE trial is based on a...