Nimotuzumab significantly improves overall survival for KRAS wild-type advanced pancreatic cancer
As patients with pancreatic cancer diagnosed at an advanced stage have a poor prognosis, more effective treatment options are urgently needed. In the Chinese phase III NOTABLE study, median overall survival was longer for patients in the nimotuzumab-gemcitabine group compared to those who received gemcitabine plus a placebo, especially in those patients who do not need surgery to remove a biliary obstruction.
Pancreatic cancer is one of the most lethal malignant tumours and 80% of pancreatic cancers are in an advanced stage at diagnosis. With the current treatment regimens, a median overall survival (mOS) of only 6-8 months can be obtained. As such, there is a high unmet medical need for effective therapy to prolong survival of patients with advanced pancreatic cancer. Nimotuzumab, a humanised anti-EGFR monoclonal antibody, can disrupt the interaction of EGFR with its ligand, specifically block the EGFR signalling pathway, induce EGFR endocytosis and degradation and was taken as potential effective drug for advanced pancreatic cancer. Previously, the German phase II PCS07 study demonstrated that nimotuzumab plus gemcitabine versus placebo plus gemcitabine significantly improved mOS of locally advanced or metastatic pancreatic cancer, especially for the KRAS wild-type subgroup. The present phase III NOTABLE study aims to further evaluate the efficacy and safety of nimotuzumab plus gemcitabine in this setting.
The NOTABLE study is a prospective, randomised, controlled, double-blind, multicentre phase III trial. Patients with histologically confirmed locally advanced or metastatic pancreatic cancer were randomised (1:1) to receive nimotuzumab (400 mg, weekly) followed by gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks), or placebo plus gemcitabine until progression or unacceptable toxicity. Patients must be aged 18-75 years, have at least one measurable lesion evaluated by RECIST v1.1, be KRAS wild-type and have a Karnofsky performance status of at least 60. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 92 Chinese patients were randomly assigned to the nimotuzumab-gemcitabine (Nimo-Gem, N= 46) or the placebo-gemcitabine group (placebo-Gem, N= 46). Both groups were well balanced regarding baseline demographic and clinical characteristics.
After a median follow-up of 55.3 months, median overall survival in the full analysis set (N= 41 in both arms) was longer for patients in the Nimo-Gem group compared to those who received gemcitabine plus a placebo (10.9 vs. 8.5 months, HR[95%CI]: 0.50[0.06-0.94], p= 0.024 by RMST-log test). The one-year survival rate was 43.6% in the Nimo-Gem group vs. 26.8% in the placebo-Gem group and 13.9% vs. 2.7% for three-year survival, respectively. In the per-protocol set, OS was also significantly improved for Nimo-Gem compared with placebo-Gem. The overall survival benefit in patients who did not need surgery to remove a biliary obstruction was 11.9 vs. 8.5 months. For those who had no surgical history, it was 15.8 vs. 6.0 months for Nimo-Gem and placebo-Gem, respectively.
Nimo-Gem also improved median PFS compared with placebo-Gem, with a decrease of 44% in the risk of disease progression (4.2 vs. 3.6 months, HR[95%CI]: 0.56[0.12-0.99], p= 0.013 by RMST-log test). PFS for those who had no surgical history for a biliary obstruction was 5.5 vs. 3.4 months in the Nimo-Gem vs. placebo-Gem groups, respectively (HR[95%CI]: 0.50[0.29-0.86]). Furthermore, Nimo-Gem prolonged the median time to progression (4.7 vs. 3.7 months, HR[95%CI]: 0.67[0.39-1.15], p= 0.137). The disease control rate of Nimo-Gem was slightly improved, compared to placebo-Gem (68.3% vs. 63.4%, p= 0.641).
The incidence of adverse events in the Nimo-Gem group was similar to the placebo-Gem group. The most common grade 3 adverse events for those who received Nimo-Gem were leukopenia (11.1%), neutropenia (8.9%), and thrombocytopenia (6.7%). No grade 4-5 treatment-related adverse events occurred.
Nimotuzumab combined with gemcitabine increases OS and PFS in patients with KRAS wild-type locally advanced or metastatic pancreatic cancer, with a clear and favourable safety profile. As such, the NOTABLE study demonstrated a breakthrough in the treatment of advanced pancreatic cancer and lightens a new era of target treatment of an enriched pancreatic cancer population based on a biomarker. The results of this study may change the standard of care for a subset of cancer patients with very difficult-to-treat advanced pancreatic cancer.
Qin S, et al. Nimotuzumab combined with gemcitabine versus gemcitabine in K‐ RAS wild‐type locally advanced or metastatic pancreatic cancer: A prospective, randomized‐controlled, double‐blinded, multicenter, and phase III clinical trial. Presented at ASCO 2022; Abstract LBA4011.