Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. The expectation is that this year, an estimated 62,210 people in the United States will be diagnosed with pancreatic cancer. When diagnosed at an advanced stage, current therapies provide a median overall survival (mOS) benefit of approximately six to eight months. And despite advancements in the detection and management of pancreatic cancer, the 5-year survival rate still stands at 9% only.[1][2]

In China, pancreatic cancer rates are increasing. Cases in China account for about 25.2% (124,994 new cases in 2020) of all newly diagnosed cancers and about 26.1% (121,853 deaths in 2020) of deaths from pancreatic cancer worldwide [3] . Mutations in the K-Ras gene account for 85% to 90% of all pancreatic cancers; 10% to15% of pancreatic cancers are K-Ras wild type (unmutated).

The addition of nimotuzumab, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR) on a cell’s surface and can inhibit the growth of tumor cells that overexpress EGFR, to gemcitabine (Gemzar®; Eli Lilly and Company) increases overall survival (OS) in patients with K-Ras wild-type advanced pancreatic cancer *, particularly for patients who did not need surgery for obstruction of a pancreatic bile duct.

This conclusion is based on top-line results from the NOTABLE trial, which was conducted in China and sponsored by Chineses-Cuban Biotech Pharmaceutical Corp.[4] These results were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held from June 3-7, 2022 in Chicago, Il.

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NOTABLE study
In the prospective double-blind phase III NOTABLE clinical trial, patients in China with locally advanced or metastatic pancreatic cancer were randomly assigned to receive either nimotuzumab (400 mg, every one week) followed by gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks) or placebo plus gemcitabine until progression or unacceptable toxicity.

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The primary endpoint was OS and secondary endpoints included PFS, objective response rate, and safety.

Study Findings
Median overall survival was longer for patients in the nimotuzumab-gemcitabine group (n = 46) compared to those who received gemcitabine plus a placebo (10.9 vs. 8.5 months, p = 0.025 by RMST-Log test, hazard ratio [HR], 0.50, 95% Confidence Interval [CI], 0.06 to 0.94).

The one-year survival rate was 43.6% in the nimotuzumab-gemcitabine group vs. 26.8% in the placebo-gemcitabine group and 13.9% vs. 2.7% for three-year survival, respectively.

The researchers conducted subgroup analyses based on whether the patients needed surgery to remove bile duct obstructions prior to receiving chemotherapy. The underlying reason is that patients without the need for surgery to repair obstructions have better liver function, no jaundice and may therefore better tolerate chemotherapy.

The overall survival benefit in patients who did not need surgery to remove a biliary obstruction was 11.9 vs. 8.5 months. (HR = 0.54, 95%CI 0.33-0.88, p = 0.037). For those who had no surgical history, it was 15.8 vs. 6.0 months HR = 0.40, 95%CI 0.19-0.84) for the nimotuzumab-gemcitabine vs. placebo-gemcitabine groups, respectively. PFS for those who had no surgical history for a biliary obstruction was 5.5 vs. 3.4 months in the nimotuzumab-gemcitabine vs. placebo-gemcitabine groups, respectively.

The median progression-free survival (mPFS) was 4.2 months in the nimotuzumab-gemicitabine group, as compared with 3.6 months in the placebo-gemicitabine group (HR = 0.56; 95% CI, 0.12 to 0.99; p = 0.013 ).

Patients without treatment of biliary obstruction had significantly longer PFS (5.5 vs. 3.4 months; p = 0.008 ). No statistical difference in the ORR between the two groups (p > 0.05).

Safety
Nimotuzumab was safe and the incidence of adverse events in the nimotuzumab-gemicitabine group is similar to placbo-gemicitabine group. The most common grade 3 TRAEs in Nim-Gem group were neutropenia (11.1%), leukopenia (8.9%) and thrombocytopenia (6.7%), all of which affect blood cells in the body. The researchers did not observe grade 4 TRAEs.

“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 K-Ras wild-type pancreatic cancer,” said co-lead author Shukui Qin, MD, who is a full Professor & Chief Physician of the Cancer Center, Jinling Hospital, Nanjing University of Chinese Medicine. Dr. Qin’s co-lead author is Jin Li, MD, who is a full Professor & Director of the Oncology Department at the East Hospital of Shanghai Tongji University, China.

Ongoing studies
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 U.S. Food and Drug Administration (FDA) The drug has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries.

Nimotuzumab is developed as a joint Chinese-Cuban venture, was approved by the Chinese National Medical Products Administration to be marketed in China in 2008 for the treatment of nasopharyngeal carcinoma.

Next Steps
The patients in the study continue to be followed up for effects on OS and long-term safety endpoints. The investigators continue to recruit patients in order to enroll a population that is as representative of the real-world population of pancreatic cancer patients as possible.

* Note: The KRAS gene makes a protein that is involved in cell signaling pathways that control cell growth, cell maturation, and cell death. Mutated forms of the KRAS gene have been found in some types of cancer, including non-small cell lung cancer, colorectal cancer, and pancreatic cancer.

Clinical Trials
Nimotuzumab in Adults With Pancreatic Cancer – NCT00561990
Nimotuzumab Plus S1 Versus Placebo Plus S1 as Maintenance Treatment in Patients With Unresectable Pancreatic Cancer – NCT02945267
A Study of Nimotuzumab Combinated With Gemcitabine in K-RAS Wild-type Locally Advanced and Metastatic Pancreatic Cancer – NCT02395016
Nimotuzumab in EGFR Highly Expressed Pancreatic Neuroendocrine Neoplasms – NCT05316480

Highlights of Prescribing Information
Gemcitabine (Gemzar®; Eli Lilly and Company)[Prescribing information]

Reference
[1] Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019 Feb;10(1):10-27. doi: 10.14740/wjon1166. Epub 2019 Feb 26. PMID: 30834048; PMCID: PMC6396775.
[2] NCI Cancer Statistics: Pancreatic Cancer. Online. Last accessed June 4, 2022.
[3] GLOBOCAN 2020, Global Cancer Observatory. International Agency for Research on Cancer, World Health Organization. Online. Last accesses on June 4, 2022.
[4] Qin S, Bai Y, Wang Z, Chen Z, Xu R, Xu J, Zhang H, Chen J, 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. J Clin Oncol 40, 2022 (suppl 17; abstr LBA4011) | DOI 10.1200/JCO.2022.40.17_suppl.LBA4011

Featured image: Oncology Division Chiefs & Department Chairs during Oncology Division Chiefs’ & Department Chairs’ Breakfast – at the 58th ASCO Annual Meeting. Photo courtesy: © 2022 ASCO/Zach Boyden-Holmes. Used with permission.

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