Expert Point of View: Thomas Seufferlein, MD

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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 previous phase IIb trial conducted in Germany. The previous trial evaluated nimotuzumab plus gemcitabine in 33 patients with KRAS wild-type pancreatic cancer and reported a median overall survival of 11.6 months vs 5.6 months with gemcitabine alone.2 Thus, investigators of that study advocated for further testing in a phase III trial, which led to the NOTABLE trial.

In the NOTABLE trial, nimotuzumab plus gemcitabine yielded a median overall survival of 10.9 months vs 8.5 with gemcitabine alone (hazard ratio = 0.50; P = .024). “This almost reached the planned target of 11.6 vs 5.7 months, but the extremely good performance of the control arm made this goal not really realistic,” commented Dr. Seufferlein. “Of note, the Kaplan-Meier curves separated rather late, which suggests there might be subgroups that behave differently in response to treatment with nimotuzumab.”

Nimotuzumab plus gemcitabine was favored in most subgroups, and its benefit was independent of Karnofsky performance status. “Interestingly, 50% of patients had a Karnofsky performance status of 60 to 80, and they did as well as those whose status was 90 to 100,” Dr. Seufferlein noted.

Questions to Answer

Dr. Seufferlein concluded that nimotuzumab plus gemcitabine is a novel option for a patient population who might otherwise receive gemcitabine alone. However, he suggested, “the way to deal with these data” is to arrive at answers for the following questions:

What is the efficacy of nimotuzumab plus gemcitabine vs gemcitabine plus albumin-bound (nab) paclitaxel, the true standard of care for this patient group?

What is the effect of combination chemotherapy plus gemcitabine in KRAS wild-type tumors? Combination therapy works in KRAS wild-type tumors as well as it does in mutated tumors. In other studies, nimotuzumab has been safely combined with paclitaxel, cisplatin, and other agents. 

Is there a more pronounced effect in KRAS wild-type subgroups with known alterations in the EGFR-RAS-MAPK pathway?

Finally, Dr. Seufferlein emphasized the benefit of assessing KRAS status in pancreatic cancer. “About 10% of all pancreatic cancers are KRAS wild-type, but this rate may be even higher in younger patients,” as emerging research suggests, he added.

KRAS wild-type pancreatic cancer is a role model for a molecular tumor board,” he added. This tumor often harbors additional actionable targets—more so than KRAS-mutated tumors. Thus, studies are evaluating drugs that target NTRK, BRAF, NRG, RET, ALK, and ROS and drugs that address other abnormalities such as microsatellite instability and HER2 expression.

DISCLOSURE: Dr. Seufferlein has received honoraria from Amgen, Bayer Schering Pharma, Celgene, Falk Foundation, Merck Serono, Roche, Sanofi, and Servier; has served as a consultant or advisor to Servier, Bayer, Celgene, Merck Serono, Roche/Genentech, Cantargia, and Shire; has received research funding from Celgene and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by Celgene, Merck Serono, Roche, Sanofi, and Servier.


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: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial. 2022 ASCO Annual Meeting. Abstract LBA4011. Presented June 3, 2022.

2. Schultheis B, Reuter D, Ebert MP, et al: Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: A multicenter, randomized phase IIb study. Ann Oncol 28:2429-2435, 2017. 


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