Hepatobiliary Cancer Coverage from Every Angle

James J. Harding, MD, on New Data on Neratinib for HER2-Positive Biliary Tract Cancer

Posted: Thursday, October 6, 2022

James J. Harding, MD, of Memorial Sloan Kettering Cancer Center, discusses findings from the SUMMIT trial of neratinib for patients with HER2-positive biliary tract cancer, its modest activity, and other agents being considered for investigational regimens that might improve responses.


Disclaimer: This video transcript has not been proofread or edited and may contain errors.

This year at ASCO 2022, we presented the biliary track cohort of the SUMMIT study. The SUMMIT study is a multicenter global phase 2 study of neratinib in patients with HER2 missense alterations. The SUMMIT study design is really to explore how active the tyrosine kinase inhibitor neratinib is in patients with HER2 missense mutations. The biliary tract cohort had a primary objective response rate, secondary objectives of clinical benefit rate, progression-free survival, overall survival, and correlative objectives of understanding how genomics may influence outcome. So, for biliary tract cancers, this is a disease that is heavily treated with precision medicines. A subset of biliary tract cancers harbor missense mutation in ERBB2 or HER2. This is a small proportion of patients, maybe 1 to 5% of all biliary tract cancer patients. There are also examples of genome amplification as well as HER2 overexpression. This is more common in biliary tract cancers occurring in up to 20% of patients. For this study, we specifically selected patients with HER2 missense mutations. We enrolled a total of 25 patients over several years. The majority of patients were with gallbladder cancer or intra and extrahepatic cholangiocarcinoma. The majority of patients were heavily pretreated with a median line of two prior therapies. With regard to the primary endpoint of this study, we observed the objective response rate was 16%. We observed that the secondary objective of clinical benefit rate was about 28%. We also saw that the progression-free survival and overall survival were about 2.8 and 5.6 months respectively. These data helped to credential neratinib as a therapy for HER2 missense alterations in biliary tract cancers. However, the objective response rate was still modest compared to other therapies within the field. Because of this, we embedded correlative science to try to understand both innate and acquired resistance mechanisms to this therapy. We did observe that in patients with certain histologies such as ampullary cancer tended to do worse. Those with gallbladder cancer tended to do better with this therapy. We also observed that those patients with co-occurring mutations in TP53 and CDKN2A tended to do worse than those patients without such mutations. The sample size was small, so we can't make firm conclusions about this, but this may help us select patients better for this therapy in the future. We also looked at those patients who responded to therapy and acquired both pre-treatment and on-treatment biopsies as well as serial cell-free DNA from the peripheral blood. In one of four responders, we saw that the activating mutation in ERBB2 or HER2 was lost at the time of progression and a subset of other mutations that were not seen previously appeared to grow out. So, this again illustrates that neratinib is targeting this subset of mutations and does have some modest efficacy, but the story remains incomplete. Additional studies will focus on combination therapy and look to use this as a platform to develop further drugs. In addition to neratinib, there are other HER2 targeted therapies that are now in the clinic for biliary tract cancers and these include zanidatamab and trastuzumab deruxtecan among others. So this is, I think, an important field to watch over the next five to 10 years. And hopefully, we will see more therapies for HER2 positive and HER2 missense biliary tract cancers as time evolves. Presently, in the NCCN guidelines, there is level 2A evidence for trastuzumab and pertuzumab in HER2 over express biliary tract cancers. And again, with clinical trial investigation, we hope to augment this or improve upon it with either novel therapy or combination-based therapy.

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