KEY TAKEAWAYS
- A phase 2 trial SUMMIT aimed to evaluate the efficacy of neratinib in solid tumors with oncogenic HER2 somatic mutations.
- The primary aim of the BTC cohort is to determine the initial ORR to neratinib 240 mg administered orally daily.
- The method used is an open-label, single-arm, multi-cohort trial with genomic analyses conducted in an exploratory manner.
- The ORR in the BTC cohort was 16%, with a 95% CI ranging from 4.5% to 36.1%.
- The prevalent HER2 mutations include S310F and V777L, and the prognosis seems unfavorable for patients with ampullary neoplasms or concurrent TP53.
- While neratinib has shown antineoplastic properties in individuals with recalcitrant biliary tract cancer carrying HER2 mutations, the primary objective was not achieved.
HER2 mutations are rare genomic occurrences in biliary tract malignancies (BTCs). Neratinib is an oral tyrosine kinase inhibitor that is irreversible and pan-HER. It works by interfering with the activation of constitutive receptor kinase and has demonstrated efficacy in HER2-mutant tumors.
The SUMMIT study is a phase 2, open-label, single-arm, multi-cohort trial that focused on evaluating neratinib in patients with solid tumors with oncogenic HER2 somatic mutations. The test is registered on ClinicalTrials.gov under the identifier NCT01953926. The principal aim of the BTC cohort, which has reached its conclusion, is to determine the initial objective response rate (ORR) to neratinib 240 mg administered orally daily. The secondary endpoints comprise validated objective response rate, clinical benefit rate, progression-free survival, response duration, overall survival, safety, and tolerability. The genomic analyses were conducted in an exploratory manner.
In a cohort of 25 patients who were unresponsive to treatment, including 11 cases of cholangiocarcinoma, 10 cases of gallbladder cancer, and 4 cases of ampullary cancer, the overall response rate (ORR) was found to be 16% with a 95% confidence interval (CI) ranged from 4.5% to 36.1%. The prevalent HER2 mutations included S310F (n = 11; 48%) and V777L (n = 4; 17%). The prognosis was unfavorable for patients with ampullary neoplasms or concurrent oncogenic TP53 and CDKN2A mutations. The patient exhibited a loss of amplified HER2 S310F and has acquired multiple oncogenic co-mutations previously undetected during the progression. The prevailing unfavorable occurrence is diarrhea, with 14 patients (56%) experiencing diarrhea of any grade. While neratinib has exhibited antineoplastic properties in individuals with recalcitrant biliary tract cancer carrying HER2 mutations, the principal objective was not achieved, and alternative amalgamations may warrant investigation.
Source:https://pubmed.ncbi.nlm.nih.gov/36746967/
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT01953926
Harding JJ, Piha-Paul SA, Shah RH, Murphy JJ, Cleary JM, Shapiro GI, Quinn DI, Braña I, Moreno V, Borad M, Loi S, Spanggaard I, Park H, Ford JM, Arnedos M, Stemmer SM, de la Fouchardiere C, Fountzilas C, Zhang J, DiPrimeo D, Savin C, Duygu Selcuklu S, Berger MF, Eli LD, Meric-Bernstam F, Jhaveri K, Solit DB, Abou-Alfa GK. Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers. Nat Commun. 2023 Feb 6;14(1):630. doi 10.1038/s41467-023-36399-y. PMID: 36746967; PMCID: PMC9902444.
