HER kinase inhibition in patients with HER2- and HER3-mutant cancers

By D. Hyman, S. Piha-Paul, H. Won, J. Rodón, C. Saura, Geoffrey I. Shapiro, D. Juric, David I. Quinn, V. Moreno, B. Doger and 43 more. Nature, 2018

709 citations recorded by the source corpus.

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, ‘basket’ trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

Subfields: Genetics, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/559be8d9132524811840897918b18f9fac324fb6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. J. Reis-Filho
2. Nicholas J. Schork
3. Ronglai Shen

In Oncology

1. J. Reis-Filho
2. J. Baselga
3. Nikolaus Schultz
4. Larry Norton
5. K. Kerr
6. M. Hellmann
7. C. Hudis
8. M. Scaltriti

In Radiology, Nuclear Medicine and Imaging

1. J. Baselga
2. C. Hudis

Citations in the corpus

• Personalized medicine: motivation, challenges, and progress. (2018, background): “Some basket trials only have a single basket and no comparison group, but rely on determining which patient profiles appear to be associated with better outcomes for the intervention being tested.(37) Intervention matching schemes are likely to become the rule rather than the exception in medicine, ”
• The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers (2018, background): “HER2 kinase inhibitors are active in breast tumors harboring ERBB2 mutations (Hyman et al., 2018).”
• Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2018, background): “HER2 insertions are typically resistant to HER-targeting TKIs afatinib, dacomitinib and neratinib [244, 245], although some specific genotypes, e.”
• Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group. (2020, background): “ERBB2 amplifications are predictive of clinical benefit of anti-HER2 therapies, which yield an improvement of overall survival (OS) and PFS, while neratinib (an irreversible pan-HER TKI) has been associated with responses in patients with ERBB2 mutations.(55) Phase III studies reported a significant”