Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in
the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program
revealed recurrent NRG1 fusions in a substantial proportion of patients with KRAS wild-type
(KRASwt) pancreatic adenocarcinoma (PDAC) and a case of signet-ring cell carcinoma of the
appendix. NRG1 rearrangements drive tumor development through ERBB receptor-mediated
signaling, as evidenced by objective response to ERBB inhibition in two cases of
NRG1-rearranged PDAC in the MASTER cohort. Recently, NRG1 fusions have also been identified
as a therapeutic target in a substantial number of the invasive mucinous subtype of lung
adenocarcinoma (IMA) as well as in cholangiocellular carcinoma and, at low incidence, other
tumor entities, suggesting oncogenic properties across a broader spectrum of malignancies.
Within this phase II clinical trial, the investigators aim to investigate the efficacy of the
pan-ERBB inhibitor afatinib in advanced-stage NRG1-rearranged malignancies across all tumor
entities following progression on standard therapy. Due to the enrichment of
NRG1-rearrangements observed in KRASwt PDAC and IMA, two separate study arms will focus on
these tumor entities while a third arm will allow inclusion of patients with any other NRG1
rearranged malignancy. Recruitment of adequate patient numbers in this well-defined molecular
subgroup will be achieved by a multicenter approach including all DKTK partner sites and
on-site pre-screening of PDAC for KRAS mutational status. Eligible patients will be
identified by in-depth molecular characterization of tumors within the NCT/DKTK MASTER
program or identification of a NRG1-rearranged tumor by another method for fusion detection
(e.g. gene fusion panel).
Patients with NRG1-rearranged tumors fulfilling eligibility criteria will be offered to
participate in the trial and receive afatinib monotherapy until tumor progression or
discontinuation for other reasons. To assess mechanisms of secondary resistance and to
investigate the clinical impact of liquid biopsies in this setting, blood samples for exome
sequencing will be taken prior to initiation of the study treatment as well as at the time of
progression.
Phase:
Phase 2
Details
Lead Sponsor:
German Cancer Research Center
Collaborator:
German Consortium for Translational Cancer Research