NCT04410653

Afatinib in Advanced NRG1-Rearranged Malignancies

Afatinib in Advanced NRG1-Rearranged Malignancies: the NCT/DKTK PMO-1604 Phase-II Trial

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 3 (actual)
• Sponsor: German Cancer Research Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Conditions

• Metastatic and Locally Advanced NRG1-rearranged Malignancies

Interventions

Type	Name	Description
DRUG	Afatinib 40 MG	single oral dose of afatinib each day starting at a dose of 40 mg on day 1, continuously, until the development of progressive disease or unacceptable adverse events

Timeline

• Start date: 2022-07-31
• Primary completion: 2023-10-04
• Completion: 2023-10-04
• First posted: 2020-06-01
• Last updated: 2024-04-05

Locations

2 sites across 1 country: Germany