NCT04410653

Afatinib in Advanced NRG1-Rearranged Malignancies

Completed Phase 2 Last updated 5 April 2024

What this trial tests

Phase 2 trial testing Afatinib 40 MG in Metastatic and Locally Advanced NRG1-rearranged Malignancies in 3 participants. Completed in 4 October 2023.

Timeline

31 July 2022

Primary endpoint
4 October 2023

4 October 2023

Quick facts

Lead sponsor	German Cancer Research Center
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	3
Start date	31 July 2022
Primary completion	4 October 2023
Estimated completion	4 October 2023
Sites	2 locations across Germany

Drugs / interventions tested

• Afatinib 40 MG — full drug profile →

Conditions studied

• Metastatic and Locally Advanced NRG1-rearranged Malignancies — all drugs for Metastatic and Locally Advanced NRG1-rearranged Malignancies →

Sponsor

German Cancer Research Center — full company profile →

Who can join

18 and older, any sex, with Metastatic and Locally Advanced NRG1-rearranged Malignancies. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Agnostic Approvals in Oncology: Getting the Right Drug to the Right Patient with the Right Genomics.
   Tateo V, Marchese PV, Mollica V, Massari F, et al · · 2023 · cited 59× · PMID 37111371 · DOI 10.3390/ph16040614
2. Neuregulin 1 Gene (<i>NRG1</i>). A Potentially New Targetable Alteration for the Treatment of Lung Cancer.
   Rosas D, Raez LE, Russo A, Rolfo C. · · 2021 · cited 29× · PMID 34680187 · DOI 10.3390/cancers13205038
3. Precision oncology for intrahepatic cholangiocarcinoma in clinical practice.
   Tomczak A, Springfeld C, Dill MT, Chang DH, et al · · 2022 · cited 28× · PMID 35986087 · DOI 10.1038/s41416-022-01932-1
4. Clinically relevant fusion oncogenes: detection and practical implications.
   Sorokin M, Rabushko E, Rozenberg JM, Mohammad T, et al · · 2022 · cited 25× · PMID 36601633 · DOI 10.1177/17588359221144108
5. NCT/DKFZ MASTER handbook of interpreting whole-genome, transcriptome, and methylome data for precision oncology.
   Mock A, Teleanu MV, Kreutzfeldt S, Heilig CE, et al · · 2023 · cited 22× · PMID 37884744 · DOI 10.1038/s41698-023-00458-w
6. Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives.
   Lellouche L, Palmieri LJ, Dermine S, Brezault C, et al · · 2021 · cited 13× · PMID 34285720 · DOI 10.1177/17588359211018539
7. Expert Consensus on the Diagnosis and Treatment of &lt;i&gt;NRG1/2&lt;/i&gt; Gene Fusion Solid Tumors.
   Xu C, Wang Q, Wang D, Wang W, et al · · 2024 · cited 8× · PMID 38414979 · DOI 10.1055/s-0044-1781457
8. NRG1 Fusions in NSCLC: Being eNRGy Conscious.
   Gupta B, Gosa Barrett L, Liu SV. · · 2024 · cited 5× · PMID 39376790 · DOI 10.2147/lctt.s464626