Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series

Abstract

Background: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.

Patients and methods: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.

Results: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.

Conclusion: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.

Key points: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

Keywords: Afatinib; Case series; ErbB-targeted treatment; Gene fusion; NRG1.

Figure 1

Computed tomography images of patients with metastatic lung cancer showing response to afatinib treatment. Case 1: Nonmucinous lung adenocarcinoma. (A): Prior to treatment in February 2015. (B): Partial response (PR) in April 2015 after 2.5 months on afatinib treatment. Case 2: Nonmucinous lung adenocarcinoma. (C): Prior to treatment in December 2017. (D): PR in November 2018 after 11 months on afatinib treatment. Case 3: Invasive nonmucinous lung adenocarcinoma. (E): Prior to treatment in July 2018. (F): Stable disease for 4 months in December 2018 after 4 months of afatinib treatment in December 2018. (Scans taken early December 2018 before PD.) Case 4: Invasive mucinous lung adenocarcinoma. (G): Prior to treatment in July 2017. (H): PR in March 2019 after 18 months of afatinib treatment. Case 5: Invasive mucinous lung adenocarcinoma. (I): Prior to treatment in Jan 2018. (J): PR in March 2018 after afatinib treatment. (K): Progressive disease (PD) in June 2018 while on afatinib. (L): PR in August 2018 after an afatinib dose increase to 50 mg/day.

Figure 2

Timelines for new cases of patients with metastatic NRG1 fusion‐driven solid tumors who were treated with afatinib. Abbreviations: CEA, carcinoembryonic antigen; FOLFOX, 5‐fluorouracil, oxaliplatin, and folinic acid; NRG1, neuregulin 1; PD, progressive disease; PR, partial response; qd, every day; RT, radiotherapy; SBRT, stereotactic body radiation; SD, stable disease.

Figure 3

Case 4: Total body positron emission tomography‐computed tomography (PET‐CT) scan with fusion imaging. (A): May 2019, preoperative PET‐CT staging showed a non‐RECIST progression of the left lower lobe only residual target lesion (yellow circle) while the patient received afatinib (40 mg/day). (B): October 2019, the patient was admitted for spine and sacrum pains. PET‐CT showed numerous osteolytic and osteocondensant bone metastatic lesions (red circles). Comparison between May (C) and October (D) PET‐CT fusion centered on the sacrum.

Figure 4

Computed tomography imaging from Case 6 of a patient with metastatic colorectal cancer showing stable disease while on afatinib treatment. (A): Pretreatment in August 2018. (B): After 2 months of treatment with afatinib in November 2018. (C): After 4 months of treatment with afatinib in January 2019. (D): After 7 months of treatment with afatinib in April 2019. Abbreviation: RT, radiotherapy.