NRG1 Fusion-Positive Tumour Therapies Show Early Potential

Author: By Lynda Williams, medwireNews Reporter 

medwireNews: Positive trial results for two treatments targeting NRG1 fusion-positive cancers – zenocutuzumab and seribantumab – have been presented at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA.  

Chromosomal rearrangements involving NRG1 are rare oncogenic drivers associated with solid tumours, including poor-prognosis lung cancer, explained Alison Schram, from Memorial Sloan Kettering Cancer Center in New York, USA. 

She presented phase I/II eNRGy trial data for the bispecific antibody zenocutuzumab targeting HER2 and HER3, relevant to NRG1 fusion-positive tumours because the NRG1 ligand binds to HER2, preventing HER2–HER3 dimerisation. 

“There are currently no approved therapies targeting NRG1 fusion-positive cancer and zeno [zenocutuzumab] offers a potential new standard of care”, the investigator commented, noting that the agent has been granted US Food and Drug Administration fast-track designation for NRG1-positive cancer and orphan drug status for pancreatic cancer. 

The trial recruited 83 patients with locally advanced, unresectable or metastatic solid tumours and an RNA or DNA sequencing or NanoString confirmation of an NRG1 fusion, most commonly partnered with CD74 (31%), SLC3A2 (16%) or ATP181 (13%). 

The participants were aged a median of 59 years, 59% were women and most were White (57%) or Asian (33%); the majority had non-small-cell lung cancer (NSCLC, 57%) or pancreatic ductal adenocarcinoma (PDAC, 23%). Other solid tumours represented included breast cancer, cholangiocarcinoma and colorectal cancer. 

The patients had received up to eight prior lines of treatment (median two) and at time of data analysis, 24% of participants were continuing treatment with zenocutuzumab given orally at a dose of 750 mg every 2 weeks.  

Overall, 70% of patients experienced tumour reduction and the overall response rate across the cohort was 34%, rising to 42% for patients with PDAC and 35% for those with NSCLC. At the time of analysis, the median duration of treatment was 6.3 months and treatment was ongoing in 24% of the cohort. 

Responses to zenocutuzumab were “durable”, the presenter said, lasting a median of 9.1 months, and the 6- and 12-month rates of response were 76% and 27%, respectively. 

“Zeno is extremely well tolerated”, continued Alison Schram, noting that there was no evidence of immunogenicity and that less than 1% of patients had discontinued treatment due to adverse events. The rate of grade 3 or more severe treatment-related adverse events was 5.5% and there was a “low” incidence of severe gastrointestinal or skin toxicity and no clinical cardiotoxicity, she said. 

The phase 2 CRESTONE trial findings were presented by Daniel Carrizosa, from the Levin Cancer Institute in Charlotte, North Carolina, USA, who said that the “initial data support the ability of seribantumab to produce deep and durable benefit for patients with previously treated solid tumours harbouring NRG1 fusions.” 

He reported the primary endpoint of objective response rate for 15 patients in cohort 1 of the study who had received the HER-3 inhibitor at a dose of 3 mg/week, of whom 14 had NSCLC and one pancreatic cancer. 

The participants were aged a median of 61 years, 67% were women and 67% were White, and the most common NRG1 fusion partners were CD74 (40%), SLC3A2 (33%) and SDC4 (13%). 

Efficacy analysis of 12 patients in cohort 1 showed an objective response rate of 33%, including a complete and partial response in 17% each. A further 58% of participants achieved stable disease, giving a disease control rate of 92%. The corresponding values for the 11 evaluable NSCLC patients in cohort 1 were 36%, 18%, 18%, 55% and 91%. 

Daniel Carrizosa noted that seribantumab achieved responses across a range of NRG1 fusion partners, with complete responses in tumours with the fusion partners SLC3A2 and ITGB1. 

At the time of analysis, 75% of responding patients and 53% of cohort 1 were continuing seribantumab therapy and the median duration of response has not yet been reached, he added. 

The trial’s safety summary, including all 15 patients of cohort 1 and 20 other patients who had received at least one dose of seribantumab in other cohorts, showed that any grade and grade 3 or more severe treatment-related adverse events occurred in 86% and 6% of patients, respectively. 

“Seribantumab was generally well tolerated”, the investigator said. He reported one case of dose-limiting toxicity of grade 2 fatigue and two dose reductions related to grade 1 liver enzyme elevation and grade 2 fatigue, but there were no treatment discontinuations for toxicity. 

“These data support the continued evaluation of seribantumab in the ongoing phase 2 CRESTONE study as a potential new standard of care for patients with solid tumours harbouring NRG1 fusions”, Daniel Carrizosa summarised. 

“Comprehensive genomic profiling, particularly RNA-based [next-generation sequencing], will be important to identify patients with gene fusions.” 

References 

Schram AM, Goto K, Kim D-W, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol 2022; 40 (suppl 16; abstr 105). doi: 10.1200/JCO.2022.40.16_suppl.105
 

Carrizosa DR, Burkard ME, Elamin YY, et al. CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions. J Clin Oncol 2022; 40 (suppl 16; abstr 3006). doi: 10.1200/JCO.2022.40.16_suppl.3006