Real-World Study Confirms NRG1 Fusions in NSCLC, Supports Afatinib Studies

Ajeet Gajra, MD

NRG1 fusions are detectable in patients with non–small cell lung cancer (NSCLC), providing a rationale to perform larger, retrospective studies assessing therapeutic outcomes in patients with NRG1 fusion–positive tumors and evaluate afatinib (Gilotrif) in this patient subgroup, according to results of a real-world feasibility study that were presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer (WCLC).¹

Findings showed that 107 patients with NRG1 gene fusions were identified. Most patients who were treated with afatinib (n = 66) had NSCLC (39%), followed by pancreatic cancer (17%), cholangiocarcinoma (11%), colorectal cancer (CRC; 11%), ovarian cancer (6%), bladder cancer (6%), breast cancer (5%), renal cell carcinoma (RCC; 3%), thyroid cancer (2%), and other (2%).

Additionally, the total number of lines of treatment administered varied among patients treated with afatinib versus another systemic treatment in the frontline (3 vs 15, respectively), second- (18 vs 6), third- (4 vs 2), and fourth-line settings (1 vs 0).

“The data from this feasibility study support previous findings that NRG1 gene fusions are detectable in significant numbers in patients with NSCLC,” Ajeet Gajra, MD, vice president of Cardinal Health, and coinvestigators wrote in a poster presentation during the meeting. “These findings provide a rationale to perform a larger, retrospective, chart-based, real-world study assessing treatment outcomes in patients with NRG1 gene fusion–positive tumors.”

NRG1 fusions may be oncogenic, and oncogenic fusions of NRG1 may cause excess accumulation of the NRG1-fusion protein at the cell surface. This can cause persistent activation of ErbB receptor tyrosine kinases that drive excess activity in the mTOR and MAPK pathways and promote tumorigenesis, the investigators noted.

Previously, afatinib was shown to demonstrate responses with patients with NRG1 fusion–positive tumors, including those with NSCLC, suggesting that it may be a novel treatment option for this patient population.² Currently, afatinib is being explored in NRG1 gene fusion–positive tumors in the prospective TAPUR (NCT02693535) and DRUP trials (NCT02925234).

In the real-world study, investigators sought to determine the number of patients with NRG1 fusion-positive tumors in an effort to evaluate the feasibility of the trial, and also to explore treatment approaches these patients receive and how NRG1 is detected. The plan was to gain insight for a larger, retrospective, real-world study of this patient population.

In the retrospective, multicenter, feasibility trial, physicians from Cardinal Health Oncology Provider Network identified up to 30 eligible patients each with data from electronic medical records. Patient data were provided via electronic case report form, and all forms were reviewed by Cardinal Health.

Patients must have been at least 18 years old at the time of diagnosis with an NRG1 gene fusion and had initiated either afatinib or another systemic therapy with no prior afatinib; 8 or more weeks of follow-up was required.

Patients were stratified into cohorts based on if they received afatinib or another systemic treatment. The key end points were the number of patients with NRG1 gene fusions identified, number of patients treated with afatinib or another drug, and the total number of lines of systemic treatment received.

In the cohort of patients who received another systemic therapy (n = 41) the prevalence of NRG1 fusions occurred in those with NSCLC (56%), followed by breast cancer (10%), pancreatic cancer (7%), cholangiocarcinoma (7%), CRC (7%), bladder cancer (7%), ovarian cancer (2%), and RCC (2%).

Results of the NSCLC subset comprised the data presented at the 2020 WCLC. Here, the median age across both cohorts was 62 years, and nearly half of all patients were female. Most patients were White (68%), followed by Asian (12%), Black/African American (28%), and other (2%). Additionally, the majority of patients were non-Hispanic/non-Latinx (89.5%).

Investigators also noted that most molecular testing was conducted at specialist laboratories. For most patients with NSCLC, NRG1 fusion testing was performed prior to receiving frontline treatment in the afatinib (n = 15) and other systemic treatment cohorts (n = 19). The median time from testing to initiation of therapy in the afatinib group was 3 weeks in the frontline setting, 2 weeks in the second-line setting, and 3.5 weeks in the third-line setting. In the other systemic treatment group, the median time from testing to start of treatment was 2, 2, and 4 weeks, respectively.

SDC4 and CD74 were found to be the most commonly observed NRG1 fusion partners in patients with NSCLC in both the afatinib (n = 8 and 9, respectively) and other systemic therapy (n = 1 and 3, respectively) cohorts. NRG1 fusions were also most commonly detected using mRNA sequencing (n = 21; 43%).

At the time of data collection, 61% of patients in the afatinib cohort were currently on active therapy versus 35% on the other systemic treatment group; the rates of those receiving palliative care only were 19% and 17%, respectively. Three patients on afatinib had died compared with 6 on the other cohort. Four patients in the other systemic treatment arm were alive not currently on treatment versus 0 on afatinib. The number of patients who progressed on therapy were 19% and 22% on afatinib and other treatment, respectively.

Data also showed that afatinib was most commonly received as second-line treatment in patients with NSCLC (n = 17), versus the frontline (n = 4), third- (n = 5), and fourth-line settings (n = 1). Other treatment was most often given up front (n = 23), compared with the second- (n = 8) and third-line settings (n = 2).

In the other systemic therapies cohort, patients received a broad range of agents up front (n = 23), including: carboplatin/paclitaxel (22%); pembrolizumab (Keytruda), cisplatin/paclitaxel or nab-paclitaxel (Abraxane; 17%); cisplatin/pemetrexed with or without bevacizumab (Avastin; 17%); pembrolizumab/carboplatin/pemetrexed (13%); cisplatin/vinorelbine with or without bevacizumab (9%); atezolizumab (Tecentriq), bevacizumab, carboplatin, and docetaxel; cisplatin/gemcitabine with or without bevacizumab; carboplatin/pemetrexed and bevacizumab; cisplatin/docetaxel with or without bevacizumab; and pembrolizumab (all n = 1 each; 4%).

In the second-line setting (n = 8), patients received pembrolizumab alone (75%), ramucirumab (Cyramza) and docetaxel (12.5%), or nivolumab (Opdivo; 12.5%). As third-line treatment (n = 2), the options were single-agent paclitaxel or erlotinib (Tarceva; 50% each).

References

1. Gajra A, Klink AJ, Kaufman J, et al. A real-world feasibility study of patients with solid tumors harboring NRG1 gene fusions: NSCLC subset analysis. Presented at: 2020 International Association for the Study of Lung Cancer; January 28-31, 2021; Virtual. Abstract P86.11.
2. Gay ND, Wang Y, Beadling C, et al. Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions. J Thorac Oncol. 2017;12(8):e107-e110. doi:10.1016/j.jtho.2017.04.025