John V. Heymach, MD, PhD, chair, professor, and David Bruton Jr. Chair in Cancer Research, Department of Thoracic/Head and Neck Medical Oncology, professor, Department of Cancer Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the potential utility of afatinib (Gilotrif) in 

 fusion–positive non–small cell lung cancer (NSCLC). 

 fusions are generated from a protein that includes a ligand for the EGFR receptor, says Heymach. Although the protein is in the EGFR family, the fusion is not driven by 

 activating mutations and is, instead, driven by persistent activity of the ligand, Heymach explains. Moreover, inhibiting HER3 is likely tied to 

 fusions because HER2 and HER3 are drivers of the alteration’s activity. Additionally, heregulin can bind to HER4, Heymach says.

As such, agents with a broader spectrum of activity may have clinical utility in 

 fusion–positive NSCLC. Afatinib, a pan-ErbB family inhibitor, has shown activity in patients with 

 fusion–positive NSCLC and may have utility as a novel treatment option in this patient population. Additionally, HER3-directed monoclonal antibodies are also being evaluated in this space, concludes Heymach.

Videos

John V. Heymach, MD, PhD, discusses the potential utility of afatinib in NRG1 fusion–positive non–small cell lung cancer.  



Dr. Heymach on the Potential Utility of Afatinib in NRG1 Fusion+ NSCLC 

Stephen Liu, MD, an associate professor of medicine, director of thoracic oncology, and director of developmental therapeutics at Georgetown Lombardi Comprehensive Cancer Center, discusses the rationale for examining afatinib (Gilotrif) in patients with non–small cell lung cancer (NSCLC) harboring 

 fusions are different from other fusion events that occur in patients with NSCLC, as they don’t lead to a constitutively active kinase, Liu says. NRG1 is the ligand for the transmembrane receptor. The fusion brings the EGF-like domain of NRG1 into close proximity with its receptor, which is either ErbB3 or HER3. HER3 then tends to heterodimerize with HER2, although it could also do so with HER4, HER1 or EGFR, Liu explains.

Current strategies are focused on targeting receptors, as effective agents are already available, Liu notes. Afatinib is an orally bioavailable pan ErbB kinase that was developed to inhibit the abnormal signaling downstream of 

Stephen Liu, MD, discusses the rationale for examining afatinib in patients with non–small cell lung cancer harboring NRG1 fusions.

Dr. Liu on the Rationale for Examining Afatinib in NSCLC Harboring NRG1 Fusions

 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 

 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).

 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 

 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 

 fusions may be oncogenic, and oncogenic fusions of 

-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 

 fusion–positive tumors, including those with NSCLC, suggesting that it may be a novel treatment option for this patient population.

 Currently, afatinib is being explored in 

 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 

 fusion-positive tumors in an effort to evaluate the feasibility of the trial, and also to explore treatment approaches these patients receive and how 

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 

 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 

 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 

 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, 

 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 

 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. 

 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).

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.

Gay ND, Wang Y, Beadling C, et al. Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions

. 2017;12(8):e107-e110. doi:10.1016/j.jtho.2017.04.025

Articles

January 28, 2021 - NRG1 fusions are detectable in patients with non–small cell lung cancer, providing a rationale to perform larger, retrospective studies assessing therapeutic outcomes in patients with NRG1 fusion–positive tumors and evaluate afatinib in this patient subgroup.

Updates in NRG1+ Tumors | Supplements And Featured Publications

Dr. Heymach on the Potential Utility of Afatinib in NRG1 Fusion+ NSCLC

Dr. Liu on the Rationale for Examining Afatinib in NSCLC Harboring NRG1 Fusions

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