 fusions, which are often first detected by RNA-based sequencing, confer a more molecularly, pathologically, and clinically diverse subtype of lung cancer compared with historical hypotheses, according to data from the eNRGy1 Global Multicenter Registry that were published in the 

Notably, these tumors, which are often PD-L1–low or –negative and have low tumor mutational burden (TMB), are modestly responsive to a variety of cytotoxic, immune-based, and targeted therapeutic approaches.

In the dataset, 72% (n = 33) of tumors (n = 46) had no PD-L1 expression, whereas 24% (n = 11) had PD-L1 expression of 1% to 49% by immunohistochemistry (IHC).

The median TMB was 0.9 mutations/megabase (range, 0-2.6; n = 11) in patients with 

 fusion–positive lung cancer. This was lower compared with patients with mutations in 

 fusions should capture molecularly heterogeneous events and not be biased toward particular clinical or pathologic features. To develop novel therapeutic strategies, stakeholders should prioritize research into the underexplored biology of 

 fusion–positive tumors and the development of rationally designed drugs,” lead study author Alexander Drilon, MD, a medical oncologist and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, and co-authors wrote in the study publication.

Lung cancer is a disease enriched with genetic activating fusions, some of which encode cancer-driving chimeric oncoproteins. Proper identification of these aberrations can match patients to highly efficacious, approved targeted therapies.

fusions have been observed across many tumor types, including lung cancer, but they have been historically difficult to characterize because of their rarity. Given the mechanism of 

 fusions, potential approaches to target the fusions have centered around inhibiting ERBB2 and/or ERBB3.

The eNRGy1 global multicenter consortium aimed to characterize the clinical, pathologic, and molecular features of 

 fusion–positive cancers, as well as their responsiveness to systemic therapies.

Investigators included in the consortium were identified by prior contributions to existing registries for other molecularly defined subtypes of lung cancer.

Eligibility criteria for patients stated that they needed to have a pathologically confirmed diagnosis of lung cancer that harbored an 

 fusion identified by an accredited laboratory by certain assays of fluorescence in situ hybridization, DNA- or RNA-based next-generation sequencing, reverse transcription-polymerase chain reaction, or detection of imbalanced gene expression.

The data submitted were anonymized to a database maintained at a single institution between June 2018 and February 2020.

Most patients included in the dataset (n = 110) were female (n = 62; 59%), Asian (n = 43; 52%), and never smokers (n = 48; 57%) living in the United States (n = 47; 43%). Patients were a median of 64 years old (range, 29-88). At diagnosis, most patients had stage I disease (n = 26; 32%), followed by stage IV disease (n = 24; 29%), stage II disease (n = 19; 23%), and stage III disease (n = 13; 16%). The vast majority of patients had adenocarcinoma (n = 103; 94%), most of which was invasive mucinous (n = 59; 57%). In patients with metastatic disease (n = 44), the most common sites of metastasis were the lung (n = 31; 71%), bone (n = 15; 34%), and lymph node (n = 10; 23%).

Additionally, of the patients with a prior smoking history (former, n = 25, 30%; current, n = 11; 13%), the median pack-year history was 37 (range, 1-135).

 fusions were identified by RNA-based assays (74%), followed by DNA-based assays (26%).

Further results revealed that the median overall survival (OS) was not reached in patients with stage 1 disease at diagnosis (95% CI, 51.5 months-undefined) compared with 52.9 months for stage II disease (95% CI, 38.8-undefined), 78.2 months for stage III disease (95% CI, 11.0-undefined), and 15.5 months for stage IV disease (95% CI, 10.3-64.5).

 fusions, upstream gene partners were noted in 84% of fusions and breakpoints were noted in 61%. Moreover, 18 unique upstream gene partners were identified, 13 of which depicted known exonic breakpoints. The most common upstream partners identified were 

which was observed in 41% of fusions, and 

, which was observed in 20% of fusions. Less common partners included 

most commonly occurred after exon 6, whereas the breakpoints for 

most commonly occurred after exon 5. The breakpoint most commonly involved with 

 fusions was exon 6, and all fusions included the 

 fusions were mutually exclusive with other known oncogenic drivers in 94% of patients (n = 103), whereas the remaining 7 patients had concurrent drivers, including 

Of the evaluable patients who received platinum-doublet chemotherapy (n = 15), 13% responded (n = 2). The disease control rate was 60% and the median progression-free survival (PFS) was 5.8 months. Patients who received a taxane following progression on a platinum doublet (n = 7) had a 14% response rate (n = 1), 71% had progressive disease (n = 5), and the median PFS was 4 months (95% CI, 0.8-5.3; range, 0.8-5.5).

Limited responses were observed with checkpoint inhibitors as well, which was consistent with the immunophenotype of 

Afatinib (Gilotrif), a pan-ERBB inhibitor, demonstrated a 25% response rate (n = 5) in evaluable patients treated with the agent (n = 20), but the most common response was progressive disease (60%; n = 12). The median PFS with afatinib was 2.8 months (95% CI, 1.9-4.3; range, 0.3-25.3) and did not differ in patients harboring a 

 fusion partner vs other fusion types. No significant OS difference was observed either among patients who received afatinib vs not (

 fusions have a diversity of fusion partners and an 

 binding domain that binds ERBB3. The development of novel therapeutics for these cancers is thus an unmet need,” concluded Drilon and co-authors.

Drilon A, Duruisseaux M, Han JY, et al. Clinicopathologic features and response to therapy of 

 fusion–driven lung cancers: the eNRGy1 global multicenter registry. 

. Published online June 2, 2021. Accessed June 24, 2021. doi:10.1200/JCO.20.03307

Articles

NRG1 fusions, which are often first detected by RNA-based sequencing, confer a more molecularly, pathologically, and clinically diverse subtype of lung cancer compared with historical hypotheses. 

NRG1 Fusions Confer Low PD-L1, Low TMB, and Limited Immunotherapy Responses in Lung Cancer

Alison Schram, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the results of the phase 1/2 eNRGy trial (NCT02912949), which were presented during the 2021 ASCO Annual Meeting, in 

Findings from the eNRGy trial demonstrated a 29% overall response rate (ORR) with zenocutuzumab, an investigational bispecific antibody, in patients with locally advanced, unresectable or metastatic, 

Confirmed partial responses (PRs) were observed in 42% of the 12 patients with 

 fusion–positive pancreatic ductal adenocarcinoma treated with the novel agent. An additional 50% of these patients derived stable disease from zenocutuzumab, Schram says. In this cohort, 100% of patients with elevated CA 19-9 measurements experienced a decline of more than 50%, Schram explains. 

The ORR was 25% in the non–small cell lung cancer cohort (n = 24) and responses were observed irrespective of prior afatinib (Gilotrif) treatment, Schram says. In the basket cohort, one patient each with breast cancer and cholangiocarcinoma derived a PR, yielding a confirmed ORR of 22% in this cohort (n = 9), Schram says.

Notably, 40% of patients had treatment ongoing at the time of the data cut-off, Schram says. As such, zenocutuzumab could offer patients with heavily pretreated 

 fusion–positive solid tumors an effective treatment option, concludes Schram. 

Videos

Alison Schram, MD, discusses the results of the phase 1/2 eNRGy trial, which were presented during the 2021 ASCO Annual Meeting, in NRG1 fusion–positive solid tumors.  



Dr. Schram on the Results of the Phase 1/2 eNRGy Trial in NRG1+ Solid Tumors 

Zenocutuzumab (MCLA-128) represents a promising novel targeted therapeutic option for patients with 

 fusion–positive cancers, according to an analysis of pooled data from the ongoing phase 1/2 eNRGy study (NCT02912949) and a global early access program presented during the 2021 ASCO Annual Meeting.

In 45 evaluable patients treated with zenocutuzumab the confirmed overall response rate (ORR) was 29%. Specifically, the ORRs for 12 patients with pancreatic adenocarcinoma (PDAC), 24 patients with non–small cell lung cancer (NSCLC), and 9 patients with other 

 fusion–positive cancers were 42%, 25%, and 22%, respectively. Additionally, tumor reduction was reported for 34 patients (76%).

“Zenocutuzumab is highly effective in pretreated 

 fusion-positive pancreatic cancer, with rapid and durable responses,” said Alison M. Schram, MD, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “There is activity across multiple NRG1 fusion-positive cancer types and an extremely well tolerated safety profile.”

NRG1, a ligand that binds to HER3, has been shown to be a clinically active target and tumors harboring 

 fusions are sensitive to HER2-, HER3-directed therapies. Zenocutuzumab is a bispecific, humanized, full-length IgG1 antibody with enhanced antibody-dependent cell-mediated cytotoxic activity that inhibits the HER3 signaling pathway. The agent has previously shown single-agent antitumor activity in several tumor types, specifically in heavily pretreated patients with metastatic breast cancer whose disease progressed on HER2 therapies in a phase 1/2 trial (NCT02912949).

eNRGy enrolled a total of 61 adult patients with locally advanced, unresectable, or metastatic sold tumors that harbor 

 gene fusions. Patients were previously treated with, or unable to receive, standard therapy and had an ECOG performance status of 2 or less. The data cutoff date was April 13, 2021, at which point 47 patients were included in the primary analysis population.

The primary end point was investigator-assessed ORR. Secondary end points included ORR per central independent radiologist review, duration of response, and safety. Zenocutuzumab was administered at a dose of 750 mg intravenously every 2 weeks until disease progression. Tumor assessments occurred every 8 weeks. Patients included in the primary analysis population were those who had the opportunity for at least 1 post baseline tumor assessment at the time of cutoff.

The median age in the PDAC cohort was 47.5 years (range, 22-72) and was 58 years (range, 32-84) and 63 years (range, 31-81) in the NSCLC and basket/other groups, respectively. The basket cohort encompassed patients with breast (n = 3), unknown primary (n = 2), and other (n = 5) cancers. The median duration of exposure to zenocutuzumab was 5.7 months (range, 1-19), 4.6 months (range, 1-12), and 5.0 months (range, 2-10) in the PDAC, NSCLC, and basket cohorts respectively.

Patients had a median of 2 prior lines of therapy (range, 0-6). Nearly all patients in the primary analysis population had metastatic disease (n = 46) and 8 patients (17%) were previously treated with afatinib (Gilotrif). At the time of data cutoff 19 patients remained on treatment, including 7 with PDAC, 6 with NSCLC, and 6 with other cancers. The most common reason for treatment discontinuation was disease progression (53%).

In a more detailed analysis of the PDAC cohort, the confirmed partial response rate was 42% (90% CI, 18%-69%), stable disease was reported in 50% of patients and 9 patients experienced tumor shrinkage. These patients were heavily pretreated and had a median of 2.5 (range, 1-4) prior lines of therapy. Further, 100% of patients with CA 19-9 measurements (n = 11) had a decline of greater than 50% in follow-up analysis from baseline.

In addition to patients with PDAC, Schram presented a case study of a male patient aged 48 years with -

-positive cholangiocarcinoma with metastases in the liver, lung, and lymph nodes. The patient received zenocutuzumab as third-line therapy following 2 lines of chemotherapy. “The patient had rapid tumor shrinkage and CA 19-9 normalization with an ongoing PR [partial response] of over 5 months into treatment,” Schram said.

Specifically, there was a 32% tumor reduction and an 84% reduction in CA 19-9 was observed (120 U/mL to 20 U/mL). At the time of data cutoff, the patient had received 7 cycles of zenocutuzumab and treatment was ongoing.

In terms of safety, the most common all-grade adverse effects (AEs) included asthenia/fatigue (35%), diarrhea (30%), and anemia (20%). Most AEs were grade 1 or 2 and no patients required dose reduction because of toxicity. There was a notable absence of severe gastrointestinal toxicity, skin toxicities, and clinical cardiotoxicity, Schram noted. In January 2021, the 

FDA granted fast track designation to zenocutuzumab

 for the treatment of patients with metastatic solid tumors that harbor NRG1 gene fusions and have progressed on standard-of-care treatment.

“This is the first prospective clinical validation of 

 fusions as actionable oncogenic drivers,” Schram said. “[It’s also] the first demonstration of effective targeting of a genomically-altered ligand and the first proof-of-concept that antibody-based therapy can target a fusion oncoprotein. Zenocutuzumab is the first genome-directed therapy for 

 fusion–positive cancer offering a potential new standard of care.”

Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. 

. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003

Schram A, Macarulla T, O’Reilly E, et al. Phase 2 study of zenocutuzumab (MCLA-128), a bispecific HER2/HER3 antibody in NRG1 fusion-positive advanced solid tumors. 

. 2021;16(suppl 3):S675. doi:10.1016/j.jtho.2021.01.1237

Zenocutuzumab represents a promising novel targeted therapeutic option for patients with NRG1 fusion–positive cancers.

Zenocutuzumab Demonstrates Clinical Activity in a Variety of NRG1+ Cancers

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.

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

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

NRG1 Fusions Confer Low PD-L1, Low TMB, and Limited Immunotherapy Responses in Lung Cancer

Dr. Schram on the Results of the Phase 1/2 eNRGy Trial in NRG1+ Solid Tumors

Zenocutuzumab Demonstrates Clinical Activity in a Variety of NRG1+ Cancers

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