Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer

Abstract

Background:

NRG1 fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to HER3, leading to heterodimerization with HER2 and activation of downstream survival and proliferation pathways. We evaluated the efficacy and safety of zenocutuzumab, a HER2/HER3 bispecific antibody, in patients with NRG1 fusion-positive solid tumors (NRG1+ cancer).

Methods:

In this tumor-agnostic, registrational phase 2 clinical study, patients with advanced NRG1+ cancer received zenocutuzumab at 750 mg intravenously every 2 weeks. The primary end point was overall response rate by investigator assessment. Secondary end points included duration of response, progression-free survival, and safety.

Results:

204 patients with 12 tumor types were enrolled and treated. Among 158 patients with measurable disease and enrolled at least 24 weeks before the data cutoff date, the response rate was 30% (95% confidence interval [CI], 23 to 37). The median duration of response was 11.1 months (95% CI, 7.4 to 12.9); 19% of responses were ongoing. Responses were observed in multiple tumor types, including 27 patients with non–small-cell lung cancer (NSCLC; response rate, 29%; 95% CI, 20 to 39; n=93), 15 with pancreatic adenocarcinoma (response rate, 42%; 95% CI, 25 to 59; n=36), and across multiple NRG1 fusion partners. Median progression-free survival was 6.8 months (95% CI, 5.5 to 9.1). The most common treatment-related adverse events were diarrhea (in 18% of patients), fatigue (12%), and nausea (11%). One patient discontinued due to a treatment-related adverse event.

Conclusions:

Zenocutuzumab demonstrated efficacy in patients with advanced NRG1+ cancer, notably NSCLC and pancreatic adenocarcinoma, with mainly low-grade adverse events. (Funded by Merus N.V.; eNRGy ClinicalTrials.gov number: NCT02912949)

INTRODUCTION

Neuregulin 1 (NRG1) is an epidermal growth factor (EGF) involved in nervous system and cardiac development and homeostasis.¹ Recurrent chromosomal rearrangements involving the 3’ end of NRG1 (inclusive of an encoded EGF-like domain) have been identified across diverse cancers.^2,3 NRG1 fusions occur in less than 1% of solid tumors, are enriched in invasive mucinous adenocarcinoma of the lung and KRAS wild-type pancreatic adenocarcinoma,^4–11 and are oncogenic in vitro and in vivo.^2,12,13 Chimeric NRG1 fusion proteins bind to HER3 via an EGF-like binding domain, triggering HER2/HER3 heterodimerization and activation of downstream growth and proliferation signaling pathways.^6,14 Therefore, targeting HER2 and HER3 represents a potential therapeutic approach for patients with NRG1 fusion-positive (NRG1+) cancer, regardless of tumor type.¹⁵

Zenocutuzumab (MCLA-128) is a first-in-class, humanized, full-length immunoglobulin G1 bispecific antibody directed against HER2 and HER3. After docking on HER2, zenocutuzumab independently blocks HER2/HER3 dimerization and NRG1 fusion interactions with HER3, resulting in suppression of tumor cell proliferation and survival through the PI3K/AKT/mTOR oncogenic signaling pathway. In vitro, zenocutuzumab also mediates antibody-dependent cellular cytotoxicity.¹⁶ Preclinical investigations have demonstrated the anticancer activity of zenocutuzumab in multiple tumor types.^12,16

The efficacy of zenocutuzumab was evaluated in a phase 2 clinical study (eNRGy).¹⁷ We report efficacy and safety analyses of consecutively enrolled patients with advanced solid tumors harboring an NRG1 fusion treated with zenocutuzumab monotherapy. Zenocutuzumab was also made available to patients with NRG1+ cancer via an Early Access Program (see Supplementary Appendix for details and data).

PATIENTS AND METHODS

Study Design and Treatment

The eNRGy study is the phase 2 component of an open-label phase 1/2 clinical study of zenocutuzumab in patients with NRG1+ cancer. Patients were treated at 49 centers in 12 countries (see Supplementary Appendix).

Eligible patients received zenocutuzumab 750 mg (2-hour intravenous infusion every 2 weeks) until disease progression, death, unacceptable toxicity, or withdrawal of consent. Details of dose selection are included in the Supplementary Appendix. To mitigate potential infusion-related reactions, the initial infusion was administered over 4 hours and patients received premedication with antipyretics, antihistamines, and glucocorticoids. Dose reductions were not permitted. Patients could continue treatment with zenocutuzumab beyond disease progression based on investigator assessment and approval by the sponsor.

An Early Access Program was opened to provide zenocutuzumab for patients with NRG1+ cancer who were unable to participate in the eNRGy study (see Supplementary Appendix).

Patients

Eligible patients were 18 years or older, diagnosed with an advanced or metastatic solid tumor, and had received standard therapy for their tumor type or were not candidates for standard therapy in the opinion of the investigator. Patients were required to have a tumor with an NRG1 gene fusion, identified by next-generation sequencing (DNA-/RNA-based) through local testing in a Clinical Laboratory Improvement Amendments–certified laboratory (or equivalent). Other inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 to 2 (on a scale of 0 to 5, with higher scores indicating greater disability), and investigator-assessed measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1¹⁸ (evaluable non-measurable disease was permitted for up to 10 patients). Patients with prior exposure to HER family–directed antibodies or small molecule inhibitors were eligible. Full eligibility criteria are in the eNRGy protocol available at NEJM.org. Representativeness of the eNRGy study population is shown in Table S1.

Study Oversight

The eNRGy study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable country and local regulations. All patients provided written informed consent before enrollment. The protocol was approved by the institutional review board or independent ethics committee at each participating center.

The study was designed by the sponsor (Merus N.V.) with input from the investigators. The data were collected by investigators and analyzed by statisticians employed by the sponsor. The sponsor and first and last authors developed the first draft with medical writing funded by the sponsor for the first and subsequent drafts (Oncology Therapeutic Development, LiNK Health Group). All authors contributed to the interpretation of data and preparation of the manuscript, vouch for the completeness and accuracy of the data and the fidelity of the study to the protocol.

End points

The primary end point was overall response rate per investigator assessment and RECIST version 1.1.¹⁸ The key secondary end point was duration of response per investigator assessment. Secondary end points included response rate and duration of response per blinded independent central review (BICR), time to response, progression-free survival (investigator-assessed and BICR), safety, pharmacokinetics, and immunogenicity assessments.

Assessments

Tumor assessments (computed tomography or magnetic resonance imaging) were performed at baseline and every 8 weeks until disease progression. Tumor responses were confirmed at least 4 weeks after the initial response. Adverse events were assessed from the date of the first zenocutuzumab dose up to 30 days after the last dose and graded according to the Common Terminology Criteria for Adverse Events, version 4.03. Pharmacokinetic, immunogenicity, and tumor marker analyses are detailed in the Supplementary Appendix.

Statistical Analyses

Analyses were conducted according to the statistical analysis plan available with the protocol at NEJM.org. The primary efficacy set included patients with: a documented NRG1 fusion identified by local testing or centralized prescreening using next-generation sequencing with predicted functionality (presence of an EGF-like domain, in-frame NRG1 fusion partner, 3’ direction, and identification of the fusion partner in the nucleic acid sequence); received at least one dose of zenocutuzumab 750 mg, with the first dose at least 24 weeks before the data cutoff date; absence of other known, prespecified oncogenic genomic alterations; and no exposure to prior anti-HER3–targeting antibodies. Efficacy was also investigated in prespecified subsets: patients with non–small-cell lung cancer (NSCLC) regardless of prior therapies, NSCLC previously treated with systemic anticancer therapy, and patients with pancreatic cancer (see Supplementary Appendix). Patients without measurable disease at baseline were not evaluable for the primary end point.

Different scenarios were considered according to the observed response rate to determine a sample size providing sufficient precision to exclude hypothesized response rates based on the lower bound of the 90% confidence interval (CI). Forty patients provide sufficient precision to exclude a response rate of 10% based on the lower bound of the 90% CI, assuming an observed response rate of 20%.

Two-sided 95% exact CI for the proportions were calculated using the Clopper–Pearson method. Time-to-event end points were analyzed using the Kaplan–Meier method, and the corresponding 95% confidence intervals were calculated using the Brookmeyer-Crowley method. Safety was analyzed in all patients who received at least one dose of zenocutuzumab.

RESULTS

Patient Population

Between September 25, 2019 and the data cutoff date (January 31, 2024), 204 patients with NRG1+ cancer were treated with zenocutuzumab; 43 of these patients were excluded from the primary analysis set, mostly due to receiving the first zenocutuzumab dose less than 24 weeks before the data cutoff date. Other reasons were the presence of other oncogenic drivers, prior treatment with anti-HER3 antibodies, or a non-functional NRG1 fusion; 1 patient received prohibited anticancer medication (Fig. S1). Among the 161 patients included in the primary efficacy set, 10 tumor types were reported (Table 1), primarily NSCLC (94 patients) and pancreatic adenocarcinoma (36 patients). The median age was 62 years (range, 21 to 88). Most patients were female (60%). Patient demographics, prior therapies, disease and NRG1 fusion characteristics are summarized in Tables 1, S2, and S3.

Table 1.

Demographic and Clinical Characteristics of the Primary Efficacy Set (N=161).^*

Characteristic	Value
Median age (range) — yr	62 (21─88)
Female sex — no. (%)	97 (60)
Race — no. (%)†
White	87 (54)
Asian	56 (35)
Black or African American	4 (2)
Other	5 (3)
Not reported	9 (6)
ECOG performance status — no. (%)‡
0	64 (40)
1	89 (55)
2	8 (5)
Primary tumor type — no. (%)
Non–small-cell lung cancer§	94 (58)
Pancreatic ductal adenocarcinoma¶	36 (22)
Cholangiocarcinoma	10 (6)
Breast cancer‖	9 (6)
Colorectal adenocarcinoma	6 (4)
Cancer of unknown primary	2 (1)
Endometrial sarcoma	1 (1)
Gastric cancer	1 (1)
Ovarian cancer	1 (1)
Renal cell carcinoma	1 (1)
Central nervous system metastases — no. (%)	14 (9)
NRG1 fusion partner — no. (%)
CD74	56 (35)
SLC3A2	22 (14)
ATP1B1	17 (11)
SDC4	12 (7)
RBPMS	5 (3)
Other**	49 (30)
Previous systemic therapies — median (range)	2 (0─10)
Prior systemic treatment — no. (%)
Naïve	14 (9)
Chemotherapy	142 (88)
Immunotherapy††	62 (39)
Targeted therapy‡‡	44 (27)
Hormonal therapy	8 (5)

^*Percentages may not total 100 because of rounding.

^†Race was reported by the patients.

^‡Performance status scores on the ECOG scale range from 0 (no disability) to 5 (death).

^§Includes 14 patients with invasive mucinous adenocarcinoma, and 1 patient with non-measurable disease.

^¶All 36 patients with pancreatic cancer had KRAS wild-type disease.

^‖Includes 2 patients with non-measurable disease.

^**Other fusion partners identified in single tumors were ADAMTSL3, AGRN, ALB, CCT6B, CFH, CSMD1, CXADR, DAAM1, DLGAP2, FRY, FUT10, GTF2E2, MTUS1, NSD3, PTN, PVALB, SLC34A2, SOX6, SPIDR, ST14, THBS1, TNFRSF10D, TNFSF15, VAMP2, WHSC1L1, WRN, and ZFAT; ASPH was identified in 2 patients; CD44, CDH1, SLC4A4, and VTCN1 were identified in 3 patients each; APP and NOTCH2 were identified in 4 patients each.

^††All except 1 patient received anti-PD-(L)1 therapy.

^‡‡Anti-VEGF(R) inhibitor (19 patients), afatinib (11 patients), CDK4/6 inhibitor (7 patients), other EGFR inhibitor (6 patients), mTOR inhibitor (everolimus, 3 patients), and other targeted therapies (8 patients; nintedanib [2 patients], olaparib [2 patients], tarloxotinib [1 patient], zolbetuximab [1 patient], savolitinib [1 patient], lenvatinib [1 patient]). CDK4/6 denotes cyclin-dependent kinase 4/6, ECOG Eastern Cooperative Oncology Group, EGFR epidermal growth factor receptor, mTOR mechanistic target of rapamycin, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, and VEGF(R) vascular endothelial growth factor (receptor).

Thirty-nine distinct NRG1 fusion partners were identified, primarily by RNA-based next-generation sequencing (86% of patients). The most common fusion partners among patients with NSCLC were CD74 (in 56%) and SLC3A2 (in 23%), and ATP1B1 in patients with pancreatic cancer (in 44%). Concomitant genomic driver alterations were identified in 10 of the 204 treated patients (5%) and, per protocol, all were excluded from the primary efficacy set (Table S4). Forty of the 42 treated patients (95%) with pancreatic cancer had KRAS wild-type disease, including all 36 of these patients who were evaluable for efficacy.

Of the 94 patients with NSCLC, 82 (87%) had received prior systemic therapy, including platinum-based chemotherapy (76%), immunotherapy (56%), and afatinib (9%); 72 patients (77%) had received systemic therapy for metastatic disease. Most patients with pancreatic cancer (35/36 patients; 97%) had received prior systemic therapy (FOLFIRINOX and/or gemcitabine/taxane); 33 (92%) had received systemic therapy for metastatic disease (Table S3).

At the data cutoff date, the median duration of exposure in the 204 treated patients was 5.5 months (range, 0.1 to 42.3) and treatment was ongoing in 52 patients (25%).

Efficacy

Among 158 efficacy-evaluable patients (Fig. S1), 47 had an investigator-assessed confirmed objective response, including one complete response, yielding a response rate of 30% (95% CI, 23 to 37) (Table 2, Fig. 1A). Among patients with a confirmed response, the median duration of response (investigator-assessed) was 11.1 months (95% CI, 7.4 to 12.9) (Table 2, Figs. 1B, S2), and 19% (9/47) of responses were ongoing at the data cutoff date, with a median follow-up of 7.1 months. The Kaplan–Meier probability estimates of duration of response at 6 and 12 months were 77% and 42%, respectively. The median time to response was 1.8 months, consistent with the first protocol-planned tumor assessment (Fig. 1B). Tumor reduction was observed in 114 of 158 patients (72%) (Fig. 1A).

Table 2.

Efficacy of Zenocutuzumab in NRG1+ Cancer Across Multiple Tumor Types.

	Investigator Assessment			BICR
Tumor Type	Overall Response Rate*		Median Duration of Response† (Range) in Months	Overall Response Rate*		Median Duration of Response† (Range) in Months
	n / N	% (95% CI)		n / N	% (95% CI)
All NRG1+ tumor types	47 / 158	30 (23–37)	11.1 (1.7+ to 29.5+)	50 / 160	31 (24–39)	11.5 (1.9+ to 29.5+)
Non–small-cell lung cancer	27 / 93	29 (20–39)	12.7 (1.8+ to 29.5+)	29 / 94	31 (22–41)	13.4 (1.9+ to 29.5+)
Pancreatic adenocarcinoma	15 / 36	42 (25–59)	7.4 (2.1+ to 20.7)	16 / 36	44 (28–62)	9.1 (1.9+ to 16.6)
Cholangiocarcinoma	2 / 10	20 (2–56)	9.2 (7.4–11.1)	2 / 10	20 (2–56)	8.3 (3.7–12.9)
Breast cancer	1 / 7	1 PR	1.7+	0 / 8	0	NA
Colorectal cancer	0 / 6	0	NA	1 / 6	1 PR	11.7
Cancer of unknown primary	0 / 2	0	NA	0 / 2	0	NA
Endometrial cancer	0 / 1	0	NA	0 / 1	0	NA
Gastric cancer	1 / 1	1 PR	1.9+	1 / 1	1 PR	1.9+
Ovarian cancer	1 / 1	1 PR	12.8	1 / 1	1 PR	12.8+
Renal cell carcinoma	0 / 1	0	NA	0 / 1	0	NA

^*For investigator assessment, percentages were based on the number of patients with measurable disease at baseline by investigator. For BICR, percentages were based on the number of patients with measurable disease at baseline by either the investigator or by BICR (i.e., patients were excluded if they had non-measurable disease by both investigator and BICR). Analyses were based on confirmed objective responses per the Response Evaluation Criteria in Solid Tumors, version 1.1. For tumor types with 8 or fewer patients, only confirmed objective responses and corresponding duration of response are reported. See Table S5 for details of confirmed objective responses in patients with non–small-cell lung cancer and pancreatic cancer.

^†Analyses of duration of response were performed in patients with a confirmed objective response. BICR denotes blinded independent central review, CI confidence interval, NA not applicable, NRG1+ neuregulin 1 fusion-positive, PR partial response, and + censored at the time of the data cutoff date.

Figure 1. Efficacy of Zenocutuzumab in NRG1+ Cancer.

Panel A shows a waterfall plot of the maximum percent change from baseline in target lesion tumor burden (sum of the longest diameters) per investigator assessment. The upper and lower limits of the gray shading indicate 20% growth and 30% shrinkage of target lesions, respectively. Among 158 patients in the primary efficacy set with measurable disease, 10 patients discontinued without a post-baseline target lesion response assessment. Panel B shows a swimmer plot of outcomes, including time to response, duration of exposure, and patient status in 161 patients in the primary efficacy set. Arrows indicate that treatment is ongoing at the data cutoff date. NRG1+ denotes neuregulin 1 fusion-positive, and NSCLC non-small cell lung cancer.

A. Maximum Change in Tumor Burden According to Tumor Type

B. Response Status and Exposure Duration in Individual Patients Over Time

Antitumor activity was observed across multiple tumor types (Figs. 1A, S3). Among 93 patients with NSCLC and measurable disease, investigator-assessed responses were observed in 27 patients (29%; 95% CI, 20 to 39) (Tables 2, S5 Fig. S4A), with a median duration of response of 12.7 months (95% CI, 7.4 to 20.4) (Fig. S5). For the 81 patients with previously-treated NSCLC and measurable disease, the response rate was 28% (95% CI, 19 to 39) (Table S6). Fifteen of 36 patients with pancreatic cancer responded (42%; 95% CI, 25 to 59) (Tables 2, S5, Fig. S4B), with a median duration of response of 7.4 months (95% CI, 4.0 to 11.2) (Fig. S6). Twenty-four of 31 patients (77%) with pancreatic cancer who had available cancer antigen 19–9 data at baseline, had a decline of at least 50% from baseline (Fig. S7). Other tumor types showing objective responses were cholangiocarcinoma (two patients) and breast cancer, gastric cancer, and ovarian cancer (one patient each) (Figs. 1A, S3). Median progression-free survival was 6.8 months both in the primary efficacy set (95% CI, 5.5 to 9.1) and in patients with NSCLC (95% CI, 5.3 to 7.5), and 9.2 months (95% CI, 5.5 to 11.2) in patients with pancreatic cancer (Table S7, Fig. S8).

Prespecified subgroup analyses showed consistent efficacy across NRG1 fusion partners, with confirmed responses in 14 of 37 NRG1 fusion partners (38%) in patients with measurable disease assessed for response (Table S8, Fig. S9), across number of lines of prior therapy, and other demographic and disease parameters (Fig. S10). Assessment of efficacy by BICR was consistent with investigator assessment (Tables 2, S5, S6, and S8), with a 31% response rate including 3 confirmed complete responses, and a response in an additional tumor type (colorectal cancer). In the Early Access Program, 5 of 12 patients (42%) had investigator-assessed responses (see Supplementary Appendix).

Pharmacokinetics

The pharmacokinetic profile of zenocutuzumab was consistent with that reported for other humanized monoclonal antibodies.^19,20 The geometric mean half-life at steady state was 8 days, and the median time to steady state was 8 weeks (see Supplementary Appendix). Geometric mean serum trough concentrations after administration of 750 mg every 2 weeks were 18 µg/ml following a single dose and 41 µg/ml at steady state, which were several fold higher than the concentration resulting in 50% receptor occupancy of HER3 in vitro (0.089 µg/ml).¹⁶ Maximal HER3 saturation (>95%) is expected to be maintained throughout the dosing interval. No relevant differences in the pharmacokinetic profiles of zenocutuzumab were observed across tumor types.

Safety

Table 3 shows adverse events, regardless of attribution, occurring in at least 10% of patients. Among 204 patients treated with zenocutuzumab 750 mg every 2 weeks, 194 (95%) experienced at least one adverse event, predominantly grade 1 or 2. The most common grade 3 or 4 adverse events, regardless of attribution, were anemia (5% of patients), gamma-glutamyl transferase increased (4%), and pneumonia (3%). Infusion-related reactions (composite term), which were treatment-related adverse events, occurred in 14% of patients and were all grade 1 or 2 (Table S9); two patients experienced two infusion-related reactions. These reactions were clinically manageable with glucocorticoids and antihistamines. Grade 3 or 4 events related to treatment were experienced by 14 patients (7%). The most common grade 3 treatment-related adverse events were diarrhea and anemia (three patients each), and all other grade 3 or 4 events occurred in one or two patients (Table 3). None of these events resulted in discontinuation of treatment, though 3 patients discontinued due to progressive disease before resolution of these adverse events. Fatal adverse events occurred in 9 patients (4%), none of which were considered treatment-related.

Table 3.

Adverse Events in NRG1+ Cancer Patients (N=204).^*

	Regardless of Attribution		Treatment-related
	Any Grade	Grades 3–4	Any Grade	Grades 3–4
	Number of patients (%)
Any adverse event	194 (95)	72 (35)	135 (66)	14 (7)
Serious	49 (24)	33 (16)	4 (2)	2 (1)
Led to treatment discontinuation	15 (7)	8 (4)	1 (<1)	0
Led to treatment delay	64 (31)	36 (18)	12 (6)	3 (1)
Deaths	9 (4)	0	0	0
Diarrhea	60 (29)	4 (2)	37 (18)	3 (1)
Fatigue	42 (21)	5 (2)	24 (12)	0
Nausea	40 (20)	4 (2)	23 (11)	2 (1)
Anemia	34 (17)	10 (5)	9 (4)	3 (1)
Dyspnea†	33 (16)	5 (2)	4 (2)	0
Constipation	28 (14)	0	7 (3)	0
Vomiting	28 (14)	2 (1)	12 (6)	1 (<1)
Alanine aminotransferase increased	25 (12)	6 (3)	7 (3)	1 (<1)
Abdominal pain‡	26 (13)	4 (2)	3 (1)	1 (<1)
Cough§	24 (12)	1 (<1)	3 (1)	0
Hypomagnesemia	23 (11)	4 (2)	5 (2)	0
COVID-19¶	22 (11)	1 (<1)	0	0
Arthralgia	21 (10)	0	7 (3)	0
Aspartate aminotransferase increased	21 (10)	6 (3)	6 (3)	2 (1)
Decreased appetite	20 (10)	2 (1)	5 (2)	1 (<1)

^*Investigator-reported adverse events listed are those that occurred at any grade during treatment in at least 10% of patients treated with zenocutuzumab 750 mg every 2 weeks, regardless of attribution. The relatedness of the treatment to adverse events was determined by the investigators.

^†Includes the preferred term dyspnea exertional.

^‡Includes the preferred term abdominal pain upper.

^§Includes the preferred term productive cough.

^¶Includes the preferred term COVID-19 pneumonia. One patient (<1%) had grade 5 COVID-19. COVID-19 denotes coronavirus disease 2019, and NRG1+ neuregulin 1 fusion-positive.

One patient discontinued treatment due to a drug-related toxicity (grade 2 pneumonitis). Adverse events resulting in treatment delay were reported in 31% of patients (including 6% with a treatment-related delay), and in an infusion interruption in 10% of patients. Three patients of 115 who were assessed for left ventricular ejection fraction (LVEF) shifts from baseline had an isolated treatment-emergent grade 2 LVEF decrease, deemed not clinically significant by the investigator. Among 153 patients assessable for antidrug antibodies, 7 (5%) had treatment-emergent antidrug antibodies.

DISCUSSION

In the multicenter global eNRGy study, zenocutuzumab, a HER2/HER3 bispecific antibody, demonstrated durable antitumor activity in patients with NRG1+ cancer. NRG1 fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors (NTRK, RET, ROS1, ALK, and FGFR fusions). No targeted therapy for NRG1+ cancer is approved. This clinical study targeted cancers with this rare genomic alteration, a population enriched for cancer types with limited effective treatment options.^8,9,21

The response rate with zenocutuzumab in patients with NRG1+ cancer was 30%, with an 11.1-month median duration of response. Efficacy was observed in multiple tumor types and across many fusion partners. Antitumor activity observed in the Early Access Program was consistent with the eNRGy study (see Supplementary Appendix). A broad range of solid tumor types were included in the eNRGy study, with the highest enrollment in NSCLC and pancreatic cancer. Among patients with NSCLC, the response rate was 29% with 6.8-month progression-free survival, and a 28% response rate in previously-treated patients. This compares favorably to outcomes associated with the use of standard therapy in this population.²¹ Notably, the benefit of standard therapy for NRG1+ NSCLC may be overestimated and NRG1+ invasive mucinous adenocarcinoma of the lung has been linked to aggressive clinical and histologic features.^8,9 In the largest published series of NRG1+ cancer, 110 patients with NRG1+ NSCLC (57% with invasive mucinous adenocarcinoma) had a particularly poor prognosis, with low response rates to standard-of-care treatments, including platinum-based chemotherapy (response rate 13%) and single-agent immunotherapy (response rate 20%; progression-free survival 3.6 months).⁹

Standard treatment for pancreatic cancer is associated with marginal efficacy after first-line chemotherapy.²² Zenocutuzumab demonstrated promising activity in patients with pancreatic cancer, with a response rate of 42% and median duration of response of 7.4 months. Responses were observed in additional tumor types, including cholangiocarcinoma, breast, ovarian, gastric, and colorectal cancer (the latter only by BICR).

Zenocutuzumab treatment was safe. Adverse events were primarily grade 1 or 2, and investigators did not identify any grade 3 or greater adverse events in more than 5% of patients. The safety profile is remarkable with a low incidence of gastrointestinal, skin, and cardiac toxicities, which are known side effects of wild-type HER2 inhibition.

The eNRGy study tested a specific oncogenic driver alteration in tumors using a disease-agnostic approach. Molecularly selected basket studies have been used to evaluate therapies in a number of settings. To date, eight drug–biomarker pairs have received tumor-agnostic approval for the treatment of advanced solid tumors with specific genomic profiles.^23–30 In the eNRGy study, efficacy was observed in multiple cancer types supporting the potential of zenocutuzumab as a tumor-agnostic therapy for NRG1+ cancer. Patient enrollment was substantially higher for NSCLC and pancreatic cancer compared with other tumor types, and additional data could clarify the effect of histology on efficacy. Of note, the majority of patients enrolled in this global study were White (54%) and Asian (33%), and Black participants (3%) were underrepresented in the eNRGy population (Tables S1 and S2).

Alternate agents targeting HER signaling have also demonstrated antitumor activity in NRG1+ cancer. In a retrospective series of NRG1+ NSCLC, 25% of patients treated with afatinib achieved partial responses, with a median progression-free survival of 2.8 months, while 60% had a best response of disease progression. A phase 2 study investigating treatment with seribantumab, an anti-HER3 immunoglobulin G2 monoclonal antibody, reported a response rate of 36% in 22 patients with NRG1+ cancer; however, clinical development of seribantumab was on hold as of January 2023.³¹

Importantly, NRG1 rearrangements are often not detected by DNA-based sequencing techniques as the large introns in NRG1 are not typically included in targeted next-generation sequencing panels or whole-exome sequencing.³² RNA-based sequencing, which was predominantly used in the eNRGy study, is a superior method for identifying these alterations. In line with published data,^4–6 a low incidence of concurrent driver alterations was reported in patients in the eNRGy study, supporting the use of RNA-based sequencing in patients with driver-negative tumors, including those with NSCLC and KRAS wild-type pancreatic cancer, to test more comprehensively for gene fusions.³³

In conclusion, the HER2/HER3 bispecific antibody, zenocutuzumab, demonstrates antitumor activity in patients with advanced NRG1+ cancer, notably in NSCLC and pancreatic cancer. Responses were observed across multiple tumor types and fusion partners. This study validates NRG1 fusions as an actionable therapeutic target.