Zenocutuzumab Generates Durable Responses in Advanced NRG1+ NSCLC

Alison Schram, MD

Zenocutuzumab (MCLA-128) elicited clinical activity with a tolerable safety profile in patients with advanced non–small cell lung cancer (NSCLC) harboring NRG1 fusions, including those with prior afatinib (Gilotrif) exposure, according to findings from the ongoing, phase 1/2 eNRGy trial (NCT02912949) were presented at the 2023 ESMO Congress.¹

Findings showed that in evaluable patients (n = 79), the agent elicited an investigator-assessed overall response rate (ORR) of 37.2% (95% CI, 26.5%-48.9%); 29 patients achieved a partial response (PR), 30 patients experienced stable disease, and 12 patients had progressive disease (PD).

“[This ORR] is higher than that reported for standard therapy in this population,” Alison Schram, MD, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, said in a presentation of the data.

The novel bispecific antibody zenocutuzumab targets NRG1, a ligand that binds to HER3 and promotes heterodimerization with other HER/ERBB kinases, tumorigenesis, and increased downstream signaling.² Zenocutuzumab inhibits HER2 and HER3, and in a previous study, 2 patients with chemotherapy-resistant, NRG1 ATP1B1 fusion–positive, metastatic pancreatic cancer experienced rapid symptomatic, radiographic, and biomarker responses with the agent and remained on treatment for more than 12 months. Furthermore, 1 patient with NRG1 CD74–positive NSCLC who had progressed on 6 prior lines of therapy achieved a PR.

In July 2023, the FDA granted breakthrough therapy designation to zenocutuzumab as a potential therapeutic option for patients with advanced unresectable or metastatic, NRG1-positive NSCLC who have progressed on prior systemic therapy.³

“In lung cancer, NRG1 fusions are associated with poor prognosis, lower response rates to standard chemotherapy and immunotherapy, and a shorter overall survival,” Schram noted in the presentation.

The global, multicenter, open-label eNRGy trial is enrolling patients at least 18 years of age with locally advanced, unresectable, or metastatic NRG1-positive solid tumors, including NSCLC and pancreatic ductal adenocarcinoma.1 Patients need to have previously treated disease or be ineligible for standard therapy, and have an ECOG performance status (PS) of 2 or lower.

Patients are receiving intravenous zenocutuzumab at 750 mg every 2 weeks until PD. Tumor assessment is done every 8 weeks, and the study includes a 2-year survival follow-up period.

The primary end point is investigator-assessed ORR per RECIST v1.1 criteria. Key secondary end points include duration of response (DOR), ORR per central review, and safety.

The primary analysis population comprised all patients who received at least 1 dose of zenocutuzumab, had the opportunity for a 24-week or longer follow-up at the data cutoff date of July 31, 2023, and met the criteria for the primary efficacy population. At data cutoff, eNRGy had enrolled 105 patients with NRG1-positive NSCLC. Eighty-seven patients had at least 24 weeks of follow-up, of whom 79 were eligible for the primary analysis population.

At baseline, patients had a median age of 64 years (range, 32-88), and most were female (62%), had an ECOG PS of 1 (63%), and were Asian (51%). Patients had a median of 1 prior line of therapy (range, 0-6), including platinum chemotherapy (72%) and afatinib (11%). Additionally, 15% of patients were treatment naïve. Regarding disease histology, 84%, 14%, 1%, and 1% of patients had adenocarcinoma, invasive mucinous adenocarcinoma, squamous cell carcinoma, and poorly differentiated carcinoma, respectively.

The most common NRG1 fusion partners were CD74 (57%), SLC3A2 (22%), SDC4/7 (9%), and CDH1/2 (3%). Most NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%).

At data cutoff, 25% of patients were still receiving the study treatment; 73% of patient had discontinued because of PD, and 1 patient had discontinued for another reason. The median duration of exposure was 7.4 months (range, 0.3-36.2).

Additional data showed the clinical benefit rate was 61.5% (95% CI, 49.8%-72.3%), and the median time to response of 1.8 months (range, 1.5-13.0). The median DOR was 14.9 months (95% CI, 7.4-20.4), and the 6- and 12-month DOR rates were 81% (95% CI, 60%-92%) and 57% (95% CI, 34%-75%), respectively.

The safety analysis population included 189 patients who received zenocutuzumab at the target dose. The most common treatment-emergent adverse effects (TEAEs) related to zenocutuzumab were diarrhea (any-grade, 61%; grade 3/4, 6%), infusion-related reactions (17%; 0%), fatigue (19%; 0%), nausea (8%; 1%), vomiting (6%; 1%), anemia (4%; 1%), constipation (3%; 0%), increased alanine aminotransferase (ALT; 3%; 1%), increased aspartate aminotransferase (AST; 3%; 1%), decreased appetite (3%; 1%), abdominal pain (2%; 1%), dyspnea (1%; 0%), increased gamma-glutamyl transpeptidase (GGT; 1%; 1%), decreased platelet counts (1%; 1%), hyperuricemia (1%; 1%), bacteremia (1%; 1%), and hypertransaminasemia (1%; 1%).

The most common TEAEs that emerged irrespective of causality were diarrhea (any-grade, 88%; grade 3/4, 35%), infusion-related reactions (12%; 0%), fatigue (16%; 2%), nausea (16%; 2%), vomiting (11%; 1%), anemia (15%; 4%), constipation (13%; 0%), increased ALT (10%; 3%), increased AST (7%; 3%), decreased appetite (8%; 1%), abdominal pain (11%; 2%), dyspnea (13%; 3%), increased GGT (6%; 3%), decreased platelet counts (2%; 1%), hyperuricemia (2%; 1%), bacteremia (1%; 1%), and hypertransaminasemia (1%; 1%).

No grade 5 TEAEs were observed, and no patients discontinued treatment because of TEAEs.

“Zenocutuzumab represents a potential first- and best-in-class therapy for patients with NRG1 fusion–positive NSCLC, a disease for which there is currently no approved targeted therapy and a significant unmet need,” Schram concluded.

Editor’s Note: Dr Schram reports advisory board participation with Mersana, Merus NV, and Relay Therapeutics; consultant roles with Blueprint Bio, Flagship Pioneering, and Redona Therapeutics; steering committee participation with Merus NV and Pfizer; institutional research funding from AstraZeneca, ArQule, BeiGene/SpringWorks, Black Diamond Therapeutics, Elevation Oncology, Kura, Lilly, Merus NV, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicines, and Surface Oncology; and food and beverage from PUMA and Repare Therapeutics.

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References

1. Schram A, Goto K, Kim D-W, et al. 1315MO Durable efficacy of zenocutuzumab, a HER2 x HER2 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):D756-S757. doi:10.1016/j.annonc.2023.09.2349
2. Schram AM, Odinstov I, Espinosa-Cotton M, et al. Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective therapy for tumors driven by NRG1 gene rearrangements. Cancer Discov. 2022;12(5):1233-1247. doi:10.1158/2159-8290.CD-21-1119
3. Zenocutuzumab (zeno) granted second breakthrough therapy designation by the U.S. Food & Drug Administration. News Release. Merus NV. July 5, 2023. Accessed October 31, 2023. https://ir.merus.nl/news-releases/news-release-details/zenocutuzumab-zeno-granted-second-breakthrough-therapy