NRG1+ Solid Tumors Boast Impressive Responses With Zenocutuzumab

Article

Without regard for tumor histology, NRG1-positive cancers treated with zenocutuzumab experienced promising efficacy and acceptable safety.

Results of a phase 1/2 trial (NCT02912949) of zenocutuzumab (MCLA-128) in patients with previously treated advanced NRG1-positive cancers demonstrated the agent’s ability to induce antitumor activity with acceptable safety across several tumor types, according to a presentation during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.1

At a median follow-up of 6.3 months, the HER2 x HER3 bispecific antibody elicited an investigator-assessed objective response rate (ORR) of 34% (95% CI, 24%-46%) by RECIST v1.1 criteria among all patients analyzed (n = 79), with a median time to response of 1.8 months, and a median duration of response (DOR) of 9.1 months (95% CI, 7.4-not reached).

“There are currently no approved therapies targeting NRG1-positive cancer, and zenocutuzumab offers a potential new standard of care [SOC],” Alison M. Schram, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said in a presentation on the data.

Chromosomal rearrangements involving NRG1 are rare oncogenic drivers in a wide range of solid tumors, and are enriched in pancreatic and lung cancers, according to Schram. In lung cancer, NRG1 fusions are linked with poor prognosis, lower response rates to standard chemotherapy and immunotherapy, and shorter overall survival. Zenocutuzumab has been shown to have efficacy in NRG1 fusion–positive preclinical models spanning tumor histologies.

Zenocutuzumab docks on HER2 and blocks the binding of NRG1 to HER3, preventing heterodimerization of HER2 with HER3 in downstream signaling, Schram said. In January 2021, the agent was granted a fast track designation from the FDA for use in patients with metastatic solid tumors harboring NRG1 gene fusions that had progressed on SOC treatment.2 Previously, in June 2020, the FDA granted zenocutuzumab an orphan drug designation for the treatment of patients with pancreatic cancer.3

The global, open-label, multicenter, phase 1/2 trial enrolled patients with locally advanced, unresectable or metastatic solid tumors that were NRG1 positive. To be eligible for enrollment, patients must have been at least 18 years of age, have been previously treated with or unable to receive standard therapy, and have an ECOG performance status ranging from 0 to 2.

Study participants received intravenous zenocutuzumab at 750 mg, given every 2 weeks, until disease progression. Moreover, tumor assessments were conducted every 8 weeks.

The primary end point of the trial was ORR by RECIST v1.1 criteria and per investigator assessment. DOR, ORR per central review, safety, pharmacokinetics, and assessment for antidrug antibodies served as secondary end points.

At a data cutoff date of April 12, 2022, a total of 110 patients were enrolled, and 83 patients met the predefined criteria for the primary analysis population. “The primary analysis population included those who had at least 1 dose of zenocutuzumab, had the opportunity for greater than or equal to 6 months of follow-up, and met criteria for the primary efficacy population,” Schram explained.

Among the 27 patients who were excluded from the analysis, the most common reason was having less than 6 months of follow-up (n = 21), followed by having a baseline scan that happened more than 5 weeks before the first dose of study treatment (n = 2), having other genetic drivers beyond NRG1 like KRAS (n = 2), having received prior anti-HER3 inhibitors (n = 2), or having an ECOG performance status of 3 (n = 1).

Among the 83 patients, the median age was 59 years (range, 22-84), and 59% were female. Most patients had an ECOG performance status of 0 (42%) or 1 (57%) and were White (57%) or Asian (33%). Moreover, 99% had metastatic disease and 95% had measurable disease.

The most common tumor types were non–small cell lung cancer (NSCLC; 57%) and pancreatic ductal adenocarcinoma (PDAC; 23%). Additional histologies treated included breast cancer (8%), cholangiocarcinoma (4%), colorectal cancer (4%), endometrial soft tissue sarcoma, pancreatic neuroendocrine carcinoma, renal cell carcinoma, and cancer of unknown primary (5%). Study participants received a median of 2 prior lines of systemic therapy (range, 0-8), with 11% of patients having previously received afatinib (Gilotrif).

“Qualifying NRG1 fusions included 26 distinct fusion partners, most commonly CD74 [31%], SLC3A2 [16%], and ATP1B1 [13%],” Schram noted.

Additional data showed that among the 19 patients with PDAC, “a disease with few treatment options and a poor prognosis,” zenocutuzumab produced a confirmed ORR of 42% (95% CI, 20%-67%) per investigator assessment, Schram reported. In the 46 patients with NSCLC, the ORR achieved with the bispecific antibody was 35% (95% CI, 21%-50%), “which is higher than that reported for standard chemoimmunotherapy in this population,” Schram added. Notably, 70% of patients experienced tumor shrinkage with treatment.

The median duration of exposure to treatment was 6.3 months (range, 1-21). Twenty-four percent of patients were still receiving treatment with zenocutuzumab at data cutoff. The most common reason for discontinuation was progressive disease (73%). Two other patients discontinued because of an unrelated adverse effect (AE) of dyspnea because of underlying progression (n = 1) and pregnancy (n = 1).

“Responses were durable…76% [of patients] responded for more than 6 months and 27% [responded] for at least 1 year,” Schram said.

Schram also shared a few cases that underscored the efficacy of zenocutuzumab that has been observed to date. A 51-year-old male who had ATP1B1-NRG1 fusion–positive pancreatic adenocarcinoma underwent neoadjuvant FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) and surgery, followed by the development of metastatic disease to the liver and lymph nodes. After starting zenocutuzumab, the patient experienced an “immediate and durable” partial response (PR) before coming off the study 9 months later because of disease progression.

Another 84-year-old patient with SLC3A2-NRG1 fusion–positive NSCLC that was metastatic to the lung and lymph nodes, who was deemed ineligible to receive chemoimmunotherapy, was initiated on zenocutuzumab and experienced a rapid response. This patient continues to respond to treatment nearly 16 months later and remains on study.

Lastly, a 64-year-old female with an SLC3A2-NRG1 fusion–positive, estrogen receptor–positive breast cancer with metastasis to the liver and bone had progressed following several lines of systemic treatment was given zenocutuzumab. She experienced a rapid PR per RECIST v1.1 criteria and a complete response per PERSIST criteria. “She remains on treatment and is doing well with no evidence of progressive disease,” Schram added.

Pharmacokinetics demonstrated a half-life of approximately 4 days, with greater than 95% predicted receptor occupancy for HER3 and HER2 throughout the dosing interval in most patients following the first dose of zenocutuzumab. Notably, no treatment-emergent antidrug antibodies were identified.

“Zenocutuzumab is extremely well tolerated, with a very low incidence of grade 3 and higher treatment-related AEs, including low rates of severe gastrointestinal and dermatologic toxicity and no clinically significant cardiotoxicity,” Schram said.

Among all patients who received zenocutuzumab at the recommended phase 2 dose across indications on the phase 1/2 trial—not just those with NRG1 fusions, 92% of patients experienced at least 1 all-grade AE, 36% experienced grade 3 or 4 toxicity, and 3% experienced a grade 5 effect.

All-grade treatment-related AEs (TRAEs) occurred in 61% of patients, 5% experienced grade 3 or 4 TRAEs, and 0.5% experienced a grade 5 TRAE. The most common all-grade TRAEs experienced with zenocutuzumab were diarrhea (21%), asthenia/fatigue (12%), infusion-related reactions (15%), and nausea (10%).

Less than 1 percent of patients discontinued treatment because of toxicity.

References

  1. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105
  2. Merus granted FDA fast track designation of zenocutuzumab for the treatment of patients with neuregulin 1 fusion cancers. News release. Merus NV. January 7, 2021. Accessed June 5, 2022. http://bit.ly/3bobmtY
  3. Merus announces FDA orphan drug designation of zenocutuzumab for the treatment of pancreatic cancer. Merus NV. July 27, 2020. Accessed June 5, 2022. https://bit.ly/3QeKlLN

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