MCLA-128 Shows Clinical Activity in NRG1+ Solid Tumors

Alison Schram, MD

MCLA-128 (zenocutuzumab), an investigational bispecific HER2/HER3 antibody, demonstrated radiological and clinical responses in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and metastatic non—small cell lung cancer (NSCLC) who have NRG1 fusions, according to results presented during the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.¹

All 3 patients who were treated with MCLA-128 experienced significant tumor shrinkage.

“NRG1 fusions have recently been described in several cancer types and are enriched in diseases in desperate need of better therapy, including pancreatic and lung cancer,” Alison Schram, MD, a medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, stated in a press release.² “Identifying a new, effective treatment strategy for these patients could make a big impact in their lives.”

Schram noted that less than 1% of all solid tumors harbor NRG1 fusions. MCLA-128 is designed with a dual mechanism of action, as it prevents NRG1 fusions from binding to HER3, while also blocking the interaction between HER3 and HER2.

Preclinical studies of NRG1 fusion—positive cancer cell lines and mouse xenograft models found that MCLA-128 effectively inhibited cell proliferation and caused tumor shrinkage in mice. Additionally, it has been demonstrated that MCLA-128 has a tolerable safety profile, with <5% of potential treatment-related grade 3/4 adverse events (AEs) reported. Moreover, there were no reports of clinically significant cardiotoxicity or rash, and minimal gastrointestinal toxicities were observed.

In the study, investigators conducted next-generation sequencing of solid tumors and identified 29 patients who were positive for NRG1 fusions. The sequencing was done across 8 tumor types: pancreas cancer, lung cancer, breast cancer, sarcoma, prostate cancer, gallbladder cancer, diffuse large B-cell lymphoma, and unknown primary. Three of these patients, who were resistant to chemotherapy, were treated with MCLA-128 at 750 mg every 2 weeks and all patients continue to remain on therapy. The three patients who received MCLA-128 were treated through the FDA-approved single-patient investigational drug applications initiated by Memorial Sloan Kettering Cancer Center, as part of an expanded access program.

In one 52-year-old male patient with ATP1B1-NRG1 fusion—positive advanced PDAC with liver metastases, MCLA-128 resulted in a drop in CA 19-9, which is a tumor biomarker for pancreatic cancer, from 262 units/ml to 56 units/ml. The normal rage for this protein is <40 units/ml. At 8 weeks, imaging revealed a 44% reduction in tumor diameter, which further decreased to a 54% reduction on the patient’s next scan. This was determined to be a partial response by RECIST v1.1 criteria and a complete response by PERCIST criteria. Weight gain and improvement in fatigue also occurred within weeks of the first treatment.

In a second patient with ATP1B1-NRG1 fusion—positive advanced PDA with liver metastases, results showed that MCLA-128 led to a reduction of CA 19-9 from 418 units/ml to 11 units/ml. At 6 weeks, imaging showed a 22% reduction in tumor diameter, which further decreased to a 25% reduction at their subsequent scan. Additionally, FDG-PET imaging also showed that the liver metastases were not metabolically active; disease-related abdominal pain also subsided following MCLA-128 therapy.

The third patient, who had CD74-NRG1 fusion—positive non–small cell lung cancer with brain metastases had previously progressed on 6 lines of therapy, one of which included afatinib (Gilotrif). After receiving MCLA-128, there was a 33% tumor shrinkage and improvement in brain metastases.

“Treating these three patients with MCLA-128 was a rational decision based on our understanding of biology, and our data provide important proof-of-concept demonstrating the promise of targeting NRG1 fusions with this novel approach,” Schram stated in the press release. “It is important to note that the patients felt remarkably well on treatment and reported immediate improvement in quality of life.”

Based on these data, an international, open-label, multicenter, dose-escalation phase I/II basket trial of MCLA-128 is ongoing and will treat an estimated 250 patients with NRG1 fusion—positive tumors (NCT02912949). Patients will receive MCLA-128 at the recommended phase II dose of 750 mg every 2 weeks.

Eligible patients must have an ECOG performance status of 0 or 1 and an estimated life expectancy of ≥12 weeks; those with known symptomatic or unstable brain metastases or leptomeningeal metastases are ineligible for enrollment.

The primary endpoints are characterization of safety and tolerability, objective response rate, duration of response, and correlation of antitumor activity and biomarkers. Secondary endpoints include incidence of AEs, C_max, volume of distribution, volume of distribution at steady state, half-life of MCLA-128, clinical benefit rate, and progression-free survival.

References

1. Schram A, O’Reilly E, Somwar R, et al. Clinical proof of concept for MCLA-128, a bispecific HER2/3 antibody therapy, in NRG1 fusion-positive cancers. Presented at: 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. Abstract PR02.
2. Bispecific Antibody MCLA-128 Shows Clinical Activity in Patients With Solid Tumors Harboring NRG1 Gene Fusions. American Association for Cancer Research. Published October 27, 2019. https://bit.ly/2otVIaA. Accessed October 28, 2019.