Seribantumab May Hold Pan-Tumor Potential in Cancers With NRG1 Fusions

Sam Klempner, MD

Investigators are seeking to determine whether seribantumab, a novel monoclonal antibody, can effectively treat patients with solid tumors that harbor rare NRG1 fusions. They are assessing the therapy in the phase 2 CRESTONE study (NCT04383210) in 15 tumor types with the molecular aberration.¹

Although the biological and clinical implications of NRG1 fusions remain under study, clinical findings suggest that patients with these alterations do not respond well to standard therapies. They also have poorer disease-free and overall survival outcomes, according to investigators in a poster presented at the 2021 Gastrointestinal Cancers Symposium.²

Research findings suggest that oncogenic activity associated with NRG1 fusions is driven by HER3 overactivation. Seribantumab blocks HER3 signaling and its downstream effects.²

“Seribantumab essentially binds HER3 and inhibits both NRG1-dependent activation as well as HER2 dimerization, effectively shutting down intracellular growth-promoting PI3K and MAPK pathways,” Sam Klempner, MD, an investigator on the CRESTONE study, said in an interview with OncLive^®. He is an assistant professor at Harvard Medical School and Massachusetts General Hospital, both in Boston.

“NRG1 fusions that retain the EGF-like domain are activating oncogenic events, and they result in HER2, HER3, and HER4 activation,” Klempner explained. “This drives intracellular signaling through PI3K and MAP kinase pathways, which result in activation of cellular programs for proliferation.”

NRG1 has recently emerged as a potential pan-tumor target as a result of advancements in DNA- and RNA-based next-generation sequencing, Klempner said.

Overall, NRG1 gene fusions have been identified in approximately 0.2% of solid tumors, according to an analysis of 44,570 tumor specimens. The data indicate a diversity of fusion partners and a range of incidence in tumor types. Of the specimens analyzed, NRG1 fusions were found in 54% of non–small cell lung cancers (NSCLCs), 11% of breast cancers, 7% of pancreatic ductal adenocarcinoma (PDAC) and ovarian samples, 6% of cholangiocarcinomas, and 5% of colorectal and genitourinary cancers.³

CRESTONE Study Details

CRESTONE investigators are aiming to recruit 75 adult patients with recurrent, locally advanced, or metastatic solid tumors that have progressed or have been nonresponsive to available therapies. (Figure^1,2). Tumor types to be studied include cancers of the pancreas, lung, head and neck, breast, kidney, bladder, gallbladder, bile duct, and prostate; colorectal, ovarian, esophageal, and uterine cancers; and sarcomas and cholangiocarcinoma.

Participants will be assigned to 1 of 3 parallel cohorts based on prior treatment status. The pivotal cohort will enroll 55 patients with advanced solid tumors with NRG1 gene fusions who have not been previously treated with pan-ERBB-, HER2-, or HER3- directed therapy. The second cohort will enroll 10 patients with NRG1 gene fusions whose prior treatment included those targeted therapies. The third cohort will enroll 10 participants with NRG1 fusions that lack an EGF-like domain or who have insufficient tissue for central confirmatory testing.

Figure. Seribantumab in NRG1 Fusion–Positive Solid Tumors^1,2

In all cohorts, the investigators will administer seribantumab in various doses via 1-hour intravenous infusion once weekly, every 2 weeks, and every 3 weeks. Administration will take place during the induction, consolidation, and maintenance dosing phases, respectively.

The primary end point is the objective response rate according to RECIST 1.1 criteria by independent radiologic review. Investigators will conduct an interim analysis after 20 patients with a centrally confirmed NRG1 fusion are enrolled² in cohort 1, potentially in mid-2021, according to Elevation Oncology, the company developing seribantumab.

Secondary end points include duration of response, safety, progression-free survival, overall survival, and clinical benefit rate. Exploratory investigations will include the clinical relevance of NRG1 fusion partners, impact of prior therapies, and resistance mechanisms.

The preferred method for determining a patient’s NRG1 fusion status for study participation is RNA-based sequencing, according to Klempner; a centrally confirmed result will be needed for assignment to cohort 1. “The NRG1 gene is quite large, and DNA-based platforms may have slightly lower sensitivity for fusion detection,” he said.

Nevertheless, investigators will consider for the other cohorts patients who are identified in local settings with molecular assays approved under Clinical Laboratory Improvement Amendments standards.

Favorable Seribantumab Signals

The scientific rationale for the CRESTONE study is supported by results from case reports and preclinical data, investigators said in their conference poster. Notably, they highlighted the therapeutic potential of targeting NRG1 fusions in pancreatic and other gastrointestinal cancers. In PDAC, the alterations appear to be mutually exclusive with KRAS activating mutations.²

The most extensive case report findings show that afatinib (Gilotrif), a pan-HER tyrosine kinase inhibitor, elicited partial responses or stable disease in 6 patients with NRG1 fusions: 3 had stage IV PDAC, 1 had cholangiocarcinoma, and 2 had colorectal cancer. One patient with KRAS wild-type PDAC with liver metastases achieved a partial response that is ongoing after more than 7 months and another patient with KRAS-mutant stage IVB colorectal cancer with liver and lung metastases maintained stable disease for 16 months.²

Further, seribantumab reduced tumor volume from 50% to 100% in patientderived xenograft models of invasive mucinous lung adenocarcinoma and highgrade serous ovarian cancer, according to findings presented at the 32nd EORTC-NCIAACR Symposium on Molecular Targets and Cancer Therapeutics in October 2020, hosted by the European Organisation for Research and Treatment of Cancer, National Cancer Institute, and the American Association for Cancer Research.

Investigators found that seribantumab was more effective than afatinib in these models.⁴

"The data demonstrate that treatment with seribantumab results in decreased phosphorylation of not only HER3 but also its dimerization partners HER2, HER4, and EGFR, and downstream PI3K and MAPK signaling pathways, suggesting efficient inhibition across HER3 and the entire ERBB signaling pathway,” lead author Igor Odintsov, MD, a research fellow at Memorial Sloan Kettering Cancer Center in New York, New York, said in a press release.⁵

Prior Development

CRESTONE represents another opportunity to develop seribantumab, which has been studied over the years in monotherapy and combination trials.² Formerly known as MM-121, seribantumab was evaluated in the phase 2 SHERLOC (NCT02387216) study in combination with docetaxel in patients with previously treated advanced or metastatic heregulin-positive NSCLC. The study was terminated in October 2018 after investigators determined in an interim analysis that the combination did not improve progression-free survival over docetaxel alone.⁶ Less than a month later, Merrimack Pharmaceuticals, the company developing the drug at that time, halted all development of seribantumab, including its SHERBOC trial (NCT03241810) in combination with fulvestrant (Faslodex) in postmenopausal women with metastatic breast cancer.⁷

Elevation Oncology acquired seribantumab in 2019 and repurposed the agent to target NRG1-fusion cancers. The development program is building on prior clinical experience from more than 800 patients demonstrating consistent safety and tolerability, although previous trials did not select for tumors with an NRG1 fusion.⁸

In SHERLOC, the most common treatment-emergent adverse effects among 71 patients treated with seribantumab plus docetaxel included diarrhea (50.7%), fatigue (45.1%), nausea and decreased appetite (33.8% each), asthenia (31.0%), and neutropenia (28.2%). The most common events of grade 3 or higher severity included neutropenia (22.5%), a decrease in neutrophil count (11.3%), and pneumonia (9.9%).⁹