Development of Seribantumab for NRG1+ Advanced Solid Tumors Put On Hold

Elevation Oncology is pausing development of the human anti–HER3 IgG2 monoclonal antibody seribantumab, along with the phase 2 CRESTONE trial (NCT04383210) investigating the agent, in patients with advanced solid tumors harboring NRG1 fusions, according to an announcement from the company.¹

Elevation added that it intends to pursue further development of seribantumab only in collaboration with a partner. Further enrollment for CRESTONE will be paused, pending the emergence of such a partnership.

Additional interim data from CRESTONE are expected to be presented in the first half of 2023.

“In light of our ongoing evaluation of our pipeline, we are pausing further investment in the development of seribantumab and the CRESTONE study,” Joseph Ferra, interim chief executive officer of Elevation Oncology, stated in a news release. “Additionally, we have made the difficult decision to reduce our workforce, which will enable us to realign our resources towards advancing EO-3021 and additional pipeline programs. We would like to extend our deepest gratitude to the patients and their families, the investigators and study teams as well as our employees for their invaluable contributions to the CRESTONE study.”

EO-3021 is a clinical-stage antibody-drug conjugate designed to target Claudin18.2 and selectively deliver a cytotoxic payload directly to kill cancer cells. Claudin18.2 is a clinically validated oncology target expressed in several solid tumor types including many gastrointestinal cancers such as gastric, gastroesophageal junction and pancreatic cancer.

In data from CRESTONE presented at the 2022 ASCO Annual Meeting, seribantumab produced an overall response rate (ORR) of 33%, including a complete response (CR) rate of 17% and a partial response rate of 17%, in the primary efficacy population of cohort 1 (n = 12).² Fifty-eight percent of patients experienced stable disease, 8% had progressive disease, and the disease control rate (DCR) was 92%.

Notably, among patients with non–small cell lung cancer (n = 11), the ORR was 36% with CR and PR rates of 18% each. The stable disease rate, progressive disease rate, and DCR were 55%, 9%, and 91%, respectively.

NRG1 fusions are rare alterations found in 0.2% of all solid tumors, and NRG1 fusion proteins bind to and activate HER3. NRG1 fusions are associated with poor clinical outcomes with standard therapeutic options, including chemotherapy and immunotherapy, and no targeted therapies are currently approved for this patient population.

The trial enrolled patients with locally advanced or metastatic solid tumors harboring NRG1 fusions per local testing who received at least 1 prior systemic therapy. Patients could not have tumors harboring any other oncogenic alterations, except for those enrolled to the exploratory cohort 3.

In cohort 1, prior treatment with pan-ERBB–, HER2-, or HER3-targeted therapy was not permitted. In the exploratory cohort 3, patients were required to have a NRG1 fusion without an EGF-like domain, or a NRG1 fusion with other molecular alterations or insufficient tissue for confirmatory testing for NRG1 fusions.

All enrolled patients were treated with 3 g of seribantumab once per week.

ORR by independent central radiologic review per RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included safety, investigator-assessed ORR, duration of response, progression-free survival, overall survival, and clinical benefit rate.

Regarding safety, which was assessed in patients in cohort 1 and cohort 3, one dose-limiting toxicity (grade 2 fatigue) was reported, leading to a dose reduction during the safety run-in. Additionally, 77% of patients received the optimized phase 2 dose of 3 g of seribantumab every week. Two patients received dose reductions due to adverse effects (AEs) per investigator discretion, including 1 patient with grade 1 alanine aminotransferase increase and 1 patient with grade 2 fatigue. No patients discontinued seribantumab due to AEs.

All patients experienced at least 1 any-grade treatment-emergent AE (TEAE) with seribantumab, and 49% had at least 1 TEAE that was grade 3 or higher. The most common any-grade TEAEs included diarrhea (49%), fatigue (40%), rash (31%), hypokalemia (29%), nausea (29%), abdominal pain (23%), decrease appetite (23%), hypomagnesemia (23%), cough (20%), anemia (17%), and dysuria (17%). Grade 3 or higher TEAEs consisted of diarrhea (6%), nausea (6%), abdominal pain (6%), hypokalemia (3%), and anemia (3%).

Although enrollment for CRESTONE is being paused, the phase 2 eNRGy trial (NCT02912949) is currently enrolling patients with solid tumors harboring NGR1 fusions. The trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab (MCLA-128).³

References

1. Elevation Oncology announces pipeline prioritization, realignment of resources to advance EO-3021 and CEO transition. News release. Elevation Oncology. January 6, 2023. Accessed February 9, 2023. https://investors.elevationoncology.com/
2. Carrizosa DR, Burkard ME, Elamin YY, et al. CRESTONE: Initial efficacy and safety of seribantumab in solid tumors harboring NRG1 fusions. J Clin Oncol. 2022;40(suppl 16):3006. doi:10.1200/JCO.2022.40.16_suppl.3006
3. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Updated December 27, 2022. Accessed February 9, 2023. https://clinicaltrials.gov/ct2/show/NCT02912949