Efficacy and safety of seribantumab in NRG1 fusion-positive cancers

One of the CRESTONE researchers, Tejas Patil, MD, assistant professor of medicine and medical oncology at the University of Colorado School of Medicine at Aurora, discussed seribantumab in previously treated patients with the NRG1 fusion.

In the era of targeted therapies, identifying an actionable genomic marker can be a major breakthrough for treatment. Yet identifying a biomarker is only part of the solution – there must also be a viable therapy to target it.

Patients whose tumors harbor NRG1 mergers are in the middle of this conundrum. The mutation is present in several tumor types, but this discovery has yet to lead to reliable treatment options. The problem is compounded by the fact that the mutation is extremely rare, making it difficult to generate sufficient data to support new targeted therapies.

Investigators aim to begin addressing this issue with the CRESTONE Phase 2 trial (NCT04383210). Trial examines seribantumab, a fully human anti-HER3 immunoglobulin G2 monoclonal antibody, as a potential treatment in patients previously treated with NRG1 fusion-positive tumors. The study showed efficacy in some patients with solid tumors, but it also left some questions on the table.

One of CRESTONE’s investigators, Tejas Patil, MDassistant professor of medicine and medical oncology at the University of Colorado School of Medicine at Aurora, discussed the trial and its implications in a recent edition of Between the lines presented by CancerNetwork®. He was joined by Alexander I. Spira, MD, PhD, FACPassistant professor of oncology at the Johns Hopkins School of Medicine in Baltimore, Maryland, and director of the Virginia Cancer Specialists Research Institute and Phase I trial program at Fairfax.

Background and design

NRG1 gene fusions occur when linkage occurs with partner genes. They are found in only 0.2% of solid tumors, although Patil said there may be a higher level of enrichment in certain subgroups of patients, such as those with kras wild-type pancreatic cancers and invasive mucinous adenocarcinoma of the lung. Patients with NRG1 fusions generally have poor results with standard therapies, and there are no approved targeted therapies for such aberrations. A 2021 study found patients with NRG1 fusion-positive tumors experienced a median progression-free survival of less than 4 months with chemoimmunotherapy and immunotherapy monotherapy.1

NRG1 Fusions present another unique challenge in that they are difficult to detect, given the large intronic regions of the gene fusion, Patil said. “For this reason, RNA-based sequencing is the gold standard for detection,” he said.

The anti-HER3 monoclonal antibody seribantumab competes for HER3 binding with NRG1, its main activating ligand. “It prevents the dimerization and phosphorylation of HER3 and other HER family members, so it’s thought to inhibit downstream signaling,” Patil said.

In preclinical models, the therapy inhibited tumor growth and triggered tumor regression.

CRESTONE is a Phase 2 treatment study in patients with locally advanced or metastatic solid tumors with NRG1 fusions that had at least 1 prior line of therapy and no other oncogenic alterations.2 The primary endpoint was objective response rate by independent radiological examination. Secondary endpoints included safety and duration of response. The study included a safety run-in phase as an induction, and the recommended ultimate dose for Phase 2 was 3 g per week.

First trial results

The trial patient population was small, due to the rarity of the disease. A total of 35 patients were included in the safety analysis, 15 patients were in the primary efficacy cohort, but only 12 patients could be included in the final analysis. Most patients were female, and all but 1 patient in the efficacy cohort had non-small cell lung cancer (NSCLC); the other patient had pancreatic cancer.

A third of the participants (n=4; 33%) obtained an objective response, consisting of 2 complete responses and 2 partial responses (17% each). Of the remaining 8 study participants, 7 had stable disease and 1 experienced disease progression for a disease control rate of 92%.

In terms of safety, all patients experienced treatment-related adverse events (AEs) and most (86%) experienced AEs deemed treatment-related. However, 80% of treatment-related AEs were grade 1 or 2 in severity, and only 2 patients received dose reductions for AEs. No patient discontinued the trial due to AE. The median duration of response was not reached (range, 1.4-11.5 months).

Clinical trials vs real world

Spira said it’s important to look at safety data in context. He noted that participants in clinical trials tend to be healthier than the general population. Additionally, he noted that patients in the study had to travel weekly for treatment, suggesting they were relatively fit. He said AEs will likely increase outside of a trial setting.

“In the real world, we’ll probably see a bit higher number [of AEs] than that,” Spira said, adding that he was concerned about the burden of weekly visits for therapy, especially in areas where patients would have to travel long distances each week to receive care.

“It will be a logistical challenge, especially if it gets FDA approval,” Spira said. “We would like to see less frequent dosing, but with something new, we’ll take it for what it’s worth.”

Challenges and limitations

However, a potential obstacle to FDA approval is the rarity of the condition and therefore the small size of the trial. “These are small numbers, and we have to take them with a grain of salt,” Spira said.

Another important factor is the resulting indication that seribantumab may be granted by regulatory authorities, Spira explained. He expects the drug’s developers to seek a tumor-agnostic indication, given the rarity of tumors with NRG1 fusion. However, he said the fact that most CRESTONE enrollees had the same type of cancer would be a hurdle. “If almost all the patients in the trial [who were included in the efficacy analysis] have lung cancer, that will not be enough to get a tumor agnostic indication,” he said.

Still, Spira said even a lung cancer-specific endorsement would be meaningful. “Because we need it as much in lung cancer as we do in other tumors,” he said. “But it would be nice to get independent approval from the tumor for this.”

Unanswered questions

Other important questions about seribantumab will need to be addressed, Spira said. In CRESTONE, investigators identified NRG1 fusions with several partner genes, including CD74 was the most striking. He said it would be important to study whether the drug’s efficacy holds up across different fusion partners.

Another key question is: how does seribantumab affect the central nervous system (CNS)? “With [most] patients with [NSCLC], I have big questions about the effectiveness of the CNS, as the brain is a very common metastatic site in these patients,” Patil said. “We want to determine the efficacy of seribantumab in the CNS.”

The answer to that question likely won’t come without larger trials, Patil said. Meanwhile, CRESTONE is underway and recruiting patients from July. Investigators expect to complete the study next summer.

Impact on patient care

If seribantumab is ultimately approved by the FDA, Spira and Patil said they expect it to be a meaningful option for patients with tumors harboring NRG1 mergers. In a second-line setting for NSCLC, Patil said the data is more encouraging than what’s been seen with docetaxel for this subset of patients. Data published in 2021 revealed that docetaxel resulted in an overall 5-year survival rate of just 2.6% in patients previously treated with NSCLC.3 So the “bar is low” in this type of tumor, he said.

“I anticipate seribantumab to be a therapy that will be widely adopted,” Patil said. However, there remains an open question as to what might happen in other tumor settings. He said it will likely depend on the comparators in each given setting. For example, in the case of breast cancer, there are more viable treatment options, he explained.

“This is where it might become a more nuanced question, because even second-line breast cancer therapies can be very effective,” Patil said.

Spira accepted. He said a lung cancer approval seems likely, but it’s not yet clear how effective the therapy and its potential FDA-approved indication will be. “We need more data for that,” he said.


  1. Drilon A, Duruisseaux M, Han JY, et al. Clinicopathologic characteristics and treatment response of NRG1 fusion-induced lung cancers: the global multicenter eNRGy1 registry. J Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307
  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(supplement 16):3006. doi:10.1200/JCO.2022.40.16_suppl.3006
  3. Borghaei H, Geter S, Vokes EE, et al. Five-year results of randomized phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small cell lung cancer. J Clin Oncol. 2021;39(7):723-733. doi:10.1200/JCO.20.01605

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