Recap: Efficacy and Safety of Seribantumab in NRG1 Fusion–Positive Cancers


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

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

Patients whose tumors harbor NRG1 fusions find themselves in the middle of that conundrum. The mutation is present across multiple tumor types, but that discovery has not yet yielded reliable treatment options. Compounding the problem is the fact that the mutation is extremely rare, making it difficult to generate sufficient data to support new targeted therapies.

Investigators aim to start chipping away at this problem by way of the phase 2 CRESTONE trial (NCT04383210). The trial is examining seribantumab, a fully human anti-HER3 immunoglobulin G2 monoclonal antibody, as a potential therapy in previously treated patients with NRG1 fusion–positive tumors. The study demonstrated efficacy in certain patients with solid tumors, but it also left some questions on the table.

One of the CRESTONE investigators, Tejas Patil, MD, assistant professor of medicine–medical oncology at the University of Colorado School of Medicine in 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, FACP, assistant professor of oncology at Johns Hopkins School of Medicine in Baltimore, Maryland, and director of the Virginia Cancer Specialists Research Institute and the Phase I Trial Program in Fairfax.

Background and Design

NRG1 gene fusions result when binding occurs with partner genes. They are found in just 0.2% of solid tumors, although Patil said there may be a greater level of enrichment in certain subsets of patients, such as those with KRAS wild-type pancreatic cancers and invasive mucinous adenocarcinoma of the lung. Patients with NRG1 fusions generally face poor outcomes 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 single-agent immunotherapy.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. “Because of this, RNA-based sequencing is the gold standard for detection,” he said.

The anti-HER3 monoclonal antibody seribantumab works by competing for binding to HER3 with NRG1, its main activating ligand. “It prevents dimerization and phosphorylation of HER3 and other HER family members, then this is thought to inhibit downstream signaling,” Patil said.

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

CRESTONE is a phase 2 study of the therapy in patients with locally advanced or metastatic solid tumors with NRG1 fusions who had at least 1 prior line of therapy and no other oncogenic alterations.2 The primary end point was objective response rate by independent radiologic review. Secondary end points included safety and duration of response. The study had a safety run-in phase as induction, and the ultimate phase 2 recommended dosage was 3 g weekly.

Initial Results of the Trial

The trial’s patient population was small, owing 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 were able to be included in the final analysis. Most patients were women, and all but 1 patient in the efficacy cohort had non–small cell lung cancer (NSCLC); the other patient had pancreatic cancer.

One-third of the participants (n = 4; 33%) achieved an objective response, which was composed of 2 complete responses and 2 partial responses (17% each). Of the other 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 had treatment-emergent adverse events (AEs) and most (86%) experienced AEs that were 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 patients discontinued the trial because of AEs. The median duration of response was not achieved (range, 1.4-11.5 months).

Clinical Trials vs Real World

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

“In the real world, we will probably see a bit higher number [of AEs] than that,” Spira said, adding that he worries about the burden of weekly visits for therapy, particularly in areas where patients would have to make lengthy drives each week to receive care.

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

Challenges and Limitations

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

Another important factor is the resulting indication seribantumab may be granted by regulatory authorities, Spira explained. He expects that the drug’s developers will 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 cancer type will be a hindrance. “If almost all the patients from the trial [who were included in the efficacy analysis] have lung cancer, that’s not going to be enough to get a tumor-agnostic indication,” he said.

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

Unanswered Questions

Other important questions about seribantumab will need to be examined, according to Spira. In CRESTONE, investigators identified NRG1 fusions with several partner genes, of which CD74 was the most prominent. He said it will be important to investigate 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 having [NSCLC], I have major questions about CNS efficacy, because the brain is a very common metastatic site for these patients,” Patil said. “We want to determine how effective seribantumab in the CNS.”

The answer to that question likely will not come without larger trials, Patil said. Meanwhile, CRESTONE is ongoing and was recruiting patients as of July. Investigators expect to complete the study next summer.

Impact on Patient Care

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

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

“​​That’s where this might become a more nuanced question, because breast cancer therapies, even in the second-line setting, can be very effective,” Patil said.

Spira agreed. He said a lung cancer approval seems likely, but it is not yet clear how wide the therapy’s efficacy 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 features and response to therapy of NRG1 fusion-driven lung cancers: the eNRGy1 global multicenter 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(suppl 16):3006. doi:10.1200/JCO.2022.40.16_suppl.3006
  3. Borghaei H, Gettinger S, Vokes EE, et al. Five-year outcomes from the 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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