NEW YORK – Researchers at the American Society of Clinical Oncology's annual meeting this week provided initial insights into the activity of two drugs, Merus' zenocutuzumab and Elevation Oncology's seribantumab, both of which are intended to be developed for tissue-agnostic indications.
While the makers of these drugs have ambitions to advance these drugs as pan-cancer treatments, the data readouts at the meeting are in advanced non-small cell lung cancer and pancreatic cancers with NRG1 fusions. However, the Phase I/II eNRGy trial for zenocutuzumab, a HER2 and HER3 bispecific antibody, and the Phase II CRESTONE trial for seribantumab, an anti-HER3 monoclonal antibody, are both enrolling patients with a variety of tumor types with this biomarker.
Elena Garralda, principal investigator of the early clinical drug development group at the Vall d'Hebron Institute of Oncology in Barcelona, said in reviewing the data from these studies that while the incidence of NRG1 fusions is low, showing up in only 0.2 percent of solid tumors, the high recruitment rate in the eNRGy study emphasizes "the importance, the need, and the feasibility of performing studies in these low-prevalence tumor indications."
Alison Schram, a medical oncologist at Memorial Sloan Kettering, presented the results from the eNRGy study at the meeting and reported that 34 percent of 79 patients with NRG1 fusion-positive advanced solid tumors responded. The analysis included mostly NSCLC and pancreatic cancer patients but also some breast cancer and cholangiocarcinoma patients responded to zenocutuzumab.
The company is expecting to have data demonstrating the drug's activity in more tumor types by mid-year, enough to support a histology-agnostic regulatory filing. Merus CEO Bill Lundberg told investors on a call this week that the additional data from the eNRGy trial could support a biologics license application (BLA) submission for the drug in previously treated patients with NRG1 fusion-positive solid tumors.
"We believe we may have sufficient patients enrolled with sufficient follow-up by the middle of this year to form the basis of such a filing," Lundberg said.
Merus Chief Commercial Officer Shannon Campbell discussed the company's commercialization plan for the drug on the investor call, noting that key goals are increasing awareness among physicians of NRG1 fusions as an oncogenic driver and urging upfront testing for the biomarker to identify patients eligible for zenocutuzumab treatment. The company will provide an update on its regulatory and commercial strategy for zenocutuzumab in the second half of this year, Lundberg said.
Zenocutuzumab has received fast track designation from the US Food and Drug Administration as a treatment for NRG1 fusion-positive solid tumors and orphan drug designation in NRG1 fusion-positive pancreatic cancer.
The data that researchers presented at ASCO on zenocutuzumab included the activity seen in the eNRGy trial and in the early-access program for the drug. Schram and colleagues said that 42 percent out of 19 pancreatic cancer patients and 35 percent of 46 non-small cell lung cancer patients responded to the drug. Schram noted that the response rate seen in NSCLC to zenocutuzumab was higher than historical response rates that NRG1 fusion-positive lung cancer patients have on chemotherapy.
In the study overall, the median time to response was 1.8 months, and the median duration of response was 9.1 months. Three-quarters of patients who responded maintained a response for at least six months, and 27 percent had a response for at least 12 months.
Most patients, 77 percent, enrolled in the trial had NRG1 fusions identified by RNA sequencing, while 22 percent had alterations identified using DNA sequencing and 1 patient using molecular analysis through NanoString.
Zenocutuzumab works by blocking the heterodimerization of HER2 with HER3 and subsequent downstream signaling in the pathway. NRG1, by binding to HER3, can promote the dimerization of HER2 and HER3, Schram said. NRG1 fusions are also associated with poor prognosis, and cancer patients with these oncogenic drivers can have lower response rates to chemo and shorter overall survival.
Garralda, from the Vall d'Hebron Institute of Oncology, said in discussing the zenocutuzumab data that further understanding of the patients who respond to the drug is important.
"We need to see what the value is of the tumor histology [and NRG1] fusion partners, if there are isoforms that create a higher affinity to the receptor, the genomic complexity of the tumor, and the role of EGFR and ERBB4," Garralda said. "We really need [this data] to fully understand the optimal strategy to target NRG1."
The data on seribantumab presently is more limited. Researchers at the meeting also reported initial efficacy data from 12 patients with NRG1 fusion-positive advanced pancreatic cancer and NSCLC receiving seribantumab in the Phase II CRESTONE trial.
Across all patients, 33 percent responded to seribantumab, including two complete responses and two partial responses, all of which were in lung cancer. The group of evaluable patients included only one pancreatic cancer patient, who achieved stable disease on seribantumab. The disease control rate was 92 percent, and the duration of response ranged from 1.4 months to 11.5 months.
Even though the data reported at ASCO is largely in NSCLC, Daniel Carrizosa, a medical oncologist at Levine Cancer Institute of Atrium Health, sees tissue-agnostic potential for seribantumab, but he also noted the importance of genomic profiling. "Comprehensive genomic profiling is vital so we can find patients [with rare mutations] like these and provide personalized medicine," Carrizosa said.
In a discussion of the CRESTONE data, Philippe Bedard, a clinician investigator at the Princess Margaret Cancer Centre, noted that the data available so far on seribantumab and zenocutuzumab suggests "quite similar response rates," but noted that the eNRGy trial has enrolled more patients and a greater variety of tumor types.
There are also other HER3-directed drugs being explored in solid tumors with NRG1 fusions, including Boehringer Ingelheim's Gilotrif (afatinib) in a Phase II trial and Rain Therapeutics' tarloxotinib in a Phase II trial involving NSCLC patients.
One study of Gilotrif in patients with NSCLC with NRG1 fusions showed a 25 percent response rate, Bedard said. He noted that there have been anecdotes of Gilotrif working in other cancers with NRG1 fusions, including pancreatic, ovarian, and bile duct cancer. There are also several ongoing studies exploring Gilotrif in two trials enrolling NRG1 fusion-positive solid tumor patients, including the Phase II TAPUR trial and the DRUP trial.
Bedard said it was too early to determine whether seribantumab had tissue-agnostic activity, due to the small number of patients in this analysis, but the data showed proof-of-concept activity in NRG1 fusion-positive NSCLC.
In a statement, Elevation Oncology CEO Shawn Leland said the company will report additional data from the CRESTONE study in the first half of 2023.