Studies on EGFR Mutations and NRG1 Fusions Included in ASCO NSCLC Living Guideline Update

ASCO has issued a new update to its living guideline on treatment of stage IV non–small cell lung cancer (NSCLC) with driver alterations based on two recent studies.¹ The update, which amends the most recent version published in February 2025, includes a discussion of osimertinib therapy options in patients with EGFR exon 19 deletion or exon 21 L858R substitution as well as the use of zenocutuzumab in patients with NRG1 fusion.² An update to the living guideline for NSCLC without driver mutations was also issued.³

Jyoti D. Patel, MD

Natasha B. Leighl, BSc, MMSc, MD

“These updates recognize the rapidly evolving landscape of NSCLC therapeutics, particularly in EGFR-positive NSCLC,” said Jyoti D. Patel, MD, of Northwestern University, who co-chaired the Expert Panel along with Natasha B. Leighl, BSc, MMSc, MD, of the Princess Margaret Cancer Centre. They also demonstrate the “need for more clinical trials to delineate optimal therapies for particular patient populations and underscore the necessity for comprehensive molecular testing,” she added. Dr. Patel has since stepped down as co-chair of the Expert Panel and will leave Northwestern for a role in private industry later this summer.

Osimertinib With or Without Ramucirumab

The Expert Panel reviewed results of the RAMOSE trial, which was a phase II, open-label, randomized study that evaluated osimertinib with or without ramucirumab in a total of 139 evaluable patients with EGFR-mutated metastatic NSCLC who had not received prior tyrosine kinase inhibitor therapy.⁴ The study focused on a lower-toxicity alternative to regimens used in the FLAURA2 and MARIPOSA trials.^5,6

Most of the patients in the trial had exon 19 deletion (69%), and the remainder had L858R mutations (31%). At a preplanned interim analysis after a median of 16.6 months of follow-up, the median progression-free survival was significantly longer with the addition of ramucirumab compared with osimertinib alone at a median of 24.8 months and 15.6 months, respectively (hazard ratio = 0.55, 95% confidence interval = 0.32–0.93; P = .023).

That benefit was seen across the EGFR mutation subtypes and central nervous system metastases status. At 1 year, the progression-free survival rates with and without ramucirumab were 76.7% and 61.9%, respectively; at 2 years, those rates were 51% and 30%, respectively. Objective response rates and disease control rates did not differ significantly between the groups.

“The combination of osimertinib and ramucirumab led to a significant improvement in progression-free survival with some increase in toxicity,” Dr. Patel said. Grade 3 or higher treatment-related adverse events occurred in 53% of patients receiving the combination regimen and in 41% of those receiving osimertinib monotherapy.

The Expert Panel warned that the results of the study may be difficult to generalize because it was conducted in the United States alone; overall survival results are not yet available, and at this point, the living guideline recommendation has not changed. The guideline states that clinicians may offer either osimertinib with platinum doublet chemotherapy or amivantamab plus lazertinib in patients with EGFR mutations.

“The addition of anti-VEGF therapy to osimertinib appears to be a very reasonable and well-tolerated strategy and allows for intensification of therapy with chemotherapy and amivantamab in later lines of treatment,” Dr. Patel said. She added that the ongoing EA5182 trial (ClinicalTrials.gov identifier NCT04181060) will shed more light on this field. That study is evaluating whether adding bevacizumab to osimertinib in the first-line setting can improve outcomes in patients with metastatic, EGFR-mutant NSCLC. “This study will help us further define the best first-line therapy for EGFR-mutant NSCLC,” she said.

NRG1 Fusions

The Expert Panel also reviewed results of the phase II registrational eNRGy study.⁷ This trial examined the IgG1 bispecific antibody zenocutuzumab in patients with advanced solid tumors harboring an NRG1 fusion who had received appropriate prior therapy. Those fusions occur in less than 1% of solid tumors, and no targeted therapies for NRG1fusion–positive cancers have been approved.

The study included 158 evaluable patients and 93 patients with NSCLC. Among those patients with NSCLC, the investigator-assessed objective response rate was 29%, with a median duration of response of 12.7 months. The median progression-free survival was 6.8 months. A total of 204 patients in the trial were evaluable for safety, and the most common treatment-emergent adverse events included diarrhea (29%), fatigue (21%), and nausea (20%).

“We felt it was important to include zenocutuzumab, a bispecific antibody against HER2 and HER3, because of the durable antitumor activity in patients with NRG1 fusion–positive NSCLC,” Dr. Patel said. She added that the results reinforce the need for molecular sequencing, including RNA testing, in this setting.

The Expert Panel noted that although the eNRGy trial was a single-arm, phase II trial, the low incidence of NRG1 fusions in NSCLC and limited efficacy data for standard chemoimmunotherapy regimens make these new results relevant. The living guideline now recommends that clinicians may offer zenocutuzumab in patients with these mutations.

“NRG1 fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors (NTRK, RET, ROS1, ALK, and FGFR fusions),” Dr. Patel said. “Successful treatment represents a real milestone.”

REFERENCES

1. Reuss J, Kuruvilla S, Ismaila N, et al: Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO Living Guideline, version 2025.1. J Clin Oncol. July 17, 2025 (early release online).
2. Owen DH, Nofisat I, Ahluwalia A, et al: Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline, version 2024.3. J Clin Oncol 43:e2-e16, 2025.
3. Owen DH, Halmos B, Puri S, et al: Therapy for stage IV non-small cell lung cancer without driver alterations: ASCO Living Guideline, version 2025.1. J Clin Oncol. July 17, 2025. (early release online).
4. Le X, Patel JD, Shum E, et al: A multicenter open-label randomized phase II study of osimertinib with and without ramucirumab in tyrosine kinase inhibitor-naive EGFR-mutant metastatic non-small cell lung cancer (RAMOSE trial). J Clin Oncol 43:403-411, 2025.
5. Planchard D, Jänne PA, Cheng Y, et al: Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med 389:1935-1948, 2023.
6. Cho BC, Lu S, Felip E, et al: Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med 391:1486-1498, 2024.
7. Schram AM, Goto K, Kim DW, et al; eNRGy Investigators: Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. N Engl J Med 392:566-576, 2025.

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, July 17, 2025. All rights reserved.