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ASCO has published updated recommendations in version 2025.1 of their living guidelines for systemic therapy, outlining evidence-based treatment strategies for patients with stage IV non–small cell lung cancer (NSCLC) with or without a driver alteration.1,2
Updates for Stage IV NSCLC With Driver Alterations: Osimertinib-Based Combinations and Zenocutuzumab
For patients with EGFR exon 19 deletions or exon 21 L858R substitutions, osimertinib (Tagrisso) may be considered for use in combination with platinum doublet chemotherapy, and amivantamab-vmjw (Rybrevant) may be combined with lazertinib (Lacluze) as first-line treatment options.1
The recommendation is informed in part by data from the phase 2 RAMOSE trial (NCT03909334), a randomized, open-label study evaluating osimertinib with or without the VEGF inhibitor ramucirumab (Cyramza) in TKI-naive patients with EGFR-mutated metastatic NSCLC. At a median follow-up of 16.6 months, the median progression-free survival (PFS) was 24.8 months with the combination vs 15.6 months with the monotherapy (HR, 0.55; 95% CI, 0.32-0.93; P = .023). A PFS benefit was observed across EGFR mutation subtypes and central nervous system metastasis status.
One- and two-year PFS rates favored the combination (76.7% vs 61.9% and 51% vs 30%, respectively). The overall response rate (ORR) was 76.3% vs 80.4% and the disease control rates were 96.8% and 95.7%, respectively. Grade 3 or higher treatment-related adverse effects (AEs) were more frequent with the addition of ramucirumab (53% vs 41%), most commonly hypertension, proteinuria, and epistaxis.
Due to limitations of the RAMOSE trial, including its single-country enrollment and lack of blinded independent central review, and an imbalance in reduced clinic visits for patients in the monotherapy arm, no formal changes were made to the recommendation. The authors noted that pending results from the phase 3 ECOG-ACRIN EA5182 trial (NCT04181060) evaluating osimertinib plus bevacizumab (Avastin) could provide further insight into the benefit of VEGF inhibition in this population.
For patients with NSCLC harboring a NRG1 fusion–positive solid tumor, updated guidelines also support the use of zenocutuzumab-zbco (Bizengri), a HER2/HER3-targeted bispecific antibody. This guidance is based on evidence derived from the phase 2 eNRGy trial (NCT02912949).
In the response-evaluable population (n = 158), zenocutuzumab monotherapy achieved an ORR of 30% (95% CI, 23%-37%) and a median duration of response (DOR) of 11.1 months (95% CI, 7.4-12.9). Median PFS was 6.8 months (95% CI, 5.5-9.1). Among 93 patients with NSCLC, the ORR was 29% (95% CI, 20%-39%), and the median DOR reached 12.7 months (95% CI, 1.8-29.5). Of 204 patients evaluated for safety, grade 3 or higher treatment-emergent AEs (TEAEs) occurred in 35%, with anemia (5%) and elevated liver enzymes (3%) being the most common.
Despite the rarity of NRG1 fusions, retrospective evidence has shown limited efficacy with standard chemoimmunotherapy in this population. Therefore, zenocutuzumab has emerged as a preferred second-line option despite the single-arm design of the eNRGy study.
Updates for Stage IV NSCLC Without Driver Alterations: Nivolumab, Ipilimumab, and Chemotherapy in the First-Line Setting
For patients with good performance status (PS) of 0 or 1, any histology, and any level of PD-L1 expression, nivolumab (Opdivo) can be recommended for use in combination with ipilimumab (Yervoy) plus two cycles of platinum-based chemotherapy.2
This recommendation is based in part on findings from the NIPPON study (JCOG2007), a randomized, open-label phase 3 trial conducted in Japan. Patients with stage III or IV NSCLC and no actionable driver mutations were randomly assigned to receive either platinum-doublet chemotherapy with pembrolizumab (Keytruda; n = 147) or nivolumab plus ipilimumab (n = 148).
At a median follow-up of 15.3 months, median overall survival (OS) was 20.5 months with pembrolizumab vs 23.7 months with nivolumab and ipilimumab (P = .46). The median PFS was 7.4 months vs 6.0 months, respectively, and the ORRs were 65% and 55%, respectively. Grade 3 or higher nonhematologic AEs occurred more frequently in the nivolumab/ipilimumab group (60% vs 41%), and a higher rate of treatment-related deaths was observed (7% vs 2%).
Despite a numerically longer OS with nivolumab/ipilimumab, the difference was not statistically significant, and the regimen was associated with shorter PFS, more toxicity, and lower quality-of-life scores. Subgroup analyses did not identify any population with preferential benefit. As such, the guideline recommends cautious patient selection when considering this regimen in clinical practice.
No Recommendation Changes: Ivonescimab and Second-Line Docetaxel Combinations
The panel reviewed findings from the HARMONi-2 trial (NCT05499390), which compared ivonescimab with pembrolizumab in patients with PD-L1–positive NSCLC without EGFR or ALK alterations. Ivonescimab showed improved median PFS of 11.1 (95% CI, 7.3-not estimable) vs 5.8 months (95% CI, 5.0-8.2) with pembrolizumab (HR, 0.51; 95% CI, 0.38-0.69; one-sided P < .0001), but higher rates of grade 3 or higher treatment-related AEs (29% vs 16%). Due to limitations including immature OS data and lack of global enrollment, no guideline change was made, and the agent’s use is not currently recommended.
Similarly, the phase 3 DUBLIN-3 trial (NCT02504489) evaluated docetaxel plus plinabulin vs docetaxel alone in patients previously treated with platinum-based chemotherapy. The combination modestly improved OS, at 10.5 months (95% CI, 9.34-11.87) vs 9.4 months (95% CI, 8.38-10.68) with docetaxel alone (stratified HR, 0.82; 95% CI, 0.68-0.99), but with higher rates of serious TEAEs. Given limited prior immunotherapy exposure in the trial and the modest benefit, current second- and later-line recommendations––docetaxel with or without ramucirumab if the patient has already received platinum-based chemotherapy––remain unchanged.
References
- Reuss JE, 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. Published online July 17, 2025. doi:10.1200/JCO-25-01061
- 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. Published online July 17, 2025. doi:10.1200/JCO-25-01062