ASCO has issued a new update to its living guideline regarding therapy for stage IV non–small cell lung cancer (NSCLC) without driver alterations, based on results of three studies published recently.1 The update (the first since a previous version in February 2025) includes discussion of immunotherapy options and other agents, including ivonescimab and plinabulin.2 An update to the living guideline for NSCLC with driver alterations was also issued.3
“Despite all the progress we have seen recently, we still don’t have great data comparing current treatment options to each other, since they all were generally compared to chemotherapy alone in registrational studies,” said Dwight H. Owen, MD, of The Ohio State University, who co-chaired the Expert Panel. The NIPPON trial has now offered the first version of such a comparison.4
Pembrolizumab vs Nivolumab Plus Ipilimumab
NIPPON was a randomized, open-label, phase III study conducted in Japan.4 It included a total of 295 patients with stage III or IV NSCLC not amenable to curative intent therapy; they were randomly assigned to receive platinum-doublet chemotherapy plus either pembrolizumab or nivolumab and ipilimumab. The trial’s accrual was halted early because of a high number of treatment-related deaths in the nivolumab-plus-ipilimumab group (11 of 148 patients [7%], vs 3 of 144 patients in the pembrolizumab group [2%]).
After a median follow-up of 15.3 months, the median overall survival was 20.5 months with pembrolizumab and 23.7 months with nivolumab plus ipilimumab, which did not reach statistical significance (P = .46). The median progression-free survival in the two groups was 7.4 and 6.0 months, respectively, and the objective response rates were 65% and 55%, respectively.
“In this trial, no additional benefit from dual immunotherapy was observed in the subset analysis of patients with PD-L1 0% or squamous histology, and we saw an increased risk of treatment-related deaths,” said Lyudmila Bazhenova, MD, of the University of California, San Diego Moores Cancer Center, who co-chaired the Expert Panel with Dr. Owen. “The results of the NIPPON trial should be interpreted with caution, as it was conducted in a single-country setting.”
The living guideline recommends clinicians may offer nivolumab and ipilimumab plus two cycles of platinum-based chemotherapy in this setting.
No Change From HARMONi-2
The Expert Panel also reviewed results of the HARMONi-2 trial, a randomized, double-blind, phase III study conducted in China.5 It compared the anti–PD-1 and VEGF bispecific antibody ivonescimab with pembrolizumab in a total of 398 patients with PD-L1–positive (> 1%), EGFR- or ALK-negative metastatic or advanced NSCLC.
The study met its primary endpoint, with a median progression-free survival with ivonescimab of 11.1 months compared with 5.8 months with pembrolizumab (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.38–0.69; P < .0001). Although the Expert Panel noted that the results are promising, the use of ivonescimab is not yet recommended based on available evidence.
“We are awaiting additional studies in global cohorts and, importantly, need to understand whether the improvement in [progression-free survival] translates to [overall survival] as well to help determine which patients specifically might benefit from this strategy,” Dr. Owen said. Patients in the ivonescimab group in HARMONi-2 also had a higher rate of grade 3 or higher treatment-related adverse events (29% vs 16% with pembrolizumab).
DUBLIN-3 and Plinabulin
Finally, the Expert Panel reviewed the results of the DUBLIN-3 trial, a single-blind, randomized, phase III study comparing docetaxel and the tubulin binder plinabulin with docetaxel and placebo.6 It included a total of 559 patients with EGFR wild-type NSCLC with disease progression after platinum-based doublet chemotherapy.
The median overall survival with plinabulin was 10.5 months, compared with 9.4 months with placebo (HR = 0.82, 95% CI = 0.68–0.99). Of note, 20% of the study population had received prior immunotherapy, which is now considered standard of care; in the patients who did, there was no statistically significant improvement in overall survival with plinabulin.
“The committee felt it was important to thoroughly discuss any study with an [overall survival] difference, even if the recommendations ultimately did not change,” Dr. Owen said. The guideline recommends clinicians offer docetaxel with or without ramucirumab in the second-line setting following platinum-based chemotherapy.
Dr. Bazhenova agreed. “The study can’t be generalized to our current second-line population, where all patients would have been progressing off immunotherapy,” she added. Dr. Bazhenova noted that patients who received plinabulin had lower rates of neutropenia, although they had higher rates of serious treatment-emergent adverse events overall.
“We are just beginning to see studies comparing new treatments to the standard checkpoint inhibitor backbone regimens that we have been using since 2017,” Dr. Owen said. “We are hopeful to see continued progress here to help us have better discussions with patients about selecting first-line treatment options.”
REFERENCES
- 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).
- Leighl NB, Ismaila N, Drum G, et al: Therapy for stage IV non-small cell lung cancer without driver alterations: ASCO Living Guideline, version 2024.3. J Clin Oncol 43:e17-e30, 2025.
- 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).
- Shiraishi Y, Nomura S, Sugawara S, et al: Comparison of platinum combination chemotherapy plus pembrolizumab versus platinum combination chemotherapy plus nivolumab-ipilimumab for treatment-naive advanced non-small-cell lung cancer in Japan (JCOG2007): An open-label, multicentre, randomised, phase 3 trial. Lancet Resp Med 12:877-887, 2024.
- Xiong A, Wang L, Chen J, et al: Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): A randomised, double-blind, phase 3 study in China. Lancet 405:839-849, 2025.
- Han B, Feinstein T, Shi Y, et al: Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): A phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial. Lancet Resp Med 12:775-786, 2024.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, July 17, 2025. All rights reserved.
