ASCO has issued an update to its living guideline on systemic therapies for patients with stage IV NSCLC without driver alterations.1 The update, which includes a new recommendation regarding the PD-1 inhibitor retifanlimab-dlwr and chemotherapy, follows a recent full update to the guideline published in February 2026.2
Lyudmila Bazhenova, MD, FASCO
Natasha B. Leighl, MD, FASCO
The Guideline Expert Panel reviewed evidence from three studies that met their inclusion criteria. Although one study led to a recommendation update, evidence from the other two studies did not result in changes to the guideline. The Expert Panel was co-chaired by Lyudmila Bazhenova, MD, FASCO, of Moores Cancer Center at the University of California, San Diego, and Natasha B. Leighl, MD, FASCO, of the Princess Margaret Cancer Centre, University Health Network, Toronto.
POD1UM-304 Trial
According to the updated guideline, clinicians may offer retifanlimab plus platinum-based chemotherapy to patients with good performance status, nonsquamous cell carcinoma, and any level of PD-L1 expression. This recommendation is based on the results of the phase III, double-blind, placebo-controlled POD1UM-304 trial.3
The trial included 583 patients with previously untreated stage IV nonsquamous (65%) or squamous (35%) NSCLC without alterations to EGFR, ALK, BRAF, or ROS1. Patients received either the PD-1 inhibitor retifanlimab plus platinum-based chemotherapy or placebo plus the same chemotherapy options.3
The median overall survival with the study combination was 18.1 months, compared with 13.4 months with placebo and chemotherapy, for a hazard ratio (HR) of 0.75 (95% confidence interval [CI] [0.60, 0.93]; P = .0042). The median progression-free survival was 7.7 and 5.5 months, respectively (HR 0.64, 95% CI [0.52, 0.79]; P < .0001).3
The objective response rate also favored the retifanlimab group, at 52% vs 39%, and the retifanlimab group responses were more durable (12.7 vs 6.1 months, respectively).3
The most common treatment-related adverse events of any grade in the retifanlimab group occurred at higher rates than in the placebo group and included anemia (63% vs 58%), decreased appetite (23% vs 13%), and neutrophil count decrease (22% vs 17%). However, patients in the retifanlimab group experienced fewer elevations in alanine aminotransferase (19% vs 24%) and aspartate aminotransferase (15% vs 20%) and less nausea (21% vs 24%).3
The Expert Panel concluded that retifanlimab plus chemotherapy could represent an additional first-line treatment option. This may be of particular use in settings where access to or costs of other agents may be barriers, although the Panel noted that these results do not “fundamentally change current management paradigms.” Instead, they confirm a “class effect” of this type of agent in this setting, which may expand the set of treatment options.1
“I think this reinforces the consistency of benefit across studies, which increases confidence that this is a true class effect rather than a trial-specific finding,” Dr. Bazhenova said. “It adds to safety data in broader or more contemporary populations, which is particularly relevant as treatment is used more widely.”
HARMONi-6 and BAP BRAIN Trials
The Expert Panel also reviewed the results of two other trials, neither of which yielded changes to the guideline recommendations.
First, in the HARMONi-6 trial, a total of 532 Chinese patients with treatment-naive advanced squamous NSCLC received either the PD-1/VEGF bispecific antibody ivonescimab plus chemotherapy or the PD-1 inhibitor tislelizumab-jsgr plus chemotherapy.4
After a median follow-up of 10.3 months, the ivonescimab group showed significantly better PFS, at 11.1 vs 6.9 months (HR 0.60, 95% CI [0.46, 0.78]; P < .0001). The progression-free survival benefit was seen regardless of PD-L1 status and was greater in younger patients than in older patients.4
[Editor’s note: The mature overall survival and updated findings from the phase III HARMONi-6 trial were reported in detail at the 2026 ASCO Annual Meeting.5 Key updates included: After a median follow-up of 21.4 months, patients treated with ivonescimab plus chemotherapy achieved a median overall survival of 27.9 months (95% confidence interval [CI] = 27.89 months to not estimable), compared with 23.7 months (95% CI = 20.11 months to not estimable) for those treated with tislelizumab plus chemotherapy (hazard ratio = 0.66, 95% CI = 0.50–0.87, one-sided P = .0017). Treatment with ivonescimab reduced the risk of death by 34% during the study period. These overall survival findings build on earlier progression-free survival results from the trial discussed in this article.]
“There was some imbalance in baseline patient characteristics between the study arms, which could have influenced the observed efficacy outcomes,” Dr. Bazhenova said. In addition, she remarked, at the time of guideline development, the short follow-up period limits the assessment of long-term benefit, durability of response, and late toxicities.
Furthermore, “the study did not enroll a global population, which may limit generalizability, particularly to regions with different standards of care, access to therapies, and patient demographics,” Dr. Bazhenova explained.
The Expert Panel also considered the results of the BAP BRAIN trial, which included 153 patients in China with treatment-naive nonsquamous NSCLC with brain metastases.6 The trial evaluated the intracranial safety and efficacy of bevacizumab added to pemetrexed-platinum chemotherapy; it was conducted before first-line immunotherapy became the standard of care in this setting, and, therefore, its current relevance is limited.
BAP BRAIN found significantly improved intracranial PFS with bevacizumab and chemotherapy versus chemotherapy alone (11.07 vs 7.37 months; HR 0.494, 95% CI [0.343, 0.712]; P < .001), and OS was about 10 months longer in the bevacizumab group.5
The Expert Panel noted that platinum plus bevacizumab–containing regimens, like that used in BAP BRAIN, could be considered in patients who are not eligible for immunotherapy.
DISCLOSURE: Dr. Bazhenova reported a consulting or advisory role with: Genentech/Roche, Merck, Bayer, AbbVie, Janssen Oncology, Anheart Therapeutics, Pfizer, Boehringer Ingelheim, Summit Pharmaceuticals, Bristol-Myers Squibb GmbH & Co. KG (Germany), Natera, Revolution Medicines, Taiho Oncology, Nuvalent, Inc, and Lilly. Dr. Leighl reported travel, accommodations, expenses from AstraZeneca, Roche, Janssen, MSD Oncology, Guardant Health, Sanofi, Eisai. She reported research funding (all to her institution) from Merck Sharp & Dohme,Lilly, AstraZeneca Canada, Inivata/NeoGenomics, Janssen Oncology, Novartis, Pfizer, Guardant Health, GlaxoSmithKline Canada, Amgen, Boehringer Ingelheim, Takeda, and Bristol Myers Squibb.
REFERENCES
1. Bazhenova L, Ismaila N, Durm G, et al: Therapy for stage IV non–small cell lung cancer without driver alterations: ASCO Living Guideline, 2026.3.1. J Clin Oncol. Published online May 26, 2026.
2. Reuss JE, Bazhenova L, Ismaila N, et al: Therapy for stage IV non–small cell lung cancer without driver alterations: ASCO Living Guideline, 2026.3.0. J Clin Oncol 44:e56-e88, 2026.
3. Lu S, Vynnychenko O, Kulyaba Y, et al: Retifanlimab vs placebo in combination with platinum-based chemotherapy in patients with first-line non-squamous or squamous metastatic non-small-cell lung cancer (POD1UM-304): a phase 3, multiregional, placebo-controlled, double-blind, randomised study. Lancet Respir Med 13:1096-1107, 2025.
4. Chen Z, Yang F, Jiang Z, et al: Ivonescimab plus chemotherapy vs tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): A randomised, double-blind, phase III trial. Lancet 406(10515):2078-2088, 2025.
5. Wei Z, et al: Ivonescimab plus chemotherapy vs tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: Overall survival results of the phase III HARMONi-6 trial. Abstract LBA4. 2026 ASCO Annual Meeting. Presented May 31, 2026.
6. Li M, Pan Y, Jiang G, et al: Bevacizumab plus chemotherapy vs chemotherapy in untreated advanced non-squamous non-small-cell lung cancer patients with brain metastases (BAP BRAIN): an open-label, randomized, multicenter, phase III study. ESMO Open 10(12):105908, 2025.
Originally published in ASCO Daily News. © American Society of Clnical Oncology. ASCO Daily News, May 26, 2026. All rights reserved.
