ASCO Living Guideline Update Expands Targeted Options in Advanced NSCLC

The American Society of Clinical Oncology (ASCO) has issued a full update to its living clinical practice guideline on systemic therapy for stage IV non–small cell lung cancer (NSCLC) with driver alterations, adding repotrectinib (Augtyro) and zongertinib (Hernexeos) as recommended options for patients with ROS1 rearrangement–positive and HER2 tyrosine kinase domain (TKD)–mutant disease, respectively.¹ The update, version 2026.3.0, was developed by ASCO's Expert Panel and published in the Journal of Clinical Oncology.

For patients with ROS1 rearrangement–positive stage IV NSCLC, the guideline now lists repotrectinib alongside crizotinib (Xalkori) and entrectinib (Rozyltrek) as a first-line tyrosine kinase inhibitor (TKI) option, and, together with taletrectinib (Ibtrozi), as a subsequent-line option following progression on an earlier ROS1 TKI.^1,2 The recommendation draws on the phase 1/2 TRIDENT-1 trial (NCT03093116), in which TKI-naive patients treated with repotrectinib had a confirmed objective response rate of 79%, a median duration of response of 34.1 months, and a median progression-free survival of 35.7 months.³ Among patients who had received 1 prior ROS1 TKI without chemotherapy, the objective response rate was 38%, including responses in patients harboring the ROS1 G2032R solvent-front resistance mutation. The Expert Panel notes that agent selection among ROS1-directed TKIs should account for prior TKI exposure, central nervous system disease, toxicity profile, drug-drug interactions, and availability.²

For HER2 exon 20–mutated NSCLC, the panel added zongertinib and sevabertinib (Hyrnuo) as options in the second-line setting, including for patients previously treated with trastuzumab deruxtecan (T-DXd; Enhertu).^1,2 Zongertinib's addition is supported by the phase 1a/1b Beamion LUNG-1 trial (NCT04886804), which enrolled patients with HER2-mutant advanced NSCLC and reported high response rates with a manageable toxicity profile.^1,2 In the previously treated cohort, zongertinib produced a confirmed objective response rate of approximately 67% by blinded independent central review.⁴ Sevabertinib's inclusion is based on the phase 1/2 SOHO-01 trial.¹

Sonam Puri, MD, co-chair of the Expert Panel, said the panel will continue to monitor emerging trial data that could refine treatment sequencing, including studies of earlier use of currently available agents, novel combinations, and additional targets.¹ The update reinforces ASCO's broader emphasis on comprehensive molecular profiling—next-generation sequencing paired with immunohistochemistry for HER2 and MET—to guide biomarker-directed treatment selection at diagnosis and at progression.^1,2

For clinicians, the practical implications center on sequencing and dosing rather than a wholesale change in first-line strategy. Repotrectinib is dosed at 160 mg orally once daily for 14 days, followed by 160 mg twice daily, and its safety profile is notable for TRK-related adverse events, including dizziness, dysgeusia, ataxia, and paresthesia, most of low grade.^2,3 Zongertinib dosing is weight-based—120 mg orally once daily for patients under 90 kg and 180 mg once daily for patients at or above 90 kg—with labeling that includes warnings for hepatotoxicity, left ventricular dysfunction, and interstitial lung disease/pneumonitis.²

The panel also cautioned that evidence for some newly incorporated agents remains less mature than for longer-established options; for instance, outcomes data for repotrectinib in the NTRK fusion–positive population are still considered less well characterized than those for larotrectinib (Vitrakvi) and entrectinib, pending a full published manuscript.¹ Ongoing and planned phase 3 trials, including Beamion LUNG-2 (NCT06151574) comparing zongertinib with standard first-line therapy in HER2 TKD-mutant NSCLC, are expected to further inform where these agents fit in the treatment algorithm.^1,4

ASCO's living guideline model allows for incremental updates as new evidence emerges, rather than waiting for a full guideline revision cycle, and the Expert Panel indicated it will continue to issue interim updates as additional data on these and other targeted agents mature.^1.2

Learn more about the treatment landscape of ROS1-positive NSCLC in this interview with Dr Edgardo Santos Castillero.

REFERENCES

1. Puri S, Leighl NB, Ismaila N, et al. Therapy for stage IV non–small cell lung cancer with driver alterations: ASCO Living Guideline, version 2026.3.0. J Clin Oncol. Published online February 3, 2026.

2. Biomarker testing, incorporation of new drug approvals among new guidance in updated living guideline on stage IV NSCLC with driver alterations. ASCO Daily News. February 3, 2026. Accessed August 3, 2026. https://tinyurl.com/n9rhb8hx

3. Drilon A, Camidge DR, Lin JJ, et al. Repotrectinib in ROS1 fusion-positive non–small-cell lung cancer. N Engl J Med. 2024;390(2):118-131.

4. Heymach JV, Ruiter G, Ahn M-J, et al; Beamion LUNG-1 Investigators. Zongertinib in previously treated HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333.