ASCO has issued a new update to its Living Guideline on therapy for stage IV non–small cell lung cancer (NSCLC) with driver alterations, including new recommendations for two therapies: repotrectinib, a ROS1 tyrosine kinase inhibitor (TKI), and zongertinib, a HER2-selective, EGFR-sparing TKI.1 The update is based on results from the TRIDENT-1 and Beamion LUNG-1 trials.2,3
“Together, these studies signal a move toward more effective, next-generation targeted therapies designed for both upfront use and for overcoming resistance,” said Natasha B. Leighl, MD, MMSc, FRCPC, FASCO, of the University of Toronto and the Princess Margaret Cancer Centre in Toronto.
Natasha B. Leighl, MD, MMSc, FRCPC, FASCO
Dr. Leighl co-chaired the Expert Panel along with Sonam Puri, MD, of Moffitt Cancer Center. “The NSCLC treatment landscape is evolving at an unprecedented pace, driven by the identification of new actionable alterations and the development of highly effective targeted therapies,” Dr. Puri added.
TRIDENT-1 and Repotrectinib
The updated guideline says that clinicians may offer entrectinib, larotrectinib, or repotrectinib to patients with NTRK rearrangements. The new option, repotrectinib, is a TRK/ROS1/ALK tyrosine kinase inhibitor (TKI) with enhanced central nervous system (CNS) penetration. The recommendation adds that the agent can be offered to patients who have received a prior NTRK inhibitor.
The addition of repotrectinib is based on results from the single-arm, phase I/II TRIDENT-1 trial.2 That trial evaluated repotrectinib in 120 patients with NTRK fusion–positive locally advanced or metastatic solid tumors. In a TKI-naive cohort including 51 patients (57% with NSCLC), the confirmed objective response rate (cORR) was 59%. A total of eight TKI-naive patients (16%) had a complete response to the agent, and two of three patients with baseline measurable intracranial disease achieved a complete intracranial response. Dr. Puri said repotrectinib showed “impressive intracranial activity.”
KEY POINTS
- Repotrectinib is a ROS1 tyrosine kinase inhibitor (TKI), and zongertinib is a HER2-selective, EGFR-sparing TKI.
- The updated guideline recommends clinicians offer repotrectinib, in addition to entrectinib or larotrectinib, to patients with NTRK rearrangements, including patients who have received a prior NTRK inhibitor.
- The updated guideline also recommends zongertinib as a treatment option for patients with tumors that have HER2-activating mutations. No first-line targeted therapy was previously approved for HER2-mutant NSCLC.
- The recommendation for repotrectinib is based on results from the single-arm, phase I/II TRIDENT-1 trial, and zongertinib is now recommended as a treatment option based on the phase Ia/Ib Beamion LUNG-1 trial.
In 69 patients who had received prior TKI therapy, the response rate was 48%; 17 of these patients had NTRK fusion–positive NSCLC, and their response rate was 53%.
“TRIDENT-1 shows that next-generation TRK inhibitors like repotrectinib can overcome resistance with meaningful responses even after prior therapy and good CNS activity,” Dr. Leighl said.
Treatment-related adverse events (TRAEs) of any grade occurred in 97% of patients evaluated in TRIDENT-1. The most common TRAEs included dizziness (58%) and dysgeusia (54%). Grade 3 or higher TRAEs occurred in 34% of the cohort, including anemia (6%) and dizziness (5%). The Expert Panel noted that the safety profiles of the three available agents in this setting vary, and treatment selection may be influenced by individual toxicity considerations as well as by drug availability, patient comorbidities, and other factors.
Beamion LUNG-1 and Zongertinib
The updated guideline also recommends that clinicians offer zongertinib as a treatment option to patients with HER2-activating mutations. This addition is based on results from the phase Ia/Ib Beamion LUNG-1 study, a multicenter and multicohort trial that evaluated zongertinib in patients with advanced or metastatic NSCLC harboring HER2 mutations, which occur in 2% to 4% of patients.3
“For HER2-mutant NSCLC, no first-line targeted therapy was previously approved, and standard-of-care chemoimmunotherapy has been associated with historically poor survival in this population,” Dr. Puri said.
Zongertinib is an oral, irreversible TKI that selectively inhibits HER2. In cohort 2 of the trial, 74 patients who were treatment naive received 120 mg of zongertinib once daily. The cORR was 76%; patients with a HER2 A775_G776insYVMA mutation (68%) had a cORR of 84%. A total of eight patients (11%) achieved a complete response, and the disease control rate was 96%. After a median follow-up of 15.2 months, the median progression-free survival was 14.5 months.
The agent was generally well tolerated. Any grade TRAEs occurred in 91% of patients, with diarrhea (55%) and rash (24%) being the most common. Grade 3 or higher TRAEs were observed in 19% of the cohort, with alanine aminotransferase increase (4%) being the most common, followed by diarrhea (3%), aspartate aminotransferase increase (3%), and anemia (3%).
Cohort 4 of the trial tested zongertinib’s efficacy in 30 patients with active brain metastases. It found an intracranial cORR of 47% irrespective of prior lines of therapy for metastatic disease, and 50% among 8 patients who received zongertinib as first-line therapy.
An Evolving Field
The Expert Panel also reviewed results from three other trials that added to existing evidence but did not result in changes to the Living Guideline.
“Beyond TKIs, novel drug classes such as antibody-drug conjugates and bispecific antibodies have entered the treatment paradigm, broadening the therapeutic arsenal,” Dr. Puri said. “Underpinning all of this progress, comprehensive molecular testing at diagnosis remains the essential backbone that enables patients to access these advances.”
Dr. Leighl added that the addition of new active agents and novel targets allows for better sequencing of therapies and an increased ability to overcome and delay treatment resistance. “The field continues to move incredibly fast,” she said. “It has been wonderful to see each update bring meaningful progress for our patients.”
DISCLOSURE: Dr. Leighl reported the following disclosure information: Research Funding (Institutional): MSD, Lilly, AstraZeneca Canada, Inivata/NeoGenomics, Janssen Oncology, Novartis, Pfizer, Guardant Health, GlaxoSmithKline Canada, Amgen, Boehringer Ingelheim, Takeda, and Bristol Myers Squibb; Travel, Accommodations, Expenses: AstraZeneca, Roche, Janssen, MSD Oncology, Guardant Health, Sanofi, Eisai. Dr. Puri reported the following disclosure information: Consulting or Advisory Role: Bristol Myers Squibb Foundation, AbbVie (I), Intuitive Surgical (I), Janssen, Daiichi Sanko Inc, Amgen, AstraZeneca, Boehringer Ingelheim, ImmunityBio, Henlius, Asher Biotherapeutics, and Daiichi Sankyo/Lilly; Research Funding (Institutional): ORIC Pharmaceuticals, Johnson & Johnson/Janssen, Amgen, Biohaven Pharmaceuticals, BioNTech SE, AbbVie, Blossom Hill; Travel, Accommodations, Expenses: Dava Oncology and Henlius. For full disclosure information of all study authors, visit ascopubs.org/doi/10.1200/JCO-26-01479.
REFERENCES
1. Puri S, Ismaila N, Azar IH, et al: Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO Living Guideline, version 2026.3.2. J Clin Oncol. Published online June 29, 2026.
2. Besse B, Lin JJ, Bazhenova L, et al: Repotrectinib in NTRK fusion–positive advanced solid tumors: A phase 1/2 trial. Nature Medicine 32:682-689, 2026.
3. Heymach JV, Yamamoto N, Girard N, et al: Beamion LUNG-1 Investigators. First-line zongertinib in advanced HER2-mutant non–small-cell lung cancer. N Engl J Med 394:1675-1684, 2026.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, July 29, 2026. All rights reserved.
