Dr Raez on Oral Options Reshaping ROS1+, HER2-Mutant, and EGFR Exon 20+ NSCLC

The orals are very attractive. Instead of coming for infusions every 2 weeks or every 3 weeks for other agents, taking a pill at home is more appealing for patients. All of these agents are very good drugs, but I think the fact that they are oral makes it easier for patients and physicians to move the oral agents to the front line.

Luis E. Raez, MD, FACP, FCCP, FASCO, chief scientific officer and medical director, Memorial Cancer Institute, Memorial Healthcare System; director, Thoracic Oncology Program; co-director, MCI/Florida Atlantic University Florida Cancer Center of Excellence; clinical professor of medicine, Florida International University, discussed how oral targeted agents are reshaping frontline decisions in ROS1-positive, HER2-mutant, and EGFR exon 20 insertion–positive non–small cell lung cancer (NSCLC).

At the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, longer follow-up and additional efficacy and safety data from the phase 1/2 ARROS-1 trial (NCT05118789) of zidesamtinib (Jideytro) are expected during the second Presidential Symposium. The FDA approved the ROS1-selective TKI in July 2026 for patients with locally advanced or metastatic ROS1-positive NSCLC previously treated with a ROS1 TKI, based on ARROS-1.2

Raez said zidesamtinib has shown strong efficacy and tolerability in the second-line setting, but a move to the front line would require regulatory approval and a direct comparison against taletrectinib (Ibtrozi), which he described as the current first-line standard given its efficacy and lower toxicity relative to earlier ROS1 agents. Efficacy and toxicity, he said, will decide the choice.

In HER2-mutant disease, trastuzumab deruxtecan (Enhertu) has been used in the second line for more than 2 years, and Raez noted that a positive readout from the phase 3 DESTINY-Lung04 trial (NCT05048797), also on the plenary program, could support a first-line indication. In the interim, 2 oral HER2 TKIs have arrived: zongertinib (Hernexeos), approved in 2025, and sevabertinib (Hyrnuo), which received accelerated approval on September 9, 2026, for previously untreated HER2 tyrosine kinase domain–mutant nonsquamous NSCLC. With 2 oral first-line options, Raez said, the antibody-drug conjugate may settle into second- or third-line use regardless of the DESTINY-Lung04 result.

For EGFR exon 20 insertions, amivantamab (Rybrevant) plus chemotherapy per the phase 3 PAPILLON trial (NCT04538664) remains his standard. With the phase 3 REZILIENT3 trial (NCT05973773) of zipalertinib plus chemotherapy reporting a positive interim analysis in August, he noted that the chemotherapy backbones are identical, and the TKI-based regimen could become the preferred frontline option if its toxicity profile compares favorably with amivantamab.