Two Phase 3 Trials Show New Treatment Paths for Different Non-Small Cell Lung Cancer Types

Non-small cell lung cancer, or NSCLC, is not a single disease. Tumors behave very differently depending on their type and the genetic changes they carry. That makes treatment complicated and leaves some patients with few effective options. New phase 3 trial results presented at the American Society of Clinical Oncology Annual Meeting report two advances that target different gaps in care. One tests a targeted adjuvant drug for early-stage RET fusion-positive disease. The other tests a novel bispecific antibody for advanced squamous disease. Both showed meaningful benefits in key outcomes and could change care for the patients they target. 

Selpercatinib After Surgery Sharply Lowers the Chance Cancer will Return  

The LIBRETTO‑432 trial enrolled people whose tumors had a RET fusion and who had already had surgery or radiation plus standard adjuvant therapy. Participants were randomly assigned to take selpercatinib or a placebo for up to three years. In the higher-risk group with stage 2 to 3A disease, selpercatinib cut the risk of the cancer coming back or of death by about 83%. 

Andreas Saltos, MD

When researchers looked at how long people stayed free of cancer or progression they found the median event-free survival was not reached in the selpercatinib group. That means more than half of those patients were still free of recurrence at the time of the analysis. By comparison, the median event-free survival in the placebo group was 31.8 months. At two years, the event-free rate was 91.5% with selpercatinib versus 61.1% with placebo. 

“RET fusions are rare, but when they are present, they define a clear target,” said Andreas Saltos, MD, a medical oncologist in the Thoracic Oncology Department at Moffitt Cancer Center. “These results suggest we can now offer a targeted adjuvant option that meaningfully lowers recurrence for patients who previously had no approved targeted choice.” 

The most common serious side effects included elevated liver enzymes and other issues that can usually be managed, such as dry mouth, diarrhea and high blood pressure. The trial is still following patients, and the planned three-year treatment period will help doctors determine whether the early benefit in event-free survival leads to longer overall survival and which patients benefit most. 

Ivonescimab Plus Chemotherapy Extends Survival for Advanced Squamous NSCLC Regardless of PD‑L1 

The HARMONi‑6 trial tested ivonescimab plus chemotherapy against a standard PD‑1 inhibitor plus chemotherapy as first-line treatment for advanced squamous NSCLC. Ivonescimab is a single antibody that does two jobs at once: it helps the immune system attack the tumor by blocking PD‑1 and it blocks tumor blood vessel growth by targeting VEGF. After about 21 months of median follow-up, the median overall survival was roughly 28 months for people who received ivonescimab versus 24 months for those on the comparator. Overall, the drug lowered the risk of death by about 34%, and it also delayed tumor growth. The benefit was seen regardless of tumor PD‑L1 levels, a protein that can affect how well some immunotherapies work. 

“Squamous NSCLC has lagged behind other subtypes when it comes to new therapies,” Saltos said. “A bispecific that combines immune activation with vascular targeting and carries a low risk for excess bleeding could become an important new option, especially for patients whose tumors lack PD‑L1. Because this trial enrolled patients only in China, ongoing studies are being conducted worldwide to confirm the benefit in other populations and to ensure the safety profile is consistent across diverse groups.” 

Serious side effects were similar between the two treatment groups. Bleeding was uncommon but occurred slightly more often with ivonescimab. Larger global trials are now underway to confirm the benefit and to check safety in broader populations. 

Why These Results Matter 

These two trials address different but important gaps in NSCLC care. Selpercatinib could become the first adjuvant targeted therapy for RET fusion-positive early-stage disease, particularly if longer follow-up confirms benefit. Ivonescimab offers a promising new first-line strategy for advanced squamous NSCLC that may improve outcomes relative to conventional PD-1 targeting antibodies, but additional studies in broader populations are needed. Investigators will continue follow-up and broader testing before making any changes in standard practice.