NSCLC in Focus at WCLC: 3 Pivotal Trials Shaping the Next Wave of Treatment

As clinicians and researchers convene in Barcelona for the IASLC 2025 World Conference on Lung Cancer (WCLC), the stakes are high for new data poised to shift the therapeutic landscape for non-small cell lung cancer (NSCLC). Despite steady progress in immunotherapies and targeted treatments, NSCLC—which accounts for about 85% of all lung cancer cases—continues to carry a sobering five-year survival rate of just 32%. That persistent gap between treatment availability and long-term outcomes underscores why three ongoing Phase III trials have captured global attention.

Among them is Bayer’s sevabertinib, a tyrosine kinase inhibitor (TKI) engineered to target tumors with HER2 mutations—a less common but notoriously difficult-to-treat NSCLC subtype. The SOHO-02 trial pits this oral TKI against standard chemotherapy, aiming to determine whether precision targeting can outperform traditional regimens in efficacy and safety. Although full data won’t be available until 2027, early-stage results have suggested promising tumor response rates and a tolerable side effect profile. The drug’s dual inhibition of EGFR and HER2 echoes the mechanism behind Tagrisso (osimertinib), an EGFR-targeting TKI already established in first-line settings. The comparison raises compelling questions: Could sevabertinib offer a more versatile or synergistic option when paired with chemotherapy? Could it eventually move to first-line use for HER2-mutant NSCLC?

The race may be complicated by Boehringer Ingelheim’s recent approval of zongertinib (Hernexeos), another HER2-directed agent. As sevabertinib enters broader testing across 36 countries, head-to-head data will be crucial to determine its potential edge in efficacy, durability, and toxicity. For now, its success would mark a meaningful addition to an increasingly personalized approach to NSCLC treatment.

While Bayer seeks to refine HER2 targeting, AstraZeneca is doubling down on a riskier proposition: ATR inhibition. The LATIFY trial explores a combination of the ATR kinase inhibitor ceralasertib and the PD-L1 inhibitor durvalumab (Imfinzi), versus chemotherapy with docetaxel in patients whose cancers have progressed despite immunotherapy and platinum-based regimens. Unlike EGFR or HER2, ATR inhibition remains a relatively uncharted territory in NSCLC. Despite years of preclinical enthusiasm, no ATR or ATM inhibitors have made it to market, and past efforts have faltered due to toxicity and limited efficacy.

The LATIFY study aims to enroll nearly 600 patients and will primarily evaluate overall survival—a critical endpoint for a patient population often left with few remaining options. However, the trial design itself has raised questions. By testing the combination of ceralasertib and Imfinzi without assessing each agent as a monotherapy, it may be difficult to parse out where the therapeutic benefit lies. Moreover, early concerns about tolerability—particularly anemia, nausea, and fatigue—could limit the drug’s potential, unless future data point to a substantial survival advantage.

Still, ATR inhibitors aren’t being written off. Some experts believe their real promise may lie in carefully selected biomarker-driven subpopulations or in combination with other modalities like radiation. LATIFY could either validate that direction or highlight the need for a strategic pivot.

Meanwhile, BioNTech is charting a different course through immunotherapy. Following its acquisition of the anti-CTLA-4 monoclonal antibody gotistobart (formerly ONC-392), the German biotech is leading the PRESERVE-003 trial, testing the drug in patients who have already progressed on PD-1 or PD-L1 inhibitors. Unlike the earlier checkpoint inhibitors that reshaped the NSCLC landscape, CTLA-4–directed agents have struggled to find their place due to significant toxicity and inconsistent efficacy. Nonetheless, the trial—comparing low- and high-dose gotistobart against chemotherapy—may offer new insights into where this class could fit, particularly in immunotherapy-resistant tumors.

CTLA-4 inhibition remains a challenging balancing act. While it may stimulate immune response in tumors that are otherwise "cold," the price often comes in the form of immune-related adverse events that can be debilitating or difficult to manage. Physicians are familiar with these risks, having used drugs like Yervoy and Imjudo in other contexts. The question now is whether gotistobart can deliver meaningful clinical benefit with an acceptable toxicity profile. Early indications suggest potential benefit in specific molecular subtypes—such as tumors with STK-11 or KEAP-1 mutations—but such signals will need to be confirmed in larger datasets.

Taken together, these three trials represent a snapshot of the evolving strategy in NSCLC: not a single breakthrough, but a broadening toolkit of targeted and immune-based therapies that may, in combination or sequence, offer more tailored treatment pathways. If sevabertinib can match or surpass current TKIs in HER2-mutant patients, if ceralasertib can validate ATR as a viable target, and if gotistobart proves CTLA-4 inhibition can be safely revived, the result could be a more nuanced and effective algorithm for NSCLC care.

For now, the data are still emerging, and caution remains warranted. But as the field awaits readouts from SOHO-02, LATIFY, and PRESERVE-003, one thing is clear: the momentum behind NSCLC innovation is accelerating. Whether these efforts ultimately reshape standard of care will depend not only on statistical endpoints, but on how these therapies perform in the complexity of real-world clinical practice.