As per the data presented at ASCO 2025, the median OS was 16 months with patritumab deruxtecan compared to 15.9 months with chemotherapy, with median follow-up durations of 18.7 and 18.6 months, respectively. In patients with EGFR-mutant, locally advanced, or metastatic NSCLC, patritumab deruxtecan (HER3-DXd) did not demonstrate an OS advantage. Patritumab deruxtecan provided a significant improvement in PFS vs. chemotherapy (HR: 0.77). Median PFS with patritumab deruxtecan vs. chemotherapy was 5.8 vs. 5.4 months.

As a result of these findings, Merck withdrew its Biologics License Application (BLA) for FDA approval of the drug in this indication.

One positive is that patritumab deruxtecan is not  associated with a greater risk of death than chemotherapy across the whole study. Patritumab deruxtecan demonstrated substantial toxicity, with 58% of patients experiencing Grade 3 or higher treatment-related adverse events. This led to dose reductions in 32% of patients and treatment discontinuation in 11%. There were four treatment-related deaths, including two from interstitial lung disease (ILD), and a total of 14 ILD cases reported. In comparison, the chemotherapy group had one treatment-related death.

KOL insights

“Last year's complete response letter for Merck & Co's patritumab deruxtecan was put down to a manufacturing technicality, but the project's just revealed ASCO abstract suggests that matters are far worse. A separate trial of this anti-HER3 ADC, last year toplined positive, has shown lamentable efficacy and two deaths due to interstitial lung disease.” – Expert Opinion

“The absence of a crossover design and the fact that HER3-DXd is not currently commercially available strengthens overall survival comparisons in future analyses. The need for comparative trials against amivantamab-based regimens, particularly in combination settings, and for evaluating HER3-DXd in the first-line setting.”– Expert Opinion

Conclusion

EGFR-mutated NSCLC remains a major treatment challenge once resistance develops to current therapies like TAGRISSO (osimertinib), despite advances in targeted treatments over the past two decades. Patritumab deruxtecan showed promise in the HERTHENA-Lung01 Phase II trial, with meaningful and durable responses in heavily pretreated patients. However, despite high HER3 overexpression in this population, there are still no approved HER3-directed therapies.

Merck now faces decisions on the future of patritumab deruxtecan, while AstraZeneca avoided potential setbacks by opting not to license the ADC, due to concerns over its toxicity profile and lack of synergy with TAGRISSO.

Regulatory setbacks have stalled patritumab deruxtecan’s progress—first a Complete Response Letter in June 2024 due to manufacturing issues, followed by a voluntary withdrawal of the US BLA in May 2025 after the Phase III HERTHENA-Lung02 trial failed to show a statistically significant overall survival benefit. Safety concerns, including notable toxicity and poor combination outcomes with osimertinib, further complicate its future. As the field seeks effective post-TKI options, new therapies will need both strong efficacy and manageable safety to compete in an increasingly crowded landscape.