Patritumab Deruxtecan Does Not Improve Survival Outcomes vs Chemo in EGFR+ NSCLC

Patritumab deruxtecan doesn't improve OS vs chemotherapy in EGFR+ advanced/metastatic NSCLC: © stock.adobe.com.

Among patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC), patritumab deruxtecan (HER3-DXd) treatment did not improve overall survival outcomes compared with platinum-based chemotherapy treatment, according to data from the phase 3 HERTHENA-Lung02 study which were shared at the 2025 ASCO Annual Meeting.

The median overall survival was 16.0 months in the patritumab deruxtecan arm versus 15.9 months in the chemotherapy arm. The median follow-up was 18.7 versus 18.6 months in the two arms, respectively.

Based on these overall survival data, Merck previously withdrew its biologics license application seeking FDA approval of patritumab deruxtecan for use in this setting.

Additional Efficacy Data

Previously reported results from the primary analysis of the HERTHENA-Lung02 trial showed that patritumab deruxtecan significantly reduced the risk of disease progression or death versus chemotherapy. The median progression-free survival was 5.8 months with patritumab deruxtecan versus 5.4 months with chemotherapy. The nine-month probability of progression-free survival was 29% versus 19%, respectively. The progression-free survival benefit was sustained across most subgroups, including those defined by age, sex, geographic region, brain metastases at baseline, smoking status and ECOG performance score.

The confirmed objective response rate was 35.2% with patritumab deruxtecan versus 25.3% with chemotherapy. The disease control rate was 80.5% with patritumab deruxtecan versus 75.8% with chemotherapy. The median time to response was 1.5 months in each arm and the median duration of response was about 5.5 months in both arms.

Intracranial efficacy was evaluated in 105 and 95 patients in the treatment and control arms, respectively. The median intracranial response was 5.4 versus 4.2 months, respectively. The confirmed intracranial objective response rate was 19.0% and 11.6% in the two arms, respectively. The intracranial complete response rate was 12.4% versus 4.2% and the intracranial disease control rate was 68.6% and 61.1%, respectively. The median intracranial time to response and median intracranial duration of response were 2.1 versus 2.6 months and 4.5 versus 4.2 months, respectively.

The safety evaluable population included 290 and 280 patients in the patritumab deruxtecan and chemotherapy arms, respectively. The investigators considered the toxicities to be generally manageable and similar to prior research with the study treatments. Grade 3 (severe) or higher treatment-related side effects occurred in 57.9% versus 46.1% of the treatment and control arms, respectively. Serious treatment-related side effects were reported for 22.4% versus 12.5% of the two arms, respectively. There were four treatment-related side effect-linked deaths in the patritumab deruxtecan arm compared with one in the chemotherapy arm. Of note, the incidence of adjudicated interstitial lung disease was 5.2% for the patritumab deruxtecan arm.

HERTHENA-Lung02 Design and Patient Characteristics

The open-label phase 3 HERTHENA-Lung02 trial enrolled patients with locally advanced or metastatic NSCLC harboring an EGFR mutation. Patients had to have disease progression after received one or two prior lines of an U.S. Food and Drug-approved EGFR TKI, including a third-generation TKI.

Patient characteristics were well balanced between the patritumab deruxtecan (n = 293) and chemotherapy (293 patients) arms. The median age across both arms was 64 years (range, 34-86), about 60% of patients were female, and about 60% of patients were Asian. Just under two-thirds of patients were never-smokers, and the median time since initial diagnosis was 24.2 months (range, 2.5-146.1). About two-thirds of patients had an ECOG performance score of one, with the remainder having an ECOG performance score of zero. About 44% of patients had a history of brain metastasis, with about one-third having brain metastases at baseline.

The approximate breakdown of EGFR activating mutations was 60% with Ex19del, 39% with L858R, and 1% with dual Ex19del and L858R. Regarding prior EGFR TKIs, three-fourths of patients had previously received only third-generation EGFR TKIs, while one-fourth had received both third- and first/second-generation TKIs. Over 90% of patients had prior Tagrisso (osimertinib).

Patients received patritumab deruxtecan at 5.6 mg/kg (IV) every three weeks or platinum-based chemotherapy. Chemotherapy consisted of four cycles of pemetrexed plus either cisplatin or carboplatin, followed by optional maintenance pemetrexed in patients whose disease did not progress after the initial four combination cycles.

Progression-free survival per blinded independent central review was the primary end point, with secondary end points consisting of overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response, intracranial progression-free survival, quality of life and safety.

Regarding next steps, study investigators said, “Evaluation of the association of biomarkers, including HER3 IHC, with efficacy parameters in HERTHENA-Lung02 and their suitability as a predictive biomarker is ongoing.”

Reference

Mok T, Yu H, Lim SM, Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study. J Clin Oncol. 2025;43(suppl 17):8506. doi: 10.1200/JCO.2025.43.16_suppl.8506

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.