For patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy, current treatment options provide only limited clinical benefit. The results of phase II, HERTHENA-Lung01 study provide the largest evaluation to date of the efficacy and safety of patritumab deruxtecan once every 3 weeks monotherapy in this population and provide the largest assessment of a targeted therapy after the failure of osimertinib.
Patritumab deruxtecan demonstrated clinically meaningful efficacy, including durable intracranial responses, with a manageable safety profile in patients with previously treated EGFR-mutated NSCLC. The study results are published by Dr. Helena A. Yu of the Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center in New York, NY, US, and colleagues on 10 September 2023 in the JCO. The findings from a primary analysis of HERTHENA-Lung01 study were presented in part at the 2023 IASLC World Conference on Lung Cancer in Singapore (9-12 September 2023).
The authors explained in background that initial treatment for patients with EGFR–mutated advanced NSCLC typically includes one or two EGFR TKI regimens comprising either a third-generation EGFR TKI or a first- or second-generation EGFR TKI followed by a third-generation EGFR TKI when the EGFR T790M mutation is detected. After disease progression on EGFR TKI therapy, patients are usually treated with platinum-based chemotherapy with or without an immune checkpoint inhibitor and antiangiogenic therapy. Salvage therapies after disease progression on platinum-based chemotherapy have limited efficacy.
HER3 expression has been reported in 83% of NSCLC and in 85-100% of tumours harbouring an activating EGFR mutation; it is implicated in resistance to EGFR TKI therapy and is associated with metastatic progression and shorter relapse-free survival. Patritumab deruxtecan is an investigational HER3-directed antibody-drug conjugate. A phase I dose-escalation/dose-expansion study of patritumab deruxtecan in heavily pretreated patients with EGFR-mutated NSCLC showed that patritumab deruxtecan 5.6 mg/kg administered intravenously once every 3 weeks was associated with a tolerable and manageable safety profile and resulted in a confirmed objective response rate (ORR) of 39% in patients with previous treatment with osimertinib and platinum-based chemotherapy.
In the phase I study, patritumab deruxtecan once every 3 weeks was effective in patients with diverse mechanisms of resistance to EGFR TKIs, including EGFR-dependent and -independent mechanisms. The promising data from the phase I study led to initiation of the phase II HERTHENA-Lung01 study of patritumab deruxtecan in patients with EGFR-mutated NSCLC who had previously been treated with EGFR TKI therapy and platinum-based chemotherapy. Patients received patritumab deruxtecan 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary endpoint was confirmed ORR per RECIST v1.1 by blinded independent central review (BICR), with a null hypothesis of 26.4% based on historical data.
Enrolment into the uptitration arm closed early based on a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 study. A total of 225 patients received patritumab deruxtecan 5.6 mg/kg once every 3 weeks. As of 18 May 2023, median study duration was 18.9 months (range, 14.9-27.5). Confirmed ORR by BICR was 29.8% (95% confidence interval [CI] 23.9 to 36.2). Median duration of response was 6.4 months. Median progression-free survival was 5.5 months and median overall survival was 11.9 months.
The subgroup of patients with previous treatment with osimertinib and platinum-based chemotherapy had similar outcomes. Efficacy was observed across a broad range of pretreatment tumour HER3 membrane expression levels. Additional correlative analyses of the HER3 immunohistochemistry data are ongoing and are incorporating other parameters, including cytoplasmic expression of the receptor. In HERTHENA-Lung01 study, antitumour activity was also observed across subgroups of EGFR TKI resistance detected at baseline, including tumours harbouring EGFR-dependent, EGFR-independent, or unidentified mechanisms of resistance. Durable responses to patritumab deruxtecan once every 3 weeks were also seen in patients with tumours with EGFR C797X or MET amplification, which comprise the most common mechanisms of resistance to third-generation EGFR TKIs.
Patritumab deruxtecan once every 3 weeks treatment yielded clinically meaningful responses in NSCLC CNS metastases, which have been reported in 70% of patients with advanced EGFR-mutated NSCLC. In 30 patients with non-irradiated brain metastases at baseline, the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI 17.3 to 52.8). The CNS penetration and pharmacodynamic activity of patritumab deruxtecan in patients with CNS metastasis are being evaluated further in the recently initiated PARAMETer window-of-opportunity study.
The safety profile was manageable and tolerable, consistent with previous observations. There was a low rate of treatment-related discontinuation due to adverse events. Thrombocytopenia was the most frequent grade ≥3 treatment-emergent adverse event, and it typically occurred early in treatment and was transient; bleeding events in the setting of thrombocytopenia were rare. Grade ≥3 neutropenia was also transient and was rarely associated with fever and/or infection.
The incidence of adjudicated drug-related interstitial lung disease (ILD) of 5.3% (grade 5 in 0.4%) was consistent with previous reports of patritumab deruxtecan once every 3 weeks in patients with NSCLC, and in most instances were grade 1 or 2 in severity. Vigilant observation for signs and symptoms associated with ILD, prompt interruption of patritumab deruxtecan, and intervention with high-dose corticosteroid treatment may mitigate the development of severe ILD.
Clinical evaluation of patritumab deruxtecan once every 3 weeks is ongoing in a phase III HERTHENA-Lung02 study versus platinum-based chemotherapy in patients with EGFR-mutated NSCLC after progression on EGFR TKI treatment.
The study was supported by Daiichi Sankyo, Inc.
Reference
Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. JCO; Published online 10 Sptember 2023. DOI: 10.1200/JCO.23.01476
