FDA Issues CRL to Patritumab Deruxtecan in Advanced EGFR-Mutated NSCLC


Patritumab deruxtecan has been issued a complete response letter to its biologics license application for the treatment for patients with advanced non-small cell lung cancer with EGFR mutations after prior treatment with 2 or more lines of therapy.

  • The FDA has issued a complete response letter (CRL) for the biologics license application (BLA) of patritumab deruxtecan (HER3-DXd) for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations.
  • The CRL cites findings from an inspection of a third-party manufacturing facility.
  • No issues with safety or efficacy data were noted.

The BLA for the ADC patritumab deruxtecan has been issued a CRL from the FDA, citing issues with third-party manufacturing. However, no issues with safety or efficacy have been identified.1

Patritumab deruxtecan was seeking FDA approval as a treatment for patients with advanced NSCLC harboring EGFR mutations that had been previously treated with 2 or more systemic therapies.

Findings from the HERTHENA-Lung01 presented during the 2023 World Conference on Lung Cancer (WCLC) and simultaneously published in the Journal of Clinical Oncology support the BLA.2,3 In this patient population of those with EGFR-mutated NSCLC that had previously progressed despite treatment with an EGFR-targeted tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy, the confirmed overall response rate (ORR) among patients treated with a previous EGFR TKI and platinum-based chemotherapy (n = 225) was 29.8% (95% CI, 23.9%-36.2%). This included 1 patient who achieved a complete response (CR).

Additional results showed that the disease control rate (DCR) was 73.8% (95% CI, 67.5%-79.4%), the median duration of response (DOR) was 6.4 months (95% CI, 4.9-7.8), the median progression-free survival (PFS) was 5.5 months (95% CI, 5.1-5.9), and the median overall survival (OS) was (95% CI, 11.2-13.1).

Holographic concept of lung cancer display, lung disease: © catalin - stock.adobe.com

Holographic concept of lung cancer display, lung disease: © catalin - stock.adobe.com

HERTHENA-Lung01 included patients with advanced EGFR-mutated NSCLC who experienced disease progression on their most recent systemic therapy and randomized them 1:1 to receive patritumab deruxtecan at a fixed dose of 5.6 mg/kg (n = 225) or via an uptitration dosing schedule (n = 50). At the 2023 WCLC Annual Meeting, only data from the 5.6-mg/kg arm were presented.

Efficacy was observed across patient subgroups, including those who previously received treatment with a third-generation TKI and platinum-based chemotherapy (n = 209). The confirmed ORR in this subgroup was 29.2% (95% CI, 23.1%-35.9%), including 1 CR; the DCR was 72.7% (95% CI, 66.2%-78.6%); the median PFS was 5.5 months (95% CI, 5.1-6.4); and the median OS was 11.9 months (95% CI, 10.9-13.1).

Of those with EGFR-dependent disease (n = 34), the ORR was 32.4% (95% CI, 17.4%-50.5%), 27.2% (95% CI, 17.9%-38.2%) for those with EGFR-independent disease (n =81), 37.5% (95% CI, 21.1%-56.3%) for both EGFR-dependent and independent disease (n = 32), and 27.3% (95% CI, 17.7%-38.6%) for patients with no identified resistance mechanisms (n = 77).

Thirty patients with brain metastases at baseline who did not undergo prior radiotherapy had intracranial efficacy with patritumab deruxtecan. The confirmed intracranial ORR by central nervous system (CNS) BICR per CNS RECIST criteria was 33.3% (95% CI, 17.3%-52.8%). The CR rate was 30.0%, the DCR was 76.7% (95% CI, 57.7%-90.1%), and the median DOR was 8.4 months (95% CI, 5.8-9.2).

Looking at safety, treatment with patritumab deruxtecan was manageable and demonstrated a tolerable safety profile. Almost all patients (99.6%) experienced an any-grade treatment-emergent adverse effect (TEAEs). TEAEs were linked to treatment discontinuation (7.1%), dose reduction (21.3%), and dose interruption (40.4%).

A total of 5.3% of patients had interstitial lung disease which was reported at grade 1 (0.4%), grade 2 (3.6%), grade 3 (0.9%), and grade 5 (0.4%) severity. Additional grade 1 or 2 TEAEs observed were nausea (63%), thrombocytopenia (44%), decreased appetite (39%), and constipation (34%). Grade 3 or higher TEAEs included thrombocytopenia (21%), neutropenia (19%), anemia (14%), and leukopenia (10%).

1. Patritumab deruxtecan BLA submission receives complete response letter from FDA due to inspection findings at third-party manufacturer. News release. Merck. June 26, 2024. Accessed June 27, 2024. https://tinyurl.com/3yycw5f6
2. Yu HA, Goto Y, Hayashi H, et al. Patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC following EGFR TKI and platinum-based chemotherapy: HERTHENA-Lung01. Presented at: 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.
3. 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. J Clin Oncol. Published online September 10, 2023. doi:10.1200/JCO.23.01476
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