Patritumab Deruxtecan Granted FDA Breakthrough Therapy Designation for Metastatic or Locally Advanced EGFR+ NSCLC

The FDA has granted breakthrough therapy designation to patritumab deruxtecan for the treatment of patients with metastatic or locally advanced EGFR-mutated non-small cell lung cancer (NSCLC) with disease progression on or after treatment with a third-generation tyrosine kinase inhibitor (TKI) and platinum-based therapies, according to a press release issued by Daiichi Sankyo Company, Limited.¹

“The Breakthrough Therapy Designation for patritumab deruxtecan acknowledges the need for new treatment approaches to overcome resistance and improve survival in patients with metastatic TKI-resistant, EGFR-mutated non-small cell lung cancer,” said Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, in the press release.

Patritumab deruxtecan is a potential first-in-class HER3-directed antibody-drug conjugate, which signaled efficacy in a phase 1 dose-escalation and dose-expansion study (U31402-A-U102; NCT03260491), which primarily assessed the safety and tolerability of patritumab deruxtecan in patients with EGFR-mutant NSCLC with resistance to EGFR TKIs. As secondary end points, the study explored investigator-assessed objective response rate (ORR), safety, and pharmacokinetics.

According to extended follow-up results from the dose-escalation portion and cohort 1 of the dose-expansion portion of the study, the agent achieved a confirmed ORR of 39% (95% CI, 26%-52%) in 57 patients with EGFR-positive NSCLC who had prior exposure to a TKI and platinum-based chemotherapy when administered at 5.6 mg/kg. The disease control rate (DCR) observed was 72% (59%-83%) and the progression-free survival (PFS) of 8.2 months (95% CI, 4.4-8.3).²

Further, among the osimertinib (Tagrisso) and platinum-based chemotherapy pretreated subgroups of 44 patients, the ORR was 39% (95% CI, 24%-55%) and the DCR was 68% (95% CI, 52%-81%. Patritumab deruxtecan also showed a median PFS of 8.2 months (95% CI, 4.0–not evaluable [NE]) in these subgroups.

The safety analysis showed that treatment-emergent adverse events occurred in 96% of patients and 54% of these events were grade 3 or higher. The most common grade ≥ 3 TEAEs were hematologic. The grade ≥ 3 that occurred in more than 5% of patients included decreased platelet count, decreased neutrophil count, fatigue, anemia, dyspnea, febrile neutropenia, hypoxia, decreased white blood cell count, hypokalemia, and decreased lymphocyte count.

Based on the findings, investigators concluded that the activity of patritumab deruxtecan has the potential to overcome known and unknown EGFR TKI resistance mechanisms. It may be a future treatment option for those with EGFR-mutated NSCLC with disease progression on or after treatment with a third-generation TKI.

“We are proud that the FDA has once again recognized our innovative science and technology and we look forward to bringing this potential first-in-class HER3 directed antibody-drug conjugate to patients with this specific type of lung cancer as quickly as possible,” said Takeshita, in a press release.¹

Currently, the phase 2, randomized, open-label HERTHENA-Lung01 study (NCT04619004) is underway to determine the antitumor activity of patritumab deruxtecan in patients with metastatic or locally advanced EGFR-mutated NSCLC who progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen.³

Approximately 420 patients will be enrolled in the study and evaluated for the primary end point of ORR and the secondary end points of duration of response, PFS, investigator-assessed ORR, DCR, time to response, the best percentage change in the sum of diameters of measurable tumors, overall survival, and the incidence of TEAEs. Patients are being actively recruited at 122 sites across the United States, Europe, Asia, and Oceania.

_References:

_{1. Patritumab deruxtecan granted U.S. FDA breakthrough therapy designation in patients with metastatic EGFR-mutated non-small cell lung cancer. News release. December 23, 2021. Accessed December 28, 2021. https://bit.ly/32A3C62}

_{2. Janne PA, Baik C, Su W, et al. Efficacy and safety of patritumab deruxtecan (HER2-Dxd) in EGFR inhibitor–resistant, EGFR-mutated non–small cell lung cancer. Cancer Discov. Published online September 21, 2021. doi: 10.1158/2159-8290.CD-21-0715}

_{3. HERTHENA-Lung01: Patritumab deruxtecan in subjects with metastatic or locally advanced EGFR-mutated non-small cell lung cancer. Clinicaltrials.gov. Accessed December 28, 2021.}