Patritumab Deruxtecan Demonstrates Promising Clinical Activity in EGFR-Mutated NSCLC Patients Resistant to Prior Therapies

On June 4, 2021, Daiichi Sankyo announced that its investigational HER3-targeting antibody-drug conjugate (ADC), patritumab deruxtecan, demonstrated promising clinical activity in a Phase 1 clinical trial in patients with non-small cell lung cancer (NSCLC) harboring resistant EGFR mutations. Data from this study supported the design of the recently initiated pivotal HERTHENA-Lung01 trial in a similar patient population.

Patritumab deruxtecan is one of three lead DXd ADC candidates in development by Daiichi Sankyo, comprising a humanized anti-HER3 antibody conjugated to a topoisomerase I inhibitor payload. HER3 is a member of the EGFR family of receptor tyrosine kinases and is implicated in aberrant cell proliferation and survival. Approximately 25% to 30% of lung cancer patients worldwide harbor activating EGFR mutations, and an estimated 83% of NSCLC tumors express the HER3 protein. This expression may be associated with an increased incidence of metastasis, reduced survival rates, and resistance to standard therapies. To date, no HER3-targeted therapies have been approved for the treatment of cancer.

The trial results demonstrated that among the 57 enrolled patients treated with patritumab deruxtecan (5.6 mg/kg), the objective response rate (ORR) was 39% (95% CI: 26–52%), and the disease control rate was 72% (95% CI: 59–83%). At a median follow-up of 10.2 months, the estimated median duration of response was 6.9 months, and the median progression-free survival (PFS) was 8.2 months. Regarding safety, the safety profile in patients receiving the 5.6 mg/kg dose (n=57) was consistent with the findings from the prior dose-escalation trial. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 64% of patients (n=81).

▲ Preliminary clinical trial results of patritumab deruxtecan (Image source: Reference [1])

Lung cancer is one of the most common cancers and the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases. Over the past decade, the introduction of targeted therapies and checkpoint inhibitors has improved treatment prospects for patients with advanced or metastatic NSCLC. Activating mutations in EGFR serve as oncogenic drivers and molecular targets in advanced NSCLC. Although the efficacy of targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) in patients with advanced EGFR-mutant NSCLC has been well established, patients ultimately develop resistance, typically leading to disease progression. The prognosis for these patients is particularly poor following disease progression after treatment with EGFR TKIs and chemotherapy, with a median progression-free survival (PFS) of approximately 2.8 to 3.2 months.

Note: The original text has been abridged.

References:

[1] Patritumab Deruxtecan Data at ASCO Demonstrates Tumor Response Across Multiple Resistance Mechanisms in Patients with Advanced EGFR-Mutated NSCLC. Retrieved June 6, 2021, from https://www.daiichisankyo.com/files/news/pressrelease/pdf/202106/20210604_E.pdf

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