Daiichi Sankyo Highlights Promising Efficacy of HER3-Targeted ADC Patritumab Deruxtecan in EGFR-Mutated NSCLC

September 28, 2020 /BioValleyBIOON/ -- Daiichi Sankyo recently announced the latest data from the Phase I study of patritumab deruxtecan (U3-1402), a HER3-targeting antibody-drug conjugate (ADC), for the treatment of non-small cell lung cancer (NSCLC), including the initial results from one cohort in the dose expansion part. This is a global, multicenter, open-label, two-part study conducted in patients with metastatic or unresectable EGFR-mutant NSCLC who experienced disease progression after receiving standard therapies, including an EGFR TKI.

Prior to receiving patritumab deruxtecan, patients enrolled in the study had received a median of 4 prior therapies. All patients had previously been treated with EGFR TKIs, with the majority having received osimertinib (86%); 90% had received platinum-based chemotherapy, and 40% had received an anti-PD-1/PD-L1 therapy. In this study, 47% of evaluable patients had a history of brain metastases, which were stable at study entry.

In the dose-escalation and dose-expansion phases of the study, as assessed by blinded independent central review, the objective response rate (ORR) was 25% among 56 evaluable patients treated with patritumab deruxtecan (5.6 mg/kg). Of these, one patient achieved a complete response (CR) and 13 achieved a partial response (PR). At the data cutoff, three additional patients with PR were awaiting confirmation, and six patients had undergone only oneTumorEvaluation. The disease control rate (DCR) was 70%, and the median duration of response (DOR) was 6.9 months. Disease stabilization was observed in 45% of patients.

In this study, the overall safety and tolerability of patritumab deruxtecan were consistent with those observed in the dose-escalation phase of the study. Among patients treated with patritumab deruxtecan (5.6 mg/kg), treatment-emergent adverse events (TEAEs) of any grade occurring in ≥25% of patients included fatigue (58%), nausea (54%), thrombocytopenia (53%), decreased appetite (35%), neutropenia (33%), vomiting (30%), and alopecia (30%).Anemia(26%) and constipation (25%).

The most common grade ≥3 treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients included thrombocytopenia (28%) and neutropenia (19%). Five patients (9%) experienced TEAEs leading to treatment discontinuation. Three cases (5%) were confirmed as drug-related interstitial lung disease (ILD), as determined by an independent adjudication committee.

Memorial Sloan Kettering Cancer CenterTumorDr. Helena Yu stated, “Given the lack of effective treatment options in this setting, these preliminary efficacy results of patritumab deruxtecan in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have previously received multiple therapies and developed various resistance mechanisms to EGFR-targeted therapies are highly encouraging. These data support the notion that targeting HER3 with an antibody-drug conjugate may represent an effective therapeutic strategy to overcome diverse resistance mechanisms in patients with EGFR-mutated NSCLC whose disease has progressed on currently available treatments.”

Dr. Gilles Gallant, Global Head of Oncology R&D at Daiichi Sankyo, stated: “HER3 is frequently overexpressed in non-small cell lung cancer, providing a broad mechanism of resistance to standard therapies forTumorTherapeutic intervention offers an attractive target. These preliminary results are highly encouraging, demonstrating disease control in patients treated with patritumab deruxtecan during short-term follow-up; however, long-term follow-up is required for confirmation. Based on these findings, we plan to initiate a Phase II trial to evaluate patritumab deruxtecan for the treatment of advanced or metastatic EGFR-mutated NSCLC.”

Lung cancer is the most common type of cancer worldwide and the leading cause of cancer-related deaths, with most cases diagnosed at an advanced or metastatic stage. Approximately 15–50% of patients with non-small cell lung cancer (NSCLC) harbor EGFR mutations. Among NSCLC patients, an estimated 83% express HER3 protein, which may be associated with increased incidence of metastasis, reduced survival rates, and resistance to standard-of-care cancer treatments, including tyrosine kinase inhibitors (TKIs).Currently, no HER3-targeted therapies have been approved for the treatment of NSCLC or any other cancer.

Patritumab deruxtecan is a HER3-targeting antibody-drug conjugate (ADC) developed by Daiichi SankyoTumorOne of the three lead DXd ADC therapies in the pipeline. This August,AstraZenecaReached a clinical collaboration with Daiichi Sankyo to evaluate the combination of patritumab deruxtecan and Tagrisso (generic name: osimertinib) for the treatment of patients with EGFR-mutated advanced or metastatic NSCLC. Tagrisso is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).

Previously, the two parties had separately signed agreements for two other DXd ADC therapies (Enhertu, DS-1062) in Daiichi Sankyo’s oncology pipeline, with total values of $6.9 billion and $6.0 billion, respectively.Tumoracademic collaboration. Enhertu is a HER2-targeted antibody-drug conjugate (ADC) therapy indicated for the treatment of patients with various cancers exhibiting different levels of HER2 expression or harboring HER2 mutations, including gastric cancer, colorectal cancer, and lung cancer, as well as those with low HER2 expressionBreast Cancer. DS-1062 is a TROP2-targeted antibody-drug conjugate (ADC) therapy currently under development for the treatment of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).

Enhertu, DS-1062, and patritumab deruxtecan are all next-generation antibody-drug conjugate (ADC) drugs developed by Daiichi Sankyo using its DXd ADC technology, which utilizes a tetrapeptide linker to targetTumorHumanized monoclonal antibodies targeting specific cell surface antigens—namely, anti-HER2 monoclonal antibody (trastuzumab), anti-TROP2 monoclonal antibody, and anti-HER3 monoclonal antibody (patritumab)—are conjugated with a novel topoisomerase I inhibitor, an exatecan derivative (DX-8951 derivative, DXd). This conjugation enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic drug compared with conventional chemotherapy. (Bioon.com)

Original Source: Daiichi Sankyo Announces Late-Breaking Phase 1 Dose Expansion Data for Patritumab Deruxtecan in Patients with EGFR-Mutated NSCLC