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January 29, 2021 - The HER3-directed antibody-drug conjugate patritumab deruxtecan continued to demonstrate clinically meaningful antitumor activity and a manageable safety profile at the recommended expansion dose of 5.6 mg/kg in pretreated patients with metastatic or unresectable EGFR-mutant non–small cell lung cancer.
The HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (U3-1402) continued to demonstrate clinically meaningful antitumor activity and a manageable safety profile at the recommended expansion dose of 5.6 mg/kg in pretreated patients with metastatic or unresectable EGFR-mutant non–small cell lung cancer (NSCLC), according to findings from a phase 1 study (NCT03260491) that were presented during the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer Singapore.1
As of April 30, 2020, 57 patients with EGFR-mutant NSCLC from the dose-escalation and dose-expansion portions had been treated with patritumab deruxtecan, 56 of whom were evaluable for response.
The confirmed objective response rate per blinded independent central review was 25% (n = 14; 95% CI, 14.4%-38.4%), which consisted of a 2% complete response rate (n = 1) and a 23% partial response rate (n = 13). The stable disease rate was 45% (n = 25).
“Early antitumor activity was observed in this heavily pretreated patient population, with a median follow-up time of 5 months,” wrote Helena A. Yu, MD, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center and colleagues in a presentation of the data. “These data support further clinical investigation of this HER3-directed ADC in a patient population with no available targeted therapy treatments.”
HER3 is expressed in more than 80% of EGFR-mutant NSCLC and overexpression is associated with poor outcomes.
Patritumab deruxtecan is a novel HER3-directed ADC that consists of the monoclonal antibody patritumab, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload.
The phase 1 study was comprised of a dose-escalation and dose-expansion phase. In the dose-escalation phase, patients with metastatic or unresectable EGFR-mutant NSCLC who had progressed on osimertinib (Tagrisso) or were T790M negative after progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) received 5.6 mg/kg of patritumab deruxtecan every 3 weeks. In the dose-expansion cohort, patients with metastatic or unresectable EGFR-mutant NSCLC who had received at least 1 prior EGFR TKI and at least 1 prior platinum-based chemotherapy regimen received 5.6 mg/kg of patritumab deruxtecan every 3 weeks.
Evaluation of the antitumor activity of patritumab deruxtecan served as the primary end point of the study. The safety and tolerability of the agent were evaluated as secondary end points.
Patients had a median of 4 prior lines of therapy for advanced or metastatic disease (range, 1-9). Prior therapies included osimertinib (n = 49; 86%), another EGFR targeted therapy (n = 3; 5%), platinum-based chemotherapy (n = 51; 90%), and anti–PD-1/PD-L1 therapy (n = 23; 40%).
Approximately half of patients (n = 27; 47%) had a history of central nervous system metastases.
Additional data indicated that the disease-control rate was 70% (n = 39; 95% CI, 55.9%-81.2%). The median time to response was 2.0 months (range, 1.2-2.8), and the median duration of response was 6.9 months (range, 3.0-7.0).
In terms of safety, patritumab deruxtecan continued to demonstrate a manageable safety profile. The most common grade 3 or greater treatment-emergent adverse effects (TEAEs) were thrombocytopenia (n = 16; 28%) and neutropenia (n = 11; 19%).
TEAEs associated with drug discontinuation (9%) included fatigue (n = 2), decrease appetite (n = 1), interstitial lung disease (ILD; n = 1), pneumonitis (n = 1), and upper respiratory tract infection (n = 1). No discontinuations were attributed to thrombocytopenia or neutropenia.
Three (5.3%) ILD events were determined to be related to treatment by an independent central review committee. No treatment-related TEAEs were associated with death.
An exploratory biomarker analysis, which was also presented during the meeting, reported that almost all evaluable patient tumors (n = 43) expressed membrane HER3 at baseline. The median membrane H score was 180 (range, 2-280) out of 300.
Moreover, heterogenous EGFR TKI resistance mechanisms were identified in patients’ pretreatment tumor tissue and circulating tumor DNA (ctDNA). Clinical responses were reported in patients with diverse TKI resistance mechanisms, including EGFR T790M mutations (53%), MET amplifications (8%), ERBB2 (HER2) mutations (4%), BRAF fusions, EGFR C797S mutations, and PIK3CA mutations.2
Other mutations included HER3 mutations (2%), HER4 mutations (8%), CDKN2A mutations (6%), and NTRK2 mutations (2%).
All examined patient samples showed a reduction in EGFR-activating mutations in ctDNA following treatment with patritumab deruxtecan. Patients who experienced a confirmed clinical response were more likely to have ctDNA clearance of EGFR-activating mutations at week 3 or week 6. Failure to clear EGFR-activating mutations in ctDNA was associated with a best overall response of progressive disease.
“These data provide important insights about how a HER3-directed therapy may interact in previously treated NSCLC tumors with diverse mechanisms of EGFR TKI resistance, including mechanisms not directly related to EGFR,” said Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute.3 “While an association between higher levels of HER3 expression and clinical activity was seen with patritumab deruxtecan, additional analyses from this study and additional studies are needed to better understand the role of HER3 expression alone in the optimal selection of patients.”
The phase 2 HERTHENA-Lung01 study (NCT04619004) is planned to launch in early 2021 and will evaluate single-agent patritumab deruxtecan in patients after failure of EGFR TKIs and platinum-based chemotherapy.4