HER3-Directed Antibody Therapy May Be an Effective Strategy in EGFR+ NSCLC

According to findings from a phase 1 study (NCT03260491), the antibody-drug conjugate patritumab deruxtecan (U3-1402) induced clinically meaningful antitumor activity and a manageable safety profile in pretreated patients with metastatic or unresectable EGFR-mutant non–small cell lung cancer (NSCLC).¹

These data that were presented during the 2020 World Conference on Lung Cancer Singapore showed that the HER3-directed agent administered at the recommended expansion dose of 5.6 mg/kg resulted in a confirmed objective response rate per blinded independent central review of 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).

Results were from the April 30, 2020 data cutoff, by which time 57 patients with EGFR-mutant disease from the dose-escalation and dose-expansion portions of the trial had been treated with patritumab deruxtecan, 56 of whom were evaluable for response.

“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, heterogeneous 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

References

1. Helena YA, Baik C, Gold K, et al. Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract OA03.04.

2. Jänne PA, Baik C, Hayashi H, et al. Dynamics of molecular markers in EGFR-mutated NSCLC patients treated with patritumab deruxtecan (HER3-DXd; U3-1402). Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Poster P01.04

3. New biomarker analyses from patritumab deruxtecan phase 1 study in patients with EGFR-mutated NSCLC presented at WCLC 2020. News release. Business Wire. January 29, 2020. Accessed January 29, 2021. https://bwnews.pr/3prQbLM.

4. Jänne PA, Johnson ML, Goto Y, et al. HERTHENA-Lung01: a randomized phase 2 study of patritumab deruxtecan (HER3-DXd; U3-1402) in previously treated metastatic EGFR-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Poster P01.01.