MA21.06 Preliminary Phase 1 Results of U3-1402 — A Novel HER3-Targeted Antibody–Drug Conjugate—in EGFR TKI-Resistant, EGFR-Mutant NSCLC

Abstract

7% Other. 1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p¼0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/ month. The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/ other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p¼0.0294). 69% tested blood-derived DNA, less frequently in US/ Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%) and notified when the sample was inadequate (84%). The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/ Other, and turn-around time in US/Canada. Conclusion: These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.

Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, EGFR-Mutated Non–Small Cell Lung Cancer

“…Patients in the dose escalation received 3.2 mg/kg to 6.4 mg/kg HER3-DXd IV Q3W, which was guided by a Bayesian logistic regression model following the Escalation with Overdose Control (EWOC) principle. In the dose expansion part, patients in Cohorts 1 and 2 received the RDE of 5.6 mg/kg HER3-DXd IV Q3W (40); patients in Cohort 3 were randomized 1:1 to receive the RDE (Cohort 3a), or an uptitration of HER3-DXd (Cohort 3b). Two formulations were dosed in this study: frozen liquid drug product and lyophilized drug product.…”

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

“…U3-1402 is an antibody-drug conjugate (ADC) developed by Daiichi Co., Ltd., which consists of patritumab acting on HER3 antibodies and the cytotoxic drug DX-8951 (Exitecan, a topoisomerase inhibitor). U3-1402 is effective against different drug resistance mechanisms against EGFR-TKIs, as demonstrated in phase I trial results published in 2019 (200). Another phase I study included 57 patients with EGFR-TKI resistance.…”

New era for emerging therapeutic targeting human epidermal growth factor receptor 3 (HER 3) in advanced nonsmall cell lung cancer and metastatic breast cancer

“…[43][44][45][46] Although there was no effect on PI3K/Akt signaling, a HER3-DNA topoisomerase inhibitor ADC triggered apoptosis of tumor cells in a mouse model of EGFR TKI-resistant NSCLC. 47 Similarly, a HER3-monomethyl auristatin F(MMAF) ADC was able to overcome trastuzumab resistance in HER2-positive MBC cells in xenografts. 45 These preclinical results suggest that HER3-specific ADCs may represent a promising option for overcoming therapeutic resistance in cancer cells, particularly in those that overexpress HER3.…”

“…45 These preclinical results suggest that HER3-specific ADCs may represent a promising option for overcoming therapeutic resistance in cancer cells, particularly in those that overexpress HER3. 47 Early clinical trials have reported promising results thus far in patients with either HER-3 overexpressing breast cancer or resistant EGFR-mutant NSCLC who were treated with a HER3-DNA topoisomerase inhibitor ADC (patritumab deruxtecan/HER3-DXd). 48,49…”