Preliminary Phase I Data for U3-1402 Shows Manageable Safety and Reduction in Tumor Size in NSCLC

Preliminary results from the dose escalation part of the phase I study with U3-1402, an investigational and potential first-in-class HER3 targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo, were presented during an Oral Symposium at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, IL, May 31 – June 4, 2019. (NCT03260491)

Designed using Daiichi Sankyo’s proprietary DXd ADC technology, U3-1402 is comprised of a human anti-HER3 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. The investigational agent targets and delivers the chemotherapeutic payload inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

Unmet medical need
Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide. In 2018 there were an estimated 2.1 million new cases of lung cancer and 1.8 million deaths.[1] Most lung cancers are diagnosed at an advanced or metastatic stage.[2] Non-small cell lung cancer (NSCLC) accounts for 80 to 85% of all lung cancers.[3]

The introduction of targeted therapies and checkpoint inhibitors in the past decade has improved the treatment landscape for patients with advanced or metastatic NSCLC; however, for those who are not eligible for current treatments, or whose cancer continues to progress, new therapeutic approaches are needed.[4]

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For patients with advanced EGFR mutated NSCLC, EGFR TKIs offer higher response rates and progression free survival compared to chemotherapy; however, most patients eventually develop resistance to the drugs, usually within a year, at which point treatment options become more limited.[5]

HER3 as a target
“HER3, an EGFR family member, is expressed in the majority of EGFR-mutated lung cancers. [That’s why] we wanted to explore whether targeting HER3 with an antibody–drug conjugate may be an alternative strategy to overcome resistance.” said Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, and a trial investigator.

HER3 is a member of the human epidermal growth factor receptor family of tyrosine kinase receptors, which are associated with aberrant cell growth.[6] However, scientists have, for a long time, underappreciated the therapeutic potential of HER3 due to impaired kinase activity and relatively low expression in tumors.

But that has changed. And in recent years HER3 has received attention as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance.

Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs).

HER3 is overexpressed in several types of cancers and has been linked to tumor progression and worse overall survival.[8] HER3 expression is also associated with increased metastases and reduced survival in patients with non-small cell lung cancer, where frequency has been reported as high as 75%.[7]

In recent years, researchers have recognized potential for HER3 as a therapeutic target.[6] However, currently, no HER3 targeting agents are approved for NSCLC or any cancer.

Clinical trial
The global, phase I, open label, two-part study is enrolling patients with metastatic or unresectable EGFR mutated NSCLC that has progressed while taking an EGFR TKI.

This includes patients who either experienced disease progression on erlotinib, gefitinib, dacomitinib or afatinib and tested negative for the T790M mutation or who experienced disease progression on osimertinib regardless of T790M status.

Objective
The primary objectives of the study are to assess the safety and tolerability of U3-1402 and determine the recommended dose for expansion. The secondary objectives are to characterize the pharmacokinetics of U3-1402 and to evaluate preliminary efficacy by measuring antitumor activity of U3-1402.

The study is expected to enroll more than 60 patients at approximately 17 sites globally.

Preliminary trial results
The first phase I results of U3-1402 included 23 patients with metastatic EGFR mutated, TKI resistant non-small cell lung cancer (NSCLC) (ASCO Abstract #9010)[9]

Preliminary efficacy data for 16 evaluable patients at the time of data cut-off who received U3-1402 at dose levels from 3.2 mg/kg to 6.4 mg/kg showed that a reduction in tumor size was observed in all 16 evaluable patients across all doses, with a median best percentage change of -29% (range -3 to -80%).

All 16 patients had received prior treatment with an EGFR tyrosine kinase inhibitor (TKI), including 15 with osimertinib. Seven patients also had prior chemotherapy. A total of 16 patients remained on treatment at the time of data cut-off on February 25, 2019.

“These initial clinical data demonstrate activity with U3-1402, including early tumor shrinkage in patients who had developed resistance to approved EGFR TKIs,” Jänne noted.

“There is a need for new treatment approaches for EGFR mutated non-small cell lung cancer that develops resistance to TKIs, especially osimertinib, and preliminary results from this study indicate that targeting HER3 with U3-1402 is a strategy that may be effective across multiple different resistance mechanisms.”

HER3 expression has been reported in up to 75% of non-small cell lung cancers.[1] In study patients, all tumors available for assessment in retrospective immunohistochemistry (IHC) analysis (n=19) showed some level of HER3 expression.

Preliminary safety data in 23 evaluable patients showed a manageable safety profile for U3-1402 with median treatment exposure of 105 days. A maximum tolerated dose has not yet been reached. The most common treatment-emergent adverse events of any grade (in ≥30% of patients) included nausea (60.9%), fatigue (39.1%), vomiting (34.7%), decreased appetite (30.4%) and platelet count decrease (30.4%).

One treatment-emergent adverse event grade ≥3 occured in >10% of patients (platelet count decrease, 26.1%). The following dose-limiting toxicities were observed in four patients: grade 4 platelet count decrease (4 patients) and grade 3 febrile neutropenia (1 patient). Six patients (26.1%) experienced treatment-emergent serious adverse events regardless of causality, with three patients (13.0%) experiencing treatment-emergent serious adverse events that were related to study treatment. One patient experienced a treatment-emergent adverse event leading to treatment discontinuation (4.3%).

“U3-1402 was designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver chemotherapy inside cancer cells that express HER3 as a cell surface antigen,” said Dalila Sellami, MD, Vice President, U3-1402 Global Team Leader, Global Oncology Research and Development, Daiichi Sankyo.

“These findings provide evidence of promising activity of U3-1402 in non-small cell lung cancer and add to our previous preliminary research demonstrating its potential use in HER3 positive metastatic breast cancer,” Sellami added.

Commenting on the results, Jänne concluded that “targeting HER3 with U3-1402 may be a practical approach to treat EGFR-mutant NSCLC with diverse mechanisms of resistance to EGFR TKIs.”

Clinical trial
U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer – NCT03260491

References
[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. [PubMed]
[2] American Cancer Society. Lung Cancer Prevention and Early Detection. 2019
[3] American Cancer Society. Types of Non-Small Cell Lung Cancer. 2019
[4] Economopoulou P, Mountzios G. The emerging treatment landscape of advanced non-small cell lung cancer.Ann Transl Med. 2018 Apr;6(8):138. doi: 10.21037/atm.2017.11.07.
[5] Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018 Oct 1;29(Supplement_4):iv192-iv237. doi: 10.1093/annonc/mdy275. (updated Jan2019) [PubMed]
[6] Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018 May 16;12(1):355. doi: 10.4081/oncol.2018.355. eCollection 2018 Jan 30. [PubMed]
[7] Mujoo K, Choi BK, Huang Z, Zhang N, An Z. Regulation of ERBB3/HER3 signaling in cancer.Oncotarget. 2014 Nov 15;5(21):10222-36.[PubMed]
[8] Müller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwäble J, Plewka S, et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer.Cancer Res. 2005 Mar 1;65(5):1778-82.[PubMed]
[9] Janne PA, Yu HA, Johnson ML, Steuer CE, Vigliotti M, Iacobucci C, Chen S, et al. Safety and preliminary antitumor activity of U3-1402: A HER3-targeted antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC. J Clin Oncol 37, 2019 (suppl; abstr 9010)[Abstract]