Updated phase I data for U3-1402, an investigational HER3 targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo, in 30 patients with metastatic EGFR mutated, TKI resistant non-small cell lung cancer (NSCLC) shows positive results.

The late-breaking results was featured in a Mini Oral Session during the IASLC 2019 World Conference on Lung Cancer (#WCLC19) being held in Barcelona, Spain, September 7 — 10, 2019 (MA21.06, Abstract #1720).

Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide; there were an estimated 2.1 million new cases of lung cancer in 2018 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]

EGFR mutation is a well-established oncogenic target for management of advanced stage NSCLC.[5] For patients with advanced EGFR mutated NSCLC, targeted therapy with EGFR TKIs offers higher response rates and progression-free survival compared to chemotherapy.[5] However, most patients eventually develop resistance to the drugs, at which point treatment options become more limited.[6] Clinical resistance to EGFR TKIs has been linked to multiple gene-based mechanisms, and in many cases, the underlying cause remains unknown.[7][8][9] At the same time, a majority of EGFR mutant NSCLCs show some level of HER3 expression.[10][11]

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HER3 is a member of the human epidermal growth factor receptor (EGFR) family of tyrosine kinase receptors, which are associated with aberrant cell growth.[12] HER3 expression has been associated with increased metastases and reduced survival in patients with non-small cell lung cancer, where frequency has been reported as high as 75 percent.[13] HER3 is overexpressed in several types of cancers.[14] In recent years, researchers have recognized potential for HER3 as a therapeutic target.[12]

Currently, no HER3 targeting agents are approved for NSCLC or any cancer.

Targeted Cancer Drug
U3-1402 is a targeted cancer drug designed to deliver a cytotoxic chemotherapeutic payload to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

The drug uses Daiichi Sankyo’s proprietary 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. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

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

The primary objectives of the study are to assess the safety and tolerability of U3-1402. Secondary study objectives are to evaluate preliminary efficacy by measuring antitumor activity of U3-1402 and to characterize the pharmacokinetics of U3-1402. Part one (dose escalation) assesses U3-1402 at four doses (3.2 mg/kg to 6.4 mg/kg) to determine a recommended dose for expansion.

Part two (dose expansion) will evaluate U3-1402 at the recommended dose for expansion of 5.6 mg/kg and include an additional cohort of patients with metastatic squamous or non-squamous NSCLC without EGFR mutation whose disease has progressed after chemotherapy and anti-PD-L1 regimens. The study is expected to enroll more than 100 patients at approximately 17 sites globally.

Trial results
Updated efficacy results for 26 patients who received U3-1402 in one of four dose cohorts, and had baseline and at least one post-baseline tumor assessment, showed six confirmed partial responses across  three dose levels. A reduction in tumor size was observed in 22 patients across all doses, with median best percentage change of -25.7% [range -82.6 percent to 13.3%].

Responses were reported in patients with and without a history of CNS metastases. All 30 patients in the trial had received prior treatment with an EGFR tyrosine kinase inhibitor (TKI) including 28 (93%) with osimertinib. Fifteen patients (50%) had also received prior chemotherapy. The median follow-up time was 4.5 months. At the time of data cut-off on May 3, 2019, a total of 17 patients remained on treatment.  

Next-generation sequencing (NGS) and cfDNA analysis determined the presence of multiple resistance mechanisms to prior EGFR TKI therapies in patients who experienced partial responses and tumor reduction while being treated with U3-1402. Three patients with confirmed partial response harbored the EGFR resistance mutations T790M, which is the target of osimertinib, and C797S, which is associated with resistance to osimertinib. Additionally, all evaluable tumors demonstrated HER3 expression at various levels in retrospective immunohistochemistry (IHC) analysis (n=25).

“As more patients are treated on study, the findings continue to demonstrate activity with U3-1402, including ongoing confirmed partial responses, in patients with EGFR-mutant metastatic non-small cell lung cancer that is no longer responding to EGFR TKI therapy,” said Helena Yu, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, and a trial investigator.

“These data suggest that targeting HER3 with U3-1402 may be an effective treatment strategy irrespective of mechanism of resistance identified in the setting of EGFR TKI resistance, where new precision treatments are needed,” Yu added.

Treatment emergent adverse events
Preliminary safety data for 30 patients who received U3-1402 in one of four doses indicated a manageable safety profile for U3-1402 at a median treatment exposure of 3.2 months. The recommended dose for expansion has been established at 5.6 mg/kg. The most common treatment-emergent adverse events (TEAEs) of any grade, occurring in ≥30 percent of patients, included nausea (63.3%), fatigue (43.3%), vomiting (36.7%) and platelet count decrease (30%).

One TEAE grade ≥3 occurred in more than 10% of patients (platelet count decrease, 20%). The following dose-limiting toxicities were observed in four patients: four grade 4 platelet count decrease and one grade 3 febrile neutropenia. One patient experienced a TEAE associated with treatment discontinuation (3.3%). Nine patients (30%) experienced treatment-emergent serious adverse events regardless of causality. Four patients (13.3%) experienced treatment-emergent serious adverse events that were drug-related.

“HER3 is frequently overexpressed in non-small cell lung cancers as well as other types of solid tumors, but no HER3 targeting therapies are approved for NSCLC or any cancer,” said Dalila Sellami, MD, Vice President, U3-1402 Global Team Leader, Global Oncology Research and Development, Daiichi Sankyo.

“U3-1402 is a potential first-in-class ADC designed to target and deliver treatment directly to HER3 expressing tumors, and based on these results, we will advance to dose expansion and broaden the scope of the trial to include patients with squamous or non-squamous NSCLC,” Sellami said.

[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.
[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, et al. Metastatic NSCLC. ESMO CPGs. Ann of Onc 29(Supp4): iv192–237 2018. updated Jan2019.
[6] Morgillo F, Della Corte CM, Fasano M, et al. ESMO Open 2016; 1:e000060.
[7] Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018 Feb 19;17(1):38. doi: 10.1186/s12943-018-0777-1.
[8] Papadimitrakopoulou, et al. Ann Oncol. 2018;29.
[9] Ramalingam, et al. Ann Oncol. 2018;29.
[10] Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW, Younes M, Cagle PT. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas.Mod Pathol. 1997 Feb;10(2):142-8
[11] Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H, Kobayashi Y, Yano M, Fujii Y. ErbB3 mRNA expression correlated with specific clinicopathologic features of Japanese lung cancers. J Surg Res. 2008 May 1;146(1):43-8. Epub 2007 Jul 13.
[12] 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.
[13] Müller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwäble J, Plewka S, Thomas M, Metzger R, et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res.2005 Mar 1;65(5):1778-82.
[14] 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.

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