Investigational ADC is Well Tolerated with Partial Dose-dependent Response in NSCLC

Square of Spain - National museum of Barcelona with fountain at summer day, Spain, retro toned

Results of a Phase I clinical study and new biomarker data for DS-1062 in 52 unselected patients with heavily pretreated advanced non-small cell lung cancer (NSCLC) shows be the trial drug to well tolerated with dose-dependent partial responses.

DS-1062 is an investigational TROP2 (trophoblast cell-surface antigen 2) targeting antibody-drug conjugate or ADC being developed by Daiichi Sankyo.

The data were featured today in a Mini Oral Session at the IASLC 2019 World Conference on Lung Cancer (#WCLC19) being held September 7 – 10, 2019 in Barcelona, Spain (#MA25.10, Abstract #3854).

Unmet Need
Lung cancer is, and remains, 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 greatly improved the treatment landscape for patients with advanced or metastatic NSCLC. But for those who are not eligible for current treatments, or for patients whose cancer continues to progress, new therapeutic approaches are desperately needed.[4] And, as a result, the five-year overall survival (OS) for patients with advanced non-small cell lung cancer (NSCLC) has not significantly changed over the past few years.

Targeted and personalized
A better understanding of cancer biology, coupled with the decoding of human cancer genome, and the advent of therapies targeting specific driver mutations, and the selection of systemic therapy changed from one size fits all approach to a more precise selection of biologic therapies targeting distinct genetic profiles, have changed the way lung cancer is treated today. [4]

These changes have also been aided by a better understanding of the interactions between tumor cells and the immune system – leading to the development of new therapeutic strategies designed to enhance the body’s own immune response towards anti-tumor immunity. And finally, the development, targeted and (hyper-) personalized therapies have been dramatically increased the available treatment options.[4]

Among the targeted treatment options is a novel drug known as DS-1062. This investigational agent, designed using Daiichi Sankyo’s proprietary DXd antibody-drug conjugate (ADC-) technology, targets cancer cells that express TROP2 as a cell surface antigen and deliver a cytotoxic chemotherapeutic payload.

The technology provides flexibility to adapt the drug-to-antibody ratio (DAR) or the number of DXd molecules conjugated per antibody. In DS-1062 the DAR is four, which is, based on initial preclinical research into the construct and the ADC is necessary for intended safety and efficacy in TROP2 expressing tumors.

In preclinical studies scientists at Daiichi Sankyo have demonstrated that DS-1062 selectively binds to the TROP2 receptor on the surface of a tumor cell. It is proposed that DS-1062 is then brought inside the cancer cell where lysosomal enzymes break down the tetrapeptide-based linker and release the novel topoisomerase I inhibitor (DXd) payload.

TROP2 is a transmembrane glycoprotein that is highly expressed on several types of solid tumors, including NSCLC.[5][6] Researchers have recognized TROP2 as a promising molecular target for therapeutic development in various types of malignancies, including NSCLC.[6][7] Overexpression of TROP2 has been associated with increased tumor aggressiveness and decreased survival in several cancers.[7] High TROP2 expression was identified in 64% of non-small cell adenocarcinomas and 75 of non-small cell squamous cell carcinomas in one study.[5]

Currently, no TROP2 targeting therapy is approved for NSCLC or any cancer.

Trial Design
The trial results presented during the IASLC 2019 World Conference on Lung Cancer included a phase I, first-in-human open-label clinical trial investigating the safety and tolerability of DS-1062 in patients with unresectable advanced NSCLC who are refractory to or have relapsed following standard treatment or for whom no standard treatment is available (NCT03401385)

The first, dose escalation, part of the study was designed to assesses the safety and tolerability of increasing doses of DS-1062 to determine the maximum tolerated dose (MTD) and recommended dose for expansion.

The second, dose expansion, part of the study was designed to will evaluate the safety and tolerability of DS-1062 at the recommended dose for expansion and will enroll 40 additional patients with advanced NSCLC.

The trial’s study endpoints include safety, pharmacokinetics, objective response rate, duration of response, disease control rate, time to response, progression-free survival, overall survival, biomarker analysis and immunogenicity.

Trial results
Updated efficacy results for 46 evaluable patients who received DS-1062 at one of eight doses (0.27 mg/kg to 10.0 mg/kg) showed 12 partial responses (10 confirmed, 2 early) observed in a dose-dependent manner. Five of the confirmed partial responses were observed among seven patients (71.4%) receiving DS-1062 at 8 mg/kg, the recommended dose for expansion. The other two patients receiving the 8 mg/kg dose experienced stable disease, and six of the seven are continuing on trial. Patients had received prior treatments, including immune checkpoint inhibitors (86.5%), EGFR inhibitors and ALK inhibitors. The data cut-off was July 3, 2019. Thirty-five patients were ongoing in the trial as of August 20, 2019.

Thirty-five patients were evaluable for TROP2 expression by immunohistochemistry (IHC) analysis. TROP2 expression trended higher in patients who experienced a partial response.

Gene analysis suggested SLFN11 expression, which has previously been associated with response to topoisomerase I inhibitors, trended higher in patients with tumor reduction.[1] In addition, data showed a decrease in cfDNA in patients who experienced partial response and stable disease.

“There is a need for new treatment options to help patients with advanced non-small cell lung cancer that continues to progress on standard therapies, and these findings with DS-1062 in heavily pretreated patients are encouraging,” said Rebecca S. Heist, MD, MPH, Medical Oncologist, Massachusetts General Hospital, Cancer Center, and a study investigator.

“Further study in more patients at the recommended expansion dose will help further assess the potential for targeting TROP2 with DS-1062 in NSCLC,” Heist added.

Updated data for 52 patients evaluable for safety as of July 3, 2019 showed that DS-1062 was well-tolerated in doses up to 8 mg/kg, which is defined as the maximum tolerated dose and the recommended dose for expansion. The most common treatment-emergent adverse events (any grade, occurring in ≥ 30% of patients) included fatigue (36.5%) and nausea (36.5%). Twenty-two patients (42.3%) experienced at least one treatment emergent adverse event (TEAE) ≥ grade 3.

Dose-limiting toxicities occurred in two patients at the 10 mg/kg dose (one mucosal inflammation and one stomatitis) and in one patient at the 6 mg/kg dose (rash maculopapular). TEAEs led to discontinuation in two patients (3.8%).

Serious TEAEs were reported in 14 patients (26.9%) regardless of causality. One patient (1.9%) with disease progression treated with the 6.0 mg/kg dose developed an adverse event of special interest (respiratory failure, grade 5).

Independent evaluation
Any pulmonary events suspected of being interstitial lung disease (ILD) or pneumonitis are considered adverse events of special interest and evaluated by an independent adjudication committee. The case was adjudicated and determined not to be ILD. Since the data cutoff, four potential cases of ILD have been reported and are pending adjudication: one grade 2 pneumonitis [6.0 mg/kg], one grade 2 organizing pneumonia [8.0 mg/kg], one grade 2 pneumonitis [8.0 mg/kg] and one grade 5 respiratory failure in a patient with disease progression [8.0 mg/kg].

“These findings support DS-1062 as a potential TROP2 targeting therapy for NSCLC and further reinforce the strength and flexibility of our DXd ADC platform, which enables each of our ADCs to be custom designed to potentially provide an optimal balance of safety and efficacy,” noted Eric Slosberg, PhD, Head, Global Translational Development, Oncology Research and Development, Daiichi Sankyo.

“As the study advances, we will continue with our translational research to help uncover underlying factors contributing to patient response and identify patients most likely to respond to DS-1062,” Slosberg concluded.

Clinical trials
First-in-human Study of DS-1062a for Advanced Solid Tumors – NCT03401385

Reference
[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. Online. Last Accessed September 10, 2019
[3] American Cancer Society. Types of Non-Small Cell Lung Cancer. Online. Last Accessed September 10, 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. [Pubmed]
[5] Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Subat S, Nagano H, et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes.Oncotarget. 2017 Apr 25;8(17):28725-28735. doi: 10.18632/oncotarget.15647. [Pubmed][Article]
[6] Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019 Mar 1;12:1781-1790. doi: 10.2147/OTT.S162447. eCollection 2019. [Pubmed][Article]
[7] Zeng, P. et al. Nature Scientific Reports 2016;6: e33658.
[8] Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015 Mar;6(3-4):84-105. [Pubmed][Article]

An edited version of this aricle was first published on September 10, 2010 in ADC Review | Journal of Antibody-drug Conjugates.