The Lung Cancer Research Foundation (LCRF), a leading nonprofit organization focused on funding innovative, high-reward research with the potential to extend survival and improve quality of life for people with lung cancer, has signed a collaboration agreement with Daiichi Sankyo and AstraZeneca to fund up to three research grants focused on antibody-drug conjugates (ADCs) to improve outcomes for people diagnosed with lung cancer.

Applications for the two-year US $ 270,000 grants are being accepted through May 31, 2023. [More info]

Lung cancer is currently the number one cause of cancer death both in the U.S. and globally among both men and women, with more than 652 new diagnoses per day in the United States. [1]

In many cases, lung cancer is not detected until it is in advanced stages of the disease, when the disease is more aggressive, and patients’ outcomes are significantly poorer than if the disease is treated early. Often, there is disease recurrence after initial treatment, resulting in a more advanced form of the disease.

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Although both targeted and immunotherapy-based therapies have been established as frontline standard-of-care for patients with advanced lung cancer, adverse events, resistance, and disease progression remain unavoidable in most instances. In this scenario, chemotherapy is a popular salvage option, but it has restricted therapeutic index.[2]

Since 2020, trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) the first ADC for the treatment of patients diagnosed with NSCLC has been Food and drug Administration (FDA-) approved and two other ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). In addition, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. [3]

A targeted approach
Unlike conventional chemotherapy treatments, ADCs are designed to specifically target cancer cells and selectively deliver a highly potent payload, which may limit damage to healthy cells. An ADC comprises a monoclonal antibody that recognizes a protein present on the cancer cells, and is bound to a cytotoxic agent, known as the payload. The use of ADCs is already common practice in several cancers, thanks to their efficacy and potentially more manageable toxicity profile, resulting from the release of the cytostatic payload directly in the tumors.[4]

Currently, early phase trials of ADCs in non-small cell lung cancer are rapidly gaining ground, with promising results.

This collaboration seeks to support research to study HER2 directed and TROP2 directed ADCs including mechanism of action, biomarkers, and resistance mechanisms.

“LCRF is honored to continue its long legacy of identifying and supporting outstanding lung cancer research projects over the years. We are excited to collaborate with these generous supporters of our mission,” said Katerina Politi, Ph.D, Chair, LCRF Scientific Advisory Board.

“The specific focus of this grant program is to further study ADCs and how they might be applied to lung cancer treatment. It is an exciting and promising area in lung cancer research,” Politi added.

Understanding the Mechanism of Action
The LCRF – Daiichi Sankyo – AstraZeneca Research Grant on Antibody Drug Conjugates will develop further understanding of the mechanism of action and biomarkers for trophoblast cell surface antigen 2 (TROP2-) directed ADCs in lung cancer and HER2 directed ADCs in HER2 mutant NSCLC and primary and acquired resistance to TROP2 directed and HER2 directed ADCs.

TROP2
TROP2 is a transmembrane glycoprotein with both extracellular and intracellular components and has been implicated in several cell signaling pathways including intracellular calcium transduction, MAPK signaling pathway, RAF, NF-κB and Cyclin D/E among others.

While TROP2 is expressed across all lung cancer subtypes, the highest expression is seen in adenocarcinoma (64%) and squamous cell carcinoma (75%) cases (the most common forms of NSCLC). [5][6] Today there are no TROP2-directed therapies are currently approved for the treatment of patients with NSCLC.[7][8][9]. However, preliminary study results have shown that datopotamab deruxtecan may be active in patients with advanced or metastatic non-small cell lung cancer. In a phase I trial, the agent elicited responses in almost a quarter of patients and had manageable side effects. [10]

HER2 mutant NSCLC
HER2 alterations are a known and distinct molecular subtype in NSCLC. Activation of HER2 in NSCLC takes place via three mechanisms, including gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein over-expression (2%-30%).

Treatment with ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) and trastuzumab deruxtecan in patients diagnosed with HER2-mutant NSCLC, have shown encouraging data with with response rates of 50% and 62%, respectively.

In addition, clinical trials with combinations ADCs with irreversible TKIs or immune checkpoint inhibitors, are planned or already already taking place.  The outcomes of these studies are expected to and will change the therapeutic landscape of HER2-driven NSCLC.

But additional research is required to meet the unmet medical needs of these patients.

Clinical trials
A Study of Dato-DXd in Chinese Patients With Advanced Non-Small Cell Lung Cancer, Triple-negative Breast Cancer and Other Solid Tumors (TROPION-PanTumor02) – NCT05460273
Study of DS-1062a in Advanced or Metastatic Non-small Cell Lung Cancer With Actionable Genomic Alterations (TROPION-Lung05) – NCT04484142
Datopotamab Deruxtecan (Dato-DXd) in Combination With Pembrolizumab With or Without Platinum Chemotherapy in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung02) – NCT04526691
Study of DS-1062a Versus Docetaxel in Previously Treated Advanced or Metastatic Non-small Cell Lung Cancer With or Without Actionable Genomic Alterations (TROPION-LUNG01) – NCT04656652
Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung04) – NCT04612751
Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab and Carboplatin for First-Line Treatment of Patients With Advanced NSCLC Without Actionable Genomic Alterations (AVANZAR) – NCT05687266
First-in-human Study of DS-1062a for Advanced Solid Tumors (TROPION-PanTumor01) – NCT03401385
Datopotamab (DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer (ICARUS-LUNG01) – NCT04940325

Highlights of Prescribing Information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) [Prescribing Information]

Reference
[1] American Cancer Society. About Lung Cancer. Key Statistics for Lung Cancer.  Online. Last accessed on march 17, 2023
[2]Abuhelwa Z, Alloghbi A, Nagasaka M. A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small cell lung cancer (NSCLC). Cancer Treat Rev. 2022 May;106:102393. doi: 10.1016/j.ctrv.2022.102393. Epub 2022 Apr 13. PMID: 35472631.
[3] Coleman N, Yap TA, Heymach JV, Meric-Bernstam F, Le X. Antibody-drug conjugates in lung cancer: dawn of a new era? NPJ Precis Oncol. 2023 Jan 11;7(1):5. doi: 10.1038/s41698-022-00338-9. PMID: 36631624; PMCID: PMC9834242.
[4] Merle, Geoffrey; Friedlaender, Alex; Desai, Aakash; Addeo, Alfredo. Antibody Drug Conjugates in Lung Cancer. The Cancer Journal 28(6):p 429-435, 11/12 2022. | DOI: 10.1097/PPO.0000000000000630
[5] Inamura K, et al. Oncotarget. 2017; 8(17):28725-28735. Inamura K, et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget. 2017; 8(17): 28725-28735.
[6] Mito R, et al. Clinical impact of TROP2 in non-small lung cancers and its correlation with abnormal p53 nuclear accumulation. Pathol Int. 2020; 70(5): 287-294.
[7] Rodríguez-Abreu D et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Onc. 2021 Jul;32(7):881-895.
[8] Zaman S, et al. Targeting Trop-2 in solid tumours: future prospects. Onco Targets Ther. 2019; 12: 1781-1790.
[9] American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Online. Last accessed on March 17, 2023
[10] TROP2 ADC Intrigues in NSCLC. Cancer Discov. 2021 May;11(5):OF5. doi: 10.1158/2159-8290.CD-NB2021-0314. Epub 2021 Feb 17. PMID: 33597275.
[11] Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open. 2021 Oct;6(5):100260. doi: 10.1016/j.esmoop.2021.100260. Epub 2021 Aug 31. PMID: 34479034; PMCID: PMC8414039.

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