Antibody Drug Conjugates Bispecific Antibodies and Lung Cancer

Antibody-drug conjugates (ADC) and Bispecific antibody constructs represent the most recent type of precision cancer medicines being developed for the treatment of cancer including patients with non–small cell lung cancer (NSCLC), and small cell lung cancer (SCLC).¹

Antibody-drug-conjugates work by delivering cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on the lung cancer cells.

Bispecific antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells. Bispecific antibodies or BiTE which is short for “bispecific T cell engager” are antibodies with two arms. One arm of the drug attaches to a specific protein on the cancer cell. The other arm of the BiTE activates immune cells in the patient to kill the cancer cells

Currently there are over 3 dozen ADCs in development for NSCLC available in clinical trials as single drugs or in combination with other lung cancer therapies – the following are the furthest along in development….

NSCLC Antibody Drug Conjugates

• Trastuzumab Deruxtecan – Targets HER2
• Datopotamab Deruxtecan – Targets TROP-2
• Patritumab Deruxtecan – Targets HER3
• Rybrevant (Amivantamab) – Targets EGFR mutations

Bispecific Antibodies

• BL-B01D1 which has an affinity for both HER3 and EGFR.
• BiTE Antibodies and EGFR NSCLC
• Zenocutuzumab targeting NRG 1 Fusions

Small Cell Lung Cancer Antibody Drug Conjugates

• ABBV-011 – Targets SEZ 6
• Tarlatamab – Targets DLL3

Tarlatamab is a bispecific T-cell engager against DLL3 that is being evaluated in small cell lung cancer (SCLC). Updated results from a multicenter clinical trial were presented at the 2023 ESMO Annual Meeting and the first BiTE approved in May 2024..¹²

Patients with SCLC had to have received at least 1 line of systemic therapy and either progressed or recurred following at least 1 platinum-based chemotherapy, as well as an ECOG performance status of 0 to 2, at least 1 measurable lesion, and adequate organ function. At a median follow-up of 11.2 months, the confirmed response rate in 64 evaluable patients with advanced disease was 40% and median DOR was 8.7 months, the median time to response was 1.8 months.

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References

1. Reckamp K. ADCs: New agents and targets in development. Presented at: 24th Annual International Lung Cancer Congress®; July 27-29, 2023; Huntington Beach, CA.
2. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386:241-251. doi:10.1056/NEJMoa2112431
3. Goto Y, Su WC, Levy BP, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC). J Clin Oncol. 2023;41(suppl 16):9004. doi:10.1200/JCO.2023.41.16_suppl.9004
4. Jänne PA, Baik C, Su W-C, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor–resistant, egfr-mutated non–small cell lung cancer. Cancer Discov. 2022;12(1):74-89. doi:10.1158/2159-8290.CD-21-0715
5. Morgensztern D, Ready NE, Johnson ML, et al. First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer. J Clin Oncol. 2023;41 (suppl 16):abstr 3002. doi:10.1200/JCO.2023.41.16_suppl.3002.
6. Zhang L, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study. J Clin Oncol. 2023;41(suppl 16):3001. doi:10.1200/JCO.2023.41.16_suppl.3001.