Bispecific Antibodies and BiTEs Under Continued Evaluation in Lung Cancer

Daniel Morgensztern, MD

Bispecific antibodies have found a role in the treatment of lung cancer, including amivantamab-vmjw (Rybrevant), which was approved by the FDA as a first-line treatment for adult patients with non–small cell lung cancer (NSCLC) who harbor EGFR exon 20 insertion mutations in May 2021. Novel bispecific agents continue to be the focus of research, including those targeting DLL3 and NRG1, according to Daniel Morgensztern, MD.

“There are many bispecific antibodies targeting two different immune checkpoint [pathways] and targeting two different tumor antigens. It’s a promising new treatment modality and I’m very confident that we’ll have more drugs developed and more drugs approved,” Morgensztern said.

In an interview with OncLive^® during the 23rd Annual International Lung Cancer Congress^®, Morgensztern, professor of medicine in the Division of Oncology, Section of Medical Oncology, at the Washington University School of Medicine and Siteman Cancer Center in St. Louis, discussed updates on the investigation of bispecific antibodies and bispecific T-cell engagers (BiTEs) in NSCLC and small cell lung cancer (SCLC).

OncLive^®: Could you expand on the mechanisms of action seen with bispecific antibodies?

Morgensztern: It is important to understand [the definition of] a bispecific antibody. It is a molecule that attaches to two different targets at the same time. The bispecific antibodies may look like an antibody with pieces of 2 antibodies joined together, or it may look like a fragment, a piece of an antibody, which is called a single-chain variable fraction. This is how the BiTEs are made.

The most common targets for the bispecific antibodies are CD3, tumor-associated antigens such as EGFR, and immune checkpoint [pathways] such as PD-1, PD-L1, and CTLA-4. The mechanism of action can be described [as the] antibody having 2 arms binding to the targets in the same cell, or, as with BiTEs, one arm binding to lymphocytes and the other arm binding with a tumor-associated antigen. This makes a bridge between the immune cells and the target cells.

When evaluating this patient population, how do you determine who would benefit most from bispecific antibodies and BiTEs?

It is important to understand who the best patients are [for these regimens]. There are 3 bispecific antibodies that have a more advanced stage of development. The first is amivantamab, which is combining arms of MET and EGFR. This is a dual body, which means it looks like an antibody, and it was approved for patients with NSCLC with EGFR exon 20 insertions.

There is also data on patients that have EGFR mutations, and amivantamab is being combined with the third-generation EGFR TKI lazertinib [Leclaza]. There is encouraging data in the first line, and the phase 3 MARIPOSA trial [NCT04487080] is evaluating first-line amivantamab plus lazertinib [vs osimertinib (Tagrisso) alone and lazertinib alone], which is an interesting study.

For patients that have EGFR exon 20 insertions, now that amivantamab has been approved, there is an interesting study called the [phase 3] PAPILLON trial [NCT04538664] where patients will receive chemotherapy with or without amivantamab.

Could you expand on the utility of tarlatamab (AMG 757)?

There is a BiTE targeting DLL3, which is called tarlatamab. This is a fragment antibody. It has been encouraging to see results with a 20% response rate in pretreated patients with SCLC, and the median duration of response was 8.7 months. DLL3 seems to be a good target for treatment in neuroendocrine cancers. DLL3 is a delta-like ligand and is expressed during embryonic life, but not so much adult life. It is highly expressed in neuroendocrine tumors and not expressed in many adult cells.

There have been studies in the past looking at antibody-drug conjugates, when the antibody is bound to a payload. The responses were good, but the treatment was too toxic. [Other BiTEs are being designed] to target DLL3. The mechanism is meant to be the same. There may be some differences in toxicity and efficacy, but the rationale is the same by trying to put the T cells together with neuroendocrine cells that have DLL3.

The proposed mechanism of action for those BiTEs is that the T cells provoke a cytolytic synapse where the T cells will [make contact], causing apoptosis of the target cells. It also stimulates the proliferation of these cells and secretion of cytokines to create a tumor microenvironment more adapted for the immune response.

What has been observed so far with zenocutuzumab (MCLA-128)?

Zenocutuzumab seems to be an interesting drug. The rationale for [the design of] zenocutuzumab is NRG1 is synthesized as a precursor, which is membrane anchored, and proteases will cleave it and release the mature form of NRG1, which will bind to distance cells.

The problem with NRG1 fusions, depending on the fusion, is that the [NGR1 fusion] becomes a poor substrate for the proteases, accumulating in the membrane and causing uncontrolled binding to HER3 and HER4. Zenocutuzumab is a bispecific antibody that binds to HER2 and HER3, and the mechanism of action has been described as dock and block. It docks on HER2, blocking the interaction between Rg1 and Rg3.

However, the initial results [from a phase 1/2 trial (NCT02912949)] were not very good. The response rate [with zenocutuzumab] was 34%. That response rate is good in general, but for targeted therapy, we are used to better response rates. There could be factors other than the mechanism of action. For example, we are not sure if the antibody is reaching the target for all the patients. There might be other factors that we don’t know, but it’s a promising drug.

What are you excited to see down the line with bispecific antibodies?

Amivantamab already has an established role in NSCLC with EGFR mutations, and it is likely that tarlatamab may be approved in the future for patients with SCLC, depending on if it is better than standard-of-care topotecan or lurbinectedin [Zepzelca].