Telisotuzumab Adizutecan Represents a Novel c-Met–Targeting ADC in MET-Amplified CRC

John H. Strickler, MD

Targeting c-Met with the novel antibody-drug conjugate (ADC) telisotuzumab adizutecan (formerly ABBV-400)has been shown to be effective and tolerable in patients with colorectal cancer (CRC), according to John H. Strickler, MD.

“This is an active therapy that looks promising for patients with gastrointestinal [GI] cancers and also for patients with MET-amplified tumors,” Strickler said in an interview with OncLive®.

In the interview, Strickler highlighted how telisotuzumab adizutecan works against the MET receptor, the rationale for targeting c-Met in CRC, and the design of the phase 1 trial (NCT05029882) that investigated the agent in patients with advanced solid tumors, including CRC.

In the CRC cohort of the trial, among patients with c-MET expression of at least 10% 3+ by immunohistochemistry who received telisotuzumab adizutecan at a dose of at least 2.4 mg/kg, the overall response rate (ORR) was 37.5%. The agent at this dose still elicited responses among patients with c-Met expression lower than 10% 3+, in whom the ORR was 14%.1

Strickler is a professor of medicine and a member of the Duke Cancer Institute in Durham, North Carolina.

OncLive: What is the mechanism of action of telisotuzumab adizutecan?

Strickler: Telisotuzumab adizutecan [comprises the] antibody telisotuzumab—previously known as ABT-700—that binds and inactivates the MET receptor linked to a drug conjugate called adizutecan, which is a topoisomerase I inhibitor. Like many ADCs, telisotuzumab adizutecan binds a receptor that’s commonly overexpressed in many different types of advanced solid tumors. It uses that antibody to enter the cell, and then that potent topoisomerase I inhibitor is released into the cell, and it’s a potent cytotoxic chemotherapy that then will destroy the cell. It also probably has some bystander effects by its mechanism of action.

What makes c-Met a promising target in CRC?

c-Met has been well described as an important oncologic target for well over a decade and is a receptor, much like other receptors in colon cancer, that is commonly overexpressed. The classic receptor we hear about is EGFR, but c-Met is another receptor tyrosine kinase. It tends to be overexpressed in approximately half of all patients with CRC and is associated with a poor prognosis.

We’ve also found over the years that c-Met has a tendency to be upregulated, or even we’ll see MET gene amplification as a driver of resistance to both chemotherapy and targeted therapies. Classically, we will see MET gene amplification and overexpression of the [c-Met] protein after exposure to targeted therapies, particularly anti-EGFR therapies. However, interestingly, in the last couple years, we’ve also seen signs that MET is important as a driver of resistance to other targeted therapies that have emerged in CRC, specifically anti-HER2 therapies and KRAS G12C inhibitors, which are now FDA approved for patients with metastatic CRC. We see [MET] broadly as a driver of acquired resistance in addition to primary resistance to those therapies.

How could a c-Met–targeted ADC like telisotuzumab adizutecan work differently than a monoclonal antibody or TKI targeting c-Met?

We have a lot of experience with TKIs and what we call the ‘naked’ [monoclonal] antibodies in CRC, and unfortunately, nearly all that experience has been unfavorable in that when we give patients these anti-MET therapies, the benefit, if it occurs at all, is transient. One of the reasons for this is that c-Met expression or amplification can be heterogeneous—some cells have it, and some cells don’t. When we give these selective antibodies and TKIs, we will see brief, transient effects, but then the c-Met–negative clones will grow out and drive rapid resistance. The ADCs have some advantage [in] that they can target c-Met–positive cells, and then with their bystander effects can potentially lead to cell death for those adjacent c-Met–negative cells. Perhaps this is a more effective strategy.

Additionally, CRC is notorious for having molecular heterogeneity, where MET amplification [will] go together with other variants, for example, KRAS mutations, NRAS mutations, or BRAF alterations. Even when you give a targeted therapy, you may see that those other variants can drive rapid resistance as well. The advantage of an ADC is it only needs expression to enter the cell; that means that if the patient has tumor cells that will drive resistance to the targeted therapy, it won’t matter because the drug will still get in and release its toxic payload to that tumor.

What was the design of the phase 1 study of telisotuzumab adizutecan in patients with advanced solid tumors?

[This trial] was designed as a classic phase 1 dose-finding study, where multiple dose levels of telisotuzumab adizutecan were tested. There were expansion cohorts based on what was thought to be higher levels of expression in various disease groups, including CRC. At this point, [the trial has] been exploring the safety, tolerability, and activity [of the agent] at various dose levels, together with expansions in some of the most promising [tumor types], of which GI cancers are well represented.

References

Sharma MR, Strickler JH, Sommerhalder D, et al. First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: results in colorectal cancer. J Clin Oncol. 2024;42(suppl 16):3515. doi:10.1200/JCO.2024.42.16_suppl.3515