Telisotuzumab Adizutecan Delivers Early Signals of Antitumor Activity in CRC

The c-Met–targeted antibody-drug conjugate (ADC) telisotuzumab adizutecan (formerly ABBV-400) is at the forefront of a potential new era in colorectal cancer (CRC) management. Although the arena keeps expanding to investigate more agents in this class, additional research is needed to confirm the efficacy and safety of these agents in gastrointestinal (GI) cancers, according to John H. Strickler, MD.

In an interview with OncLive®, Strickler, a professor of medicine and a member of the Duke Cancer Institute in Durham, North Carolina, discussed key efficacy findings from the CRC cohort of a phase 1 trial (NCT05029882) investigating telisotuzumab adizutecan in patients with advanced solid tumors, the safety profile of the agent, and this ADC’s potential to broaden the CRC treatment paradigm.

He explained the mechanism of action of telisotuzumab adizutecan and the rationale for evaluating this agent in CRC in another article.

OncLive: What key efficacy findings have been observed thus far with telisotuzumab adizutecan in the phase 1 trial?

Strickler: Focusing on GI cancers, we’ve seen promising initial results in patients with CRC. Interestingly, patients who have higher levels of c-Met expression appear to [derive an] even greater benefit. In heavily pretreated patients with metastatic CRC with c-Met expression [of 10% or more by 3+ immunohistochemistry staining intensity], the overall response rate [ORR] was 37.5% at the telisotuzumab adizutecan dose level of 2.4 mg/kg or higher.

Interestingly, a lower ORR of 14% [was observed] in patients with lower levels of c-Met expression. However, this is a group of patients where the approved standard of care [(SOC) elicits] ORRs in the less-than-5% range. Anytime we generate responses in 10% to 15% or even 30% of patients, that’s clinically meaningful and important. That supports further development [of telisotuzumab adizutecan].

We’ve also seen impressive results [with the agent] in patients with MET-amplified tumors; not just [patients with] protein expression [but those with] genomic amplification; ORRs in excess of 50% have been reported as well, albeit in small groups of patients. We also presented updated data on the safety, tolerability, and activity [of the agent] in patients with advanced gastroesophageal adenocarcinoma at the 2024 ESMO Congress.

What safety findings are important to note with telisotuzumab adizutecan?

As with any ADC, safety and tolerability are a primary concern. The typical adverse effects [AEs] we see with this class of therapy are consistent with myelosuppressive chemotherapy, [including AEs] like anemia, neutropenia, and thrombocytopenia. In addition to that, we commonly see AEs such as fatigue and nausea. There are rare cases of interstitial lung disease or pneumonitis, and that’s a class effect that we see across the whole category of ADCs that use a topoisomerase I inhibitor payload. However, so far, the safety, tolerability, and activity of this therapy are favorable and could have broad applications, not just in CRC, but other GI cancers, such as gastroesophageal adenocarcinoma, and probably [tumors] beyond GI cancers as well.

How could telisotuzumab adizutecan fill an unmet need for patients with solid tumors, including those with CRC?

Although we’ve made a lot of progress with [the treatment of] GI cancers, there’s still a lot of work to be done. One of the challenges is that once patients go through first- and second-line therapies, response rates drop off and the median progression-free survival [PFS] for the approved agents is rather short. There are promising signals, particularly among patients with higher levels of c-Met expression, [showing] that [telisotuzumab adizutecan] can generate higher response rates than the current SOC. The agent can potentially drive longer PFS, though we’ll need to see that validated in prospective studies, but [these findings] also raise the question of whether this is a therapy that’s so active it [may] need to be brought into earlier lines of therapy in combination with other cytotoxic chemotherapy.

All these questions are being investigated. Telisotuzumab adizutecan a therapeutic strategy that is currently under development and needs validation but so far looks promising.

What would you like your colleagues to take away from this research?

An important message for colleagues is that we’ve seen ADCs now enter the clinic for multiple tumor types, but we’ve not yet seen an ADC with an approval specific to colon cancer. Right now, the only ADC we have approved for colon cancer is from the pan-tumor approval of fam-trastuzumab deruxtecan-nxki [Enhertu] for patients with HER2-positive cancers. However, [within] the ADC class, we are likely to see more therapies enter the clinic. Telisotuzumab adizutecan, has significant promise to be one of these therapies, but there could be more on the horizon, which is important because patients are living longer and are in need of more therapies.

What are the next steps for researching telisotuzumab adizutecan in patients with solid tumors?

The main next step for telisotuzumab adizutecan [includes] prospective validation against SOC therapies [with] larger randomized trials that can validate that patients have improved survival, PFS, ORRs, and tolerability [with this agent] compared with the current SOC. These randomized trials are where we are now in the development [of this agent].