M9140 is the first anti-CEACAM5 ADC with a topoisomerase 1 inhibitor (Top1i) payload (exatecan). The ß-glucuronide linker connecting the M9140 antibody backbone to the payload is highly stable in circulation. M9140 has demonstrated high potency, strong antitumor activity, and bystander effect in preclinical efficacy models. 

First-in-human data of M9140 was presented at the ASCO 2024 meeting. This Phase I trial is investigating the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of M9140, in heavily pretreated patients with metastatic colorectal cancer.

At the data cutoff on 23 April 2024, the results were as follows:

Efficacy: 

In this Phase I dose escalation study in patients with 3L+ CRC:

• M9140 demonstrated a manageable and predictable safety profile with hematological DLTs consistent with Top1 payload

• No interstitial lung disease or ocular toxicities were observed

• The MTD was declared as 2.8 mg/kg:

• 2.4 mg/kg and 2.8 mg/kg are the doses selected for the ongoing randomized dose optimization 

• M9140 showed encouraging and durable antitumor activity at therapeutic doses ≥2.4 mg/kg (n=34): 

• DCR was 70.5% (confirmed PR [n = 3] + SD (n = 21])

• PFS was 6.7 months

Safety:

• The most frequently reported Grade ≥3 TEAEs were neutropenia, anemia, thrombocytopenia, and leukopenia. 

• Grade 5 TEAEs were gastrointestinal hemorrhage and sepsis, both occurring at dose level 2.8 mg/kg (n = 1 each)

• No events of ocular toxicity or interstitial lung disease were reported

• Nausea, vomiting, and diarrhea were predominantly Grade 1; no Grade ≥3 events were observed for these GI TEAES

Further evaluation is ongoing in a randomized expansion study to determine the long-term potential and effectiveness of this treatment. Evaluation of M9140 in patients with mCRC as monotherapy as well as in combinations continues in the expansion part of this study. 

KOL insights

“Two ADCs under development for colorectal cancer have released early clinical data. Both drugs share a Top1i payload but differ in their targets and linker chemistry. M9140 showed a higher incidence of hematologic toxicity, while response rates appeared similar. Notably, most patients who received these Top1i-based ADCs had prior exposure to irinotecan” – Expert Opinion.

“Solid DCR of 65% with M9140 ADC. PFS at 6.6 months is promising. Excited to see more data”– Expert Opinion.

Conclusion

Exploiting CEACAM5 overexpression in certain cancers has the potential to offer a promising approach for ADC-based therapy. Leveraging Merck’s novel linker-payload technology, M9140 is the first CEACAM5 ADC with an exatecan payload, a potent topoisomerase inhibitor (TOP1i), which has been rationally designed for stability in circulation and superior cancer cell killing activity.

To conclude, M9140 demonstrated encouraging activity in heavily pretreated patients with advanced CRC, with a manageable and predictable safety profile. Contrary to approved ADCs with Top1i payloads, no ILD or ocular toxicities were observed.